Open Neuroscience Initiative

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Open Neuroscience Initiative
First Edition
2021
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Table of Contents
Chapter 1: Introduction
1.1 What is Neuroscience?
1.2 How do we learn about Neuroscience?
1.3 What Neuroscience is NOT
1.4 Neuroscience is ever changing
1.5 Neuroscience is an integrative field of study
Chapter 2: Anatomy of the Nervous System

2.1 Central Nervous System (CNS)
Phineas Gage
2.2 Peripheral Nervous System (PNS)
2.3 Support Structures of the Nervous System
Stroke
Hydrocephalus
Meningitis
Chapter 3: Cellular Anatomy of the Nervous System

3.1 Characteristics of Neurons
3.2 Cellular Anatomy of Neurons
Multiple Sclerosis
Visualizing the Synapse
3.3 Cellular Functions of Glia
Chapter 4: Electrical Properties of Neurons

4.1 Ion Channels
4.2 The Electrochemical Gradient
4.3 The Nernst Equation
4.4 The Action Potential
Chronic Pain
Randomness in Ion Channel Properties
4.5 Movement of Action Potentials
Analgesia and Motor Signaling
Chapter 5: Signaling Between Neurons

5.1 Electrical Vs. Chemical Synapses
5.2 Properties of Vesicles
5.3 Receptors
5.4 Neurotransmitters
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Chapter 6: Methods of Neuroscience
About Resolution
Experimental Preparations
6.1 Imaging Brain Activity
6.2 Imaging Brain Function
6.3 Imaging the Cells of the Nervous System
6.4 Changing Nervous System Activity
Introduction to Computational Neuroscience
Chapter 7: Sensation and Perception: The Visual System

Sensation Vs. Perception
7.1 The Eye
7.2 The Retina
Color Vision Deficiency
Lateral Inhibition
The Blind Spot
7.3 The Optic Nerve
Glaucoma
7.4 Visual Perception in the Brain
Anatomy of Vision Loss
Dysfunction of the Dual-Stream
Chapter 8: Sensation and Perception: The Physical Senses

8.1 The Auditory System
Hearing Loss
Tinnitus
8.2 The Vestibular System
Vertigo
8.3 The Somatosensory System
Pain Disorders
Referred Pain
Chapter 9: Sensation and Perception: The Chemical Senses

9.1 The Olfactory System
Do Humans Respond to Pheromones?
9.2 The Gustatory System
9.3 Internal Chemosensory Systems
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Chapter 10: The Motor System
10.1 Motor Control in the Brain
Prosthetic Limbs
10.2 Modifiers of Descending Information
Ataxia
Huntington’s Disease
Parkinson’s Disease
10.3 The Spinal Cord
10.4 The Muscles
Myasthenia Gravis
Chapter 11: Neuropharmacology and Substance Use

11.1 Common Routes of Administration
Grapefruit
11.2 Neural Circuitry Involved in Reward
Skinner Box
11.3 Molecular Pharmacodynamics
11.4 Commonly Misused Substances
11.5 Tolerance, Withdrawal, and Dependence
11.6 Theories of Addiction
Chapter 12: Sleep and the Circadian Rhythm

12.1 Phases of Sleep
12.2 Why do we Sleep?
Peter Tripp
12.3 The Circadian Rhythm
12.4 Neurochemical Signals of Sleep and Wake
Half-Life
12.5 Brain Structures Involved in Sleep
Encephalitis Lethargica
12.6 Sleep Disorders
Fatal Familial Insomnia
REM Sleep Behavior Disorder
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Chapter 13: Learning and Memory
13.1 Patient HM
13.2 Neural Structures Involved in Learning
Hypermnesia
13.3 Cellular Mechanisms of Learning
13.4 Molecular Mechanisms of Learning
13.5 Disorders of Memory
Savant Syndrome
Chapter 14: Lateralization and Language

14.1 Lateralization
Agenesis of the Corpus Callosum
14.2 Language
Dyslexia
Chapter 15: Emotion

15.1 A History of Emotion Research
15.2 Structures Involved in Emotion
15.3 Specific Emotions
Plasmatoxmosis
Borderline Personality Disorder (BPD)
Ulcers
Obsessive Compulsive Disorder (OCD)
Chapter 16: Diseases of the Brain

16.1 Schizophrenia (SZ)
16.2 Major Depressive Disorder (MDD)
Seasonal Affective Disorder (SAD)
16.3 Bipolar Disorder (BD)
16.4 Anxiety Disorders
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Preface
For years, I had used old college textbooks to prop up my computer monitor. Of course I gained
valuable information from these texts at one point. But every time I sat down to work, I was reminded
of just how expensive college can be.
This project began as a means to overcoming the financial burden that face undergraduate
neuroscience students when buying textbooks. By compiling and writing a completely free-to-access
textbook that covers the foundations of a typical college introduction to neuroscience course, students
would have one less obstacle to overcome in their educational career, allowing them to focus their
valuable time and attention on learning rather than finances.
To make this project a reality, I began with a humble tweet in May 2019 that managed to gain a
tiny bit of traction among the neuroscience Twitter-sphere. A handful of retweets and comments later,
several experts who shared my ideology for open educational resources contacted me directly, looking
for ways to be involved in the project. Ultimately, almost half of the contributing authors or content
expert editors were recruited through Twitter, while the other half were personal connections I had
made through my time as a neuroscientist.
My choice to distribute this text freely over the internet was deliberate. We have been living in a
digital era where most (if not all) of us have completely unfettered access to the entirety of the world’s
knowledge using a desktop, laptop, or cell phone. Why shouldn’t a formal neuroscience education be
any different?
My hope for this project is to share my passion of neuroscience with the world. Additionally,
widespread adoption of open educational resources like this means increased access and decreased
inequity across the realm of higher education, opening the doors for a more inclusive and diverse
future.
Note: I did not receive any financial compensation through the writing of this textbook, and I am
hosting the complete document on my personal website. If you would like to support this endeavor and
future projects directly, you can send any donations to the following bitcoin address:
3NNosyLrZEVf6yoB7uEsj37xoCCiEKuEFZ
I acknowledge a major limitation present in all textbooks: that science is rapidly-changing and ever-
evolving. To our knowledge, the information is current as of 2021. The authors have worked with
the editors and a growing team of researchers to verify that the statements made here are backed
by peer-reviewed studies. However, I would encourage that additional sources be used to verify the
most up-to-date numbers or statistics and the current state of knowledge.
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Acknowledgements
I would like to thank the following contributing authors for lending their time, energy, and expertise to
this project:
Dr. Ben Marcus

Dr. Andrea Gaede
David Graykowski
Dr. Alexander Rajan
Claire Sun
Additionally, I am very grateful for the valuable editorial comments provided by the following experts:
Dr. Harriet de Wit

Dr. Alexandrina Guran
Dr. Monica Javidnia
Dr. Helena Ledmyr
Dr. Ben Marcus
Dr. Allison Morales
Dr. Alexander Rajan
Dr. Dana Simmons
Dr. Sandra Virtue
Dr. Katie Willis
A big thank you to Dr. Beata Mierzwa, the artist who designed the cover image. This illustration
demonstrates the wide range of topics that neuroscientists concern themselves with, spanning the level
of molecules, to neurons, all the way up to complex behaviors such as drawing. More of her work can
be found online (http://www.beatascienceart.com/).
This project was supported by the Vincentian Endowment Fund Grant through DePaul University.
Finally, thank you to my parents for their limitless love and support, to my friends who regularly endure
my frequent conversation interruptions with neuroscience facts, and to my wife for her patience through
this three-year long project.
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Open Neuroscience Initiative Downloaded from www.austinlim.com
Austin Lim, PhD (DePaul University)
Editor: Dana Simmons, PhD (University of Chicago)

In short, neuroscience is the study of the to control the movements of our muscles, or to
nervous system, the collection of nerve cells that change the activity of our internal organs. Other
interpret all sorts of information, which allows connections ascend into the brain, conveying all
the body to coordinate activity in response to the sorts of information from the world around us into
environment. a representation of our surroundings. Still, other
The study of neuroscience has taught us routes communicate between brain areas, such
that the brain is a complicated organ with several as when the sudden detection of a threat passes
connection routes, both between different through our visual system and turns into a “get
bodily organs and within itself. Some of those ready” signal that then prepares the rest of our
connections communicate information down body for conflict. Because of this complex system
towards the body, such as signals that allow us of communication, the nervous system can be
thought of as a series of highways and roads that
connect different cities (organs.)
The nervous system conveys all of these
different types of information using a combination
of electrical and chemical signals. The main
active cellular units of the nervous system, the
neurons, are highly sensitive to changes in their
environment. Similar in the way that computers
do all their work using a highly coordinated binary
signal of 0s and 1s, the electrical output of many
neurons is an all-or-nothing response called an
action potential. A wide variety of chemicals
called neurotransmitters is responsible for
Figure 1.1 Neuroscience is the study of the
passing information between neurons.
nervous system and the way the brain performs
The brain is the main computational
its many functions.
powerhouse of the body, much more complex and
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Echolocation expert Control participant
“Visual” brain areas
Acetylcholine Figure 1.3 The brain is remarkably flexible,

and blind people can use visual areas during
echolocation (left, activity in yellow and orange).
Figure 1.2 Neurons temporarily change their
electric properties during an action potential,
which allows for the release of neurotransmitters.
intricate than any artificially created system thus

far. Estimations of the computational power of
the brain suggest that we can handle somewhere
around 10^28 operations per second, processing
power that is many orders of magnitude faster
than any supercomputer to date. While it’s true
that computers can do large, mathematical
calculations that (most) humans can’t, the real
strength of our brain is its flexibility: brains are
capable of changing and adapting to a wide
variety of circumstances. Blind people use their
visual areas of the brain while echolocating ,
stroke survivors can regain lost motor functions
using the unaffected brain circuits, and babies can
effortlessly learn two languages simultaneously
in a bilingual household.
The brain is also responsible for the most
abstract and unique human functions, such as
the origin of consciousness, the place where
our thoughts, fears, and desires are born, and
the endless creativity of our species. All the
musical works of Mozart, the literary genius of
Shakespeare, and the philosophical theories of
Aristotle were produced through some complex
interaction of neurons that we may never
understand.
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Generally speaking, there are three
main research designs that have been used
Ask a question
- and will likely continue to be used - to learn
about the brain.
Draw Conduct
Experimental design conclusions research
The gold standard in science is
the use of experimental design. In an
experiment, the scientist uses a stepwise
process of developing a research question
Analyze data + Develop
and hypothesis, then answering that
draw conclusions hypothesis
question by performing tests. The main goal
of an experiment is to establish a causal
Perform
relationship between one factor that is being
experiments
changed, the independent variable, and
the factor that is influenced, the dependent
variable. A well-designed experiment has Figure 1.4 The scientific method is a circular,
variables that are carefully controlled, which stepwise process used to establish causality between
minimizes the influence of extraneous variables.
variables, often called confounding
variables. The influence of confounding variables
can be eliminated by comparing the experimental
Independent Dependent
group with a control group, a group that is variable variable
as similar as possible in every way except for
the manipulation of the independent variable.
Importantly, subjects or patients are generally
assigned to the experimental or control group at
random. Confounding
For example, consider the research variable
question: “Does studying more increase
performance on exams?” Here, the independent
variable is the number of hours studied, while the Figure 1.5 A good experiment establishes
dependent variable is the grade on the exam. causality between an independent variable and
A potential confounding variable could be the a dependent variable by eliminating the influence
number of hours slept before the exam, since poor of confounding variables.
sleep causes poor memory recall performance,
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and students may choose to study instead of design. These studies do not benefit from
sleep. To eliminate this confounding variable, it separation of patients into groups randomly,
would be good to only compare grades for the and therefore may have several uncontrolled
students who slept for roughly the same amount variables. Quasiexperimental studies are usually
of time. A control group in this experiment would done when conducting an experimental study
be a group of students who are given the test may be too impractical or otherwise unethical.
without the opportunity to study. Ideally, these An example of this type of study might aim
students will be as similar to the experimental to answer the question “Do people with traumatic
group as possible: roughly the same age, gender brain injury have worse hand-eye coordination?”
distribution, educational history, and so on. Performing an experiment with this question would
The strength of a well-designed experiment be wildly unethical, since you cannot intentionally
is that it establishes causality: a change in the give your patients head injuries (It would also
independent variable causes a change in the be challenging to find people willing to get hit
dependent variable. Because of this, assuming on the head for science!). Instead of conducting
that the sample population is representative (the this unethical experiment, you could answer this
distribution of the characteristics in the sample is question with a quasiexperimental study. In the
proportionally similar to the distribution in the total study, there would be two different populations
population,) experiments allow us to extrapolate of patients, an experimental group containing
findings to a larger population. people who have already been diagnosed
Patients who participate in an experiment with head injury, and a control group that is
are often placed into an artificial environment or demographically similar, but without a diagnosis
unnatural circumstances, which can affect their of head injury. You could then ask both groups to
performance. For example, imagine you
were participating in the “studying / test score
experiment.” Having the added pressure of Death
Early
knowing you were in a study could cause death
you to perform worse. Alternatively, knowing
that you are in the experimental group might Disease and
disability
cause you to focus more intently during your
study time, which could increase the group’s Adopting health-
risk behaviors
average. To ameliorate this unintended
effect, it’s important for participants in Social, cognitive,
the experimental group and the control emotional impairment
group to be subjected to the exact same Birth
Adverse childhood experiences
circumstances.
Observational study Figure 1.6 The Adverse Childhood Experiences

A second way to gain scientific (ACEs) was a large-scale quasi-experimental CDC
information is through an observational study, study examining 17,000 people, linking childhood
one type of which is a quasiexperimental trauma with premature death.
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perform a hand-eye coordination task and see if may not give us the same insight as studying just
there are differences in their performance. one person with a specific injury or disorder. For
The weakness here is that there is no true example , case studies have been instrumental
randomness in the groups, thus the influence of in teaching us about the brain structures involved
confounding variables may affect our interpretation with memory (Patient HM; chapter 13), language
of the data. If the head injury group performed (Patient Tan; chapter 14), and fear processing
worse on the hand-eye coordination task, you (Patient SM; chapter 15).
would be able to demonstrate correlation, but Perhaps the most famous case study in all
not causation, which may present as a “chicken of neuroscience is the 1848 story of the railroad
or the egg” problem. Perhaps the head injury worker Phineas Gage. An unfortunate workplace
group already had poor hand-eye coordination, accident left him with significant brain damage,
which led to a car / workplace / sports accident, largely to his frontal lobe. The subsequent
resulting in their head injury. In this example, we changes in his personality taught us that one of
cannot conclude whether the brain injury directly the functions of this area of the brain is regulating
causes a worsening of hand-eye coordination. our inhibitions (chapter 2).
Like a quasi-experimental study, case
Case Study studies only show correlation, not causation. It is
A third strategy is the case study, a highly difficult to generalize the findings from a case study
detailed description of a single patient and their to the population at large. Usually, case studies are
condition. A case study documents the details descriptions of nearly-one-of-a-kind individuals: A
regarding a specific deficit or enhancement, man with memory deficits in response to his brain
and is an opportunity to examine individuals being punctured by a toy fencing sword, a woman
with very rare conditions, which are useful for who had never experienced fear in her life, or a
informing about the functions of different brain man who became overwhelmingly light-hearted
structures. Examining millions of healthy people and joyful after recovering from being shot in the
head.
Case studies can be helpful for the
development of hypotheses that can later be
tested experimentally. For example, consider
Patient HM, the man who had his left and right
hippocampus surgically removed and couldn’t
create certain types of memory. A research
question based on this case study might be “Is
the hippocampus needed for the creation of
navigational memory?” Then, an experimental
study could be performed in rodents, where we
Figure 1.7 A study of a single individual with surgically remove the hippocampus (experimental
special circumstances, such as Phineas Gage group) or a different part of the brain (control
(left) and his brain damage (right), is called a group) and see how well the rodents perform on
case study. a memory task.
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As complex as the brain is, naturally “Forming memories causes new

misconceptions make their way into popular neurons to be born.”
culture. It’s valuable to address these myths Another misconception is the idea that
about neuroscience and explain the evidence each new cell in our brain represents a new
that refutes these statements . memory. While we are far from understanding
the process of exactly how memories are formed
“We only use 10% of our brain.” in the brain, we do have a few clues. Most likely,
This wildly-inaccurate statistic has been memories are stored at the sites of close contact
the foundation for several fictional movies, TV between neurons, called synapses. Changes in
shows, and books. The truth is that we use every in ways neurons connect and communicate with
part of the brain, and most of our brain is active one another is likely the mechanism behind how
most of the time - just not at the same time. memories are formed and stored, rather than the
Neurologist V.S. Ramachandran uses a great creation of new neurons.
analogy to describe the fallacy of this myth: does Even though the process of cell
a traffic light only use 33% of its lights? A properly reproduction is halted in the majority of adult
functioning traffic light will use all three lights at neurons, we are still capable of new neuronal
very precise times. The activity of the brain is growth, a process called neurogenesis. A few
closely regulated by multiple mechanisms which brain areas in particular, like the hippocampus
prevent unusual electrical activity. In fact, if too (used in learning and memory functions; chapter
many cells were active at the wrong times, just like 13) and the olfactory epithelium (used for smelling;
a traffic light showing both green and red, chaos chapter 9), do exhibit frequent birth and death of
ensues - one cause of seizures is excessive new neurons.
neural activity.
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Brain weight (kg)
0.5
0
0 20 40 60 80 100
Age (years)
Figure 1.8 A fully-functioning brain uses nearly Figure 1.9 The weight of the brain does not
100% of the component parts, but at precisely increase much beyond the teen years, but we
controlled times, like a traffic light. continue to learn throughout the rest of our lives.
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Fascinatingly, we do have one strange
“The brain cannot repair itself.”
quirk about signaling between the brain and the
If neurons aren’t being replaced in
rest of the body: signaling pathways from the left
adulthood, then how do people spontaneously
brain crosses over to communicate with the right
recover from neurological injuries like a stroke?
half of the body, and vice versa. This contralateral
One of the most amazing features of the
organization is an unintended consequence o f
brain is the phenomenon of plasticity, the ability
evolution, and is one of the major distinguishing
to change over time. Even if critical brain areas
features of the vertebrate brain.
are damaged, it is theorized that the brain learns
how to “rewire itself,” essentially figuring out how
to carry out these functions without using the
damaged connections.
Unfortunately, there are some conditions
that are neurodegenerative, meaning that their
symptoms get progressively worse over time.
Many of these disorders, like Parkinson’s disease
(chapter 10) and Alzheimer’s disease (chapter
13), currently don’t have any simple cures or
treatments that don’t carry risks and side effects.
For people with these conditions, there isn’t
strong evidence that the brain can recover from
the destruction caused by these diseases.
Figure 1.10 The vertebrate nervous system likely
“If you are analytical, you are twists in development, resulting in a contralateral
left brain dominant, but if you organization.
are creative, you are right brain
dominant.”
A common misconception is that the two
hemispheres of the brain are responsible for
wildly different functions. The truth is that nearly
every function that the left half of the brain can do,
the right half can do just as well, and vice versa.
Sensory information, voluntary control of the
muscles, memories, and many other behaviors
can be performed equally well by both the left
and right halves of the brain.
A major exception to the “left vs. right”
component is the processing and production of
language. For some reason unknown to scientists,
these functions are heavily lateralized in the left
hemisphere for most people (chapter 14).
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One of the most exciting and satisfying fate of the brain, however, was much messier:
aspects of modern science is the rapidity of new Using a pair of sticks up the nose, the brain was
discoveries the field. New findings are often blended up into a mush and flushed out of the
communicated by publishing academic studies skull using palm wine. The brain, apparently,
in scientific journals. More neuroscience studies wasn’t needed for the afterlife.
were published between 2015 and 2020 than in Around 2,000 years later, ancient Greek
the previous seventy years! But, advancements physicians had a different understanding of
in neuroscience haven’t always moved so quickly. the function of the brain. Aristotle developed a
The ritualistic funerary rites of the ancient theory that the heart was the seat of the soul,
Egyptians around 2500 BCE provide a glimpse and that blood was the life force that dictated
into how humankind’s understanding of the brain a person’s behavior. When a person was “hot
has changed over time. When important Egyptians blooded,” they acted impulsively with no regard
died, major organs including their stomach, lungs, for consequences. In his view, the function of the
and liver, were removed and stored in canopic jars brain was to cool the blood as the blood passed
in preparation for immortality in the afterlife. The through it, which calmed the temper.
For the hundreds of years that followed,
physicians attempted to correlate behaviors
with changes in the brain. In the mid 1800s,
Paul Broca was one of the first to suggest that
specific areas of the brain were responsible for
carrying out specific functions, which came to
be called localization theory. Much evidence
favors this line of thinking, such as the idea that
language comprehension starts in a small patch
of cells in the left hemisphere (Chapter 14),
Figure 1.11 The ancient Egyptians preserved Figure 1.12 Paul Broca (left), through his study
some of the important internal organs after death of the brains of patients with the language
(top), while the brain was scrambled using tools disorder aphasia (right), was a proponent of the
(bottom) and discarded. localization theory of brain function.
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perception of faces relies on a set of cells at the
base of the brain (Chapter 7), and balance and
motor coordination depends on the cerebellum
(Chapter 10). On the other hand, the opposing
view, called the distributive processing
theory, suggests that behavioral functions
require activation of cells across several different
areas of the brain. Complex behaviors such as
emotion, consciousness, or cognition (the act
of generating knowledge through a combination
of senses, memories, and thoughts) require
coordinated action across distinct brain areas.
Most likely, some behaviors are more localized
than others, but still rely on signals from across
many other brain areas. As with most fields of
biology, absolutes are rare in neuroscience.
While anatomists and physicians tried to
define the gross anatomical workings of the brain,
they missed out on a layer of understanding at the
level of cells until microscopy was widely adopted
by the scientific community. In the early 1900s, a
heated debate between two anatomists, Camillo
Golgi and Santiago Ramon y Cajal, prompted
researchers to look more closely at the neurons. Figure 1.13 An electron microscope (top) gives us
Through careful drawings of their observations, the resolution to visualize the synapse (bottom),
they concluded that neurons had different shapes the tens of nanometer distance between two
and therefore carried out different functions. This neurons.
microscopic level analysis laid the foundation for
understanding the cells that make up the nervous hair (Chapter 5). A medical diagnostic tool, the
system and the way they communicate with one functional magnetic resonance imaging device
another (Chapter 2). (fMRI), made its debut to the neuroscience world
Today, we have a clearer understanding in 1991, which allowed us to visualize brain
of the function of the brain, largely due to activity while a person is actively engaged in
the advancements brought to us by a better behaviors, such as a decision making task, or
understanding of animal biology and new while observing visual stimuli (Chapter 6). Today,
technology. In 1954, the electron microscope much excitement revolves around visualization
was aimed at the space between neurons for the strategies like CLARITY, a method to render an
first time, allowing us to see a tiny anatomical entire brain transparent, which helps us to map
component about 20 nanometers across - a out the nature of the connections that span the
thousand times smaller than the width of a human nervous system.
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The ever-changing landscape of scientific
inquiry presents a challenge. Our current
understanding of the brain, as described here,
is only a snapshot along the timeline of scientific
discoveries. As we look to the future, many
new discoveries will continue to reinforce what
knowledge we have already amassed. But some
discoveries, with help from not-yet-invented
technology, will push the frontiers of knowledge
and find compelling evidence against long-
standing accepted theories in the field , prompting
a shift in the paradigm.
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Realistically, our modern understanding Psychologists also wondered whether parts of
of “neuroscience” is a combination of several the brain in isolation have different properties
academic disciplines, all using their strengths than when those parts are working together.
to understand some aspect of the nervous This property, called emergence, is the idea that
system. Because of this integrative nature, it the whole is greater than the sum of its parts.
is possible to study neuroscience from many Psychologists examine neuroscience from a top-
different perspectives, each of them more fitting down view, aiming questions at understanding
for answering different types of questions . These the whole organism before looking at smaller
“angles” of analysis are described below. components of the organism (compare this with
At the root of the study is biology. Whenever biological approaches, often a bottom-up view
you are studying living processes, such as that starts at the level of cells or molecules.)
learning, visual perception, or consciousness, Chemistry is a strong influencer of nervous
you dip into the realm of biology. The broad field system function - just ask anyone who forgot
of biology can be subdivided into smaller, more their morning cup of coffee! We use a variety of
precise categories. Molecular neurobiologists endogenous (originating from within the body)
study proteins and gene regulation, cellular chemicals that act as signaling molecules,
neurobiologists examine how networks of neurons allowing communication between cells. These
communicate with one another, and cognitive chemicals exist in many different structures,
neuroscientists study the underlying causes of which determine their function. Some are acidic
behaviors. Understanding neuroscience involves while others are basic; some are polar, others are
genetics, such as the autosomal dominant fat soluble, and some are even gases (chapter
neurodegenerative condition, Huntington’s 5). The nervous system is also highly sensitive
disease (Chapter 10.) Other biological to influence by exogenous chemicals (meaning
subdisciplines such as ecology and evolution are they originate from outside the body), such as
also considered in neuroscience as well, such caffeine and cocaine (Chapter 11).
as the parasite Toxoplasma, which changes an Many principles of physics can be
animal’s response to fearful stimuli, allowing observed through the functioning of neurons. For
the organism to reproduce as it moves through example, neurons maintain a negative electrical
different species in the food web (Chapter 15.) charge, usually measured on the scale of tens of
Psychology provided the earliest millivolts (a millivolt is a thousandth of a volt.) The
explanations about the brain and ideas about the main way for neurons to send signals depends
origin of the mind. Some questions in this field on a temporary change in this voltage; this signal
branched off from philosophy, as people began is called an action potential. This change in
thinking about the “mind-body problem,” the voltage is brought on by the movement of charged
discussion that centered around the question ions across the cell membrane, and they closely
if a function as complex as consciousness follow the rules of magnetism: opposite charges
could result from activity of a clump of cells. attract while like charges repel (Chapter 4).
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The field of computational neuroscience advantage of the sheer mathematical strength of
has grown from the use of mathematical modeling a computer.
to describe or predict some aspect of the nervous Healthcare providers, like neurologists
system. If our current estimates are correct, we and psychiatrists, work from a different angle.
have around 86 billion neurons in the brain, a They coordinate closely with researchers to apply
number so large that it is difficult to conceptualize. scientific knowledge from the field or laboratory
It would be nearly impossible to understand that to treat patients, thus using biological principles
many components of a system without taking as therapies. For example, neurologist Dr . Oliver
Psychology
Computational
Biology neuroscience
Membrane
potential
Neuroscience
Time
Chemistry Physics
Healthcare
providers
Figure 1.14 Neuroscience is made up several academic disciplines.
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Sacks used his knowledge of the dopamine also work closely with healthcare providers to
neurotransmitter system to treat patients with translate science into therapy, such as the deep
a paralysis-like condition in the 1960s, leading brain stimulator devices for the treatment of
to the development of levadopa treatment for conditions such as Parkinson’s disease.
Parkinson’s disease (chapter 5). Other healthcare Collectively, all the people who participate
providers use imaging strategies like a CT scan to in neuroscience in some way are united by
assess the extent of a head injury or the location their interest in the workings of the body.
of a brain tumor, while an EEG can be helpful for Because of the overwhelming complexity of the
the diagnosis of epilepsy (Chapter 6). nervous system, there are many questions still
Engineers help develop the tools needed unanswered. The continual appearance of new
to understand questions in neuroscience, such questions in neuroscience keeps us wondering,
as the patch clamp rig or electron microscope, inspires curiosity, and promises a multitude of
highly specialized pieces of lab equipment. They fascinating career paths for centuries to come.
The Open Neuroscience Initiative is funded by a grant from the Vincentian Endowment Fund of
DePaul University.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
1-14
Image credits
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2-1
Editor: Helena Ledmyr, PhD, INCF (Karolinska
Institutet)
To physically take something apart is are a wide range of neurological disorders that
a great way to learn about the relationship affect humans, from injury to genetic disorders.
between structure and function. Engineers and The gross anatomy of the nervous system
electricians use schematics to help them figure is an important foundation to the studies of other
out what parts connect to where, and architects aspects of neuroscience. This chapter covers
may use blueprints to aid them in the creation of some of the major anatomical structures in the
a building. You can learn a lot about a system nervous system, starting with the brain, working
by understanding the function of the individual down the spinal cord, all the way out to non-
components and how they interact with one nervous tissue. The end of this chapter will also
another. The whole is often greater than the sum cover the many support structures that allow the
of their parts, and a failure of one part to perform nervous system to carry out their jobs.
its duty can have wide reaching consequences. Broadly speaking, the nervous system can
The nervous system is one of the most be divided into two main categories: The central
complex systems that we know of. Parts of this nervous system (CNS) and the peripheral
system malfunction frequently, and the results nervous system (PNS). Simply put, the CNS is
the brain and spinal cord, while the PNS is all the
Figure 2.1 Anatomical structures of the CNS other nerve cells in the body. The two systems
and the PNS. are not isolated from each other; information
passes rapidly between the PNS and the CNS,
Central nervous and vice versa. When a signal that originates in
system
the PNS moves to the CNS, we sometimes say
Brain that the signal is incoming or ascending, while the
CNS to PNS direction is outgoing or descending.
Spinal cord
Information that arrives into the CNS is also
Peripheral
nervous Figure 2.2 Afferent versus efferent signals.
system
Spinal cord
Nerves
Skin Afferent signal
Muscle
Efferent signal
2-2
called an afferent signal, while information something that moves away. Alternatively, an
leaving the CNS is an efferent signal. These efferent signal is something that has an effect on
two terms are frequently confused, but you can the outside world, while an afferent signal affects
use the knowledge of other words that start with the person.
“e” to remember that an “exit” or an “escape” is
Chapter 2 outline
2.1 Central nervous system (CNS)

2.2 Peripheral nervous system (PNS)
2.3 Support structures of the nervous system
2.1 Central nervous system (CNS)

Anatomically, the CNS consists of two and 90 mm tall ( ~3.5 in), it has a total volume
organs, the brain and the spinal cord. of about 1400 cubic centimeters and would fill
The brain is the main organ where about a third of a gallon. The intact adult brain
movement originates, where thoughts and plans weighs about 1.5 kg (3 pounds), which is barely
develop, and where consciousness is housed. 2% of total body weight. Despite this relatively
The brain is what pushes us to act on our drives small size, it is extremely power hungry, and
and desires, where language begins, and where uses up about one-fifth of the body’s total energy
memories are stored. At 160 mm ( ~6 in) long expenditure.
Anatomical language of the brain

When talking about parts of the brain, it is directional axis is anterior and posterior: ante-
helpful to have a set of words that can describe meaning “before” and post- meaning “after”. Often,
the location of various anatomical structures rostral and anterior are used interchangeably, as
unambiguously. Think of the following three pairs are caudal and posterior.
of anatomical words as the “north, east, south, Another axis that should be considered is
west” of the brain. the top-to-bottom direction. Brain structures that
Consider a person who is facing sideways. are above, or closer to the top of the head, are
Here, we’d like to use language that can describe described as being dorsal, while the structures
anatomical structures that are along the “front of that are below are ventral. As before, you may
the head” to the “back of the head” axis. Parts of see another pair of words that share the same
the brain that are more forward are called rostral, meaning. Sometimes, superior is used to
which comes from the Latin word meaning beak. describe a structure on top, while inferior is used
To describe structures towards the back part of to describe a structure below.
the brain, we use caudal, the opposite of rostral. Now, imagine that the person has turned
Another pair of words that describes this same to face towards you. The third axis can be
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demonstrated seen in this orientation. Brain is dorsal to the temporal lobe. These anatomical
structures that are closer to the center of the brain words can also be combined to subdivide complex
are described as being medial, while structures brain regions. The thalamus has many small
that are closer to the sides of the brain are lateral. subsections, such as the dorsomedial nucleus
Neuroanatomists use these words to or the ventropostero-lateral nucleus. Naming
describe the relationship of one structure to structures with this anatomical language is useful
another. For example, in Fig 2.7 which shows the in identifying where they are located in a brain
four lobes of the brain, the frontal lobe is anterior scan or autopsy, but these words tell us nothing
or rostral to the parietal lobe, and the parietal lobe about function.
Figure 2.3 A cartoon illustration of the brain showing anatomical langauge.
Dorsal
(Superior) Lateral Medial Lateral
Rostral Caudal
(Anterior) (Posterior)
Ventral
(Inferior)
Visualizing the brain

As a three dimensional structure, the brain a coronal section.
can be sectioned for visualization or analysis in Another way to image the brain is called a
several ways. Here, we will describe the three horizontal projection. In a horizontal slice, cuts
main orientations, each at right angles to the are made along the dorsal-ventral direction, from
others. the top of the brain to the bottom. Given that the
One projection of the brain is called a person is standing up, horizontal slices are parallel
coronal slice. Imagine that you were looking at to the plane of the ground. Another way to think
a brain of a person who was looking to the left. If of the horizontal plane is through brain imaging
the brain was cut into several sections vertically, techniques where a person moves headfirst into
slicing from anterior to posterior, the brain would a scanner. Here, the machines are capturing
be cut into coronal slices. “Corona” comes from horizontal images where each progressive image
the Latin word for crown, since looking at the is a snapshot of the brain slightly more ventral
brain cut into slices parallel to a crown would be than the last.
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myelin. This modification causes light
Coronal
to reflect, causing it to appear white to
the eye (think of the strips of fat that you
might see in a steak). Other sections of
Sagittal
brain tissue have a darker pink / gray
color, appropriately called gray matter.
These areas are usually dense with cell
bodies.
The brain has two very similar
halves, the left and right hemisphere.
Oftentimes, in the neurotypical
individual, information passes between both
Horizontal
hemispheres rapidly: what one hemisphere
senses or learns, so does the other hemisphere.
Figure 2.4 Cross sections used for visualizing the
It is the white matter tracts that allow for this
three orientations of the brain. “Sagittal” refers to
transfer of information. When a white matter
the slice that divides the brain into left and right
pathway crosses from one hemisphere to another,
hemispheres, while slices parallel to that are
we call it a decussation. In coronal or horizontal
called “parasagittal” sections.
brain slices, you may be able to observe the main
The third and last direction is a parasagittal white matter tract that allows for the passage of
slice. The parasagittal section takes cuts parallel information between the two hemispheres, called
to the midline, slicing in the medial / lateral plane. the corpus callosum.
If a person was facing you, and brain sections White matter
were taken across from left to right, these would
Gray matter Corpus callosum
be parasagittal sections. Notably, because the
parasagittal section only samples from one
hemisphere of the brain at a time, parasagittal
slices are never symmetrical. The word -sagittal
comes from the Latin word meaning arrow, like
the zodiac sign Sagittarius (If you were an archer
drawing back a bow and arrow, a parasagittal
slice would be parallel to that plane).
In a sliced section of the brain, you might
notice that brain tissue has different colored
areas. Some brain tissue is pale and almost
white, and these areas are described as white
matter. Generally, white matter represents Figure 2.5 Coronal brain section showing
pathways of communication. For neurons to send examples of white matter, gray matter, and the
signals rapidly, the cells can be modified in a corpus callosum, the major communication tract
way that adds several layers of fatty lipids called between the left and right hemispheres.
2-5
Brain structures through development
The brain is often divided into five groups It also contains areas that can detect toxins in the
based on their developmental origin. When the blood that come from dietary sources, triggering
embryo first starts to form, cells are classified vomiting.
into three main germ layers: the ectoderm,
mesoderm, and endoderm. Of the three, the b. Metencephalon
ectoderm eventually develops into the nervous The metencephalon develops into two
system. The ectoderm layer folds into itself, and structures, the pons and cerebellum. The pons,
after merging at the surface, creates the neural like the medulla, helps us perform involuntary
tube. This neural tube forms during the third to functions like breathing. It also contains several
fourth week of gestation. The cells of the neural areas that help us hear sounds and taste foods.
tube will eventually become the components of The cerebellum, or “little brain”, is best known as
the CNS. a structure that enables motor control functions,
Early in development, the neural tube has such as balance, coordination, posture, and
three distinct compartments. At this time, the learning physical actions.
undeveloped nervous system is appropriately
called the “three-vesicle stage.” One week later, 2. Mesencephalon, or midbrain
parts of this progenitor nervous system divide; The midbrain structures do not change
this becomes the “five-vesicle stage.” The names much from the three-vesicle stage to the five-
of the five vesicles can be used to describe either vesicle stage. There are many structures in the
the stages through development, or a grouping midbrain, and they can perform a wide variety of
of structures that eventually form in adulthood. functions. For example, the periaqueductal gray
From posterior to anterior, they are: allows us to respond to painful stimuli, the red
1. Rhombencephalon, or hindbrain
Figure 2.6 The future structures of the developing
Evolutionarily speaking, the
nervous system.
rhombencephalon represents the oldest part
of the CNS. These structures likely evolved
Three vesicle stage Five vesicle stage
some 570 million years ago. As these
structures develop into the five-vesicle stage,
they become subdivided into two regions: Prosencephalon Telencephalon
(Forebrain)
a. Myelencephalon Diencephalon
The myelencephalon develops into the Mesencephalon
Mesencephalon
medulla oblongata, a structure that is found (Midbrain)
at the posterior end of the brain stem. The
medulla contains many clumps of neurons that Metencephalon
Rhombencephalon
are responsible for functions that an organism (Hindbrain)
carries out unconsciously, such as breathing Myelencephalon
or changes in heart rate and blood pressure.
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nucleus and substantia nigra coordinate complex b. Telencephalon
movements, the tectum allows us to respond to Structures of the telencephalon are
incoming visual stimuli, and the ventral tegmental the basal ganglia and cerebral cortex. The
area is important for the processing of reward basal ganglia are made up of a series of brain
and motivation. structures that are used for such behaviors as
motor and habit learning, emotional processing,
3. Prosencephalon, or forebrain and action selection. The cerebral cortex
The prosencephalon eventually develops makes up the outermost layer of the brain: the
into the “higher order” brain regions, including the word cortex itself comes from the word meaning
cerebral cortex. Most of the time, when you see “bark,” the outer layer of a tree. Here, the brain
an image of an intact brain from the side or the processes behaviors such as attention, memory,
top, the structures that are visible to you are the and language.
forebrain structures. It may be useful to think of brain structures
as roughly being organized in a phylogenetic
a. Diencephalon “timeline”. The more basic features of a creature
The diencephalon contains a few major are generally controlled by posterior brain
structures. The thalamus is often referred to structures, and the more complex functions are
as a “relay station” in the brain, since almost carried out by structures towards the anterior
every sensory modality (sight, taste, touch, end of the brain. For example, the brain stem
hearing, and more) passes information through of the hindbrain contains networks of cells for
the thalamus. The hypothalamus is also within basic survival, such as respiration and simple
the diencephalon, and this structure serves as locomotion. Next, the midbrain is important for
a communication route to the body’s endocrine motivation and more coordinated movements.
system. Neural signals originating in the And finally, the forebrain carries out the highest
hypothalamus have the capability to influence the order functions, such as personality, intentional
chemistry and function of the entire body. inhibition of actions, and planning out long
term actions. All of the structures work together
simultaneously to produce the whole range of
animal activities.
Major lobes of the cortex

Most of what we see when we imagine the longitudinal fissure is the most obvious fissure
brain is cortex, the bumpy outer surface that is in the brain. It divides the two hemispheres,
made up of raised ridges (gyri, singular gyrus) running along the anterior-posterior axis, visible
and grooved indentations (sulci, singular sulcus; from a dorsal view of the brain. If you were to
sometimes also called a fissure). Although each cut along the longitudinal fissure completely, you
gyrus and sulcus has a name that either identifies would get two symmetrical portions of brain, the
its function or location, there are only three sulci left and right hemispheres. The central sulcus is
that we will introduce here to help orient us around a large fissure that starts at the dorsal part of the
the neuroanatomical features of the cortex. The brain at about the halfway point on the anterior-
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posterior axis. In a sagittal view, the central Central sulcus
sulcus runs ventrally about half the length of Frontal Parietal
the brain. The other groove worth noting is the lobe lobe
lateral fissure. This one runs roughly along
the anterior to posterior direction, and curves
gently dorsally. Again in a sagittal view, it is Occipital
roughly seen in the middle third of the brain in lobe
the anterior-posterior axis.
The cortex is roughly divided into
4 major lobes, which are named after the Cerebellum
Lateral
bones of the skull that surround each section Temporal
fissure
lobe
of brain. The lobes are paired, meaning that
the whole brain contains two of each, a left
and a right. In general, the structures are roughly
symmetrical. The four lobes of the cortex and
their functions, approximately from posterior to
anterior, are:
1. Occipital lobe
The occipital lobe is the posterior most
section of the brain. Anatomically, there is not an
obvious border that separates the occipital lobe
from adjacent areas of the cortex. The occipital
lobe is the smallest of the four lobes. Figure 2.7 Lobes of the telencephalon and two
The main function of the occipital lobe of the major sulci from a lateral view (top) and
is for processing of visual stimuli. Our eyes are a midsagittal view (bottom). The insular cortex is
capable of capturing light and converting that not visible from the outside.
light into signals. The primary visual cortex of
the occipital lobe, also called V1, interprets those the skull. The name comes from the Latin word
signals into a representation of the visual world. meaning time: the passage of time in adults is
Other vision-related stimuli, such as objects in often marked by graying hair, and these gray
motion, object orientation, and color are also hairs may first appear at the temples.
processed by neurons in the occipital lobe. The auditory system allows our brain
to interpret sound waves. We can distinguish
2. Temporal lobe between voices talking, instruments playing,
The temporal lobe is the ventral-most and dogs barking. This is possible because of a
lobe of the brain, and the lateral fissure marks its population of cells located in the temporal lobe
dorsal border. It is anterior to the occipital lobe. It called the primary auditory cortex, or A1.
is the lobe of the brain that is immediately behind The ability to remember important facts
the temple, the structure on the lateral aspect of depends on memory-related processes. These
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functions are carried out in part by a brain is also processed by neurons of the parietal lobe.
structure called the hippocampus, which is These functions are carried out by the primary
buried medially and ventrally in the temporal lobe. somatosensory cortex, or S1 (soma- referring
The temporal lobe also houses some to the body).
structures that are important for language.
Patients with injuries in parts of the temporal lobe 4. Frontal lobe
may experience deficits in the comprehension of The frontal lobe is the anterior most part of
language, while different injuries lead to a deficit the brain. The posterior border of the frontal lobe
in the production of language. is the lateral sulcus. Among mammals, it is the
largest of the four lobes.
3. Parietal lobe The frontal lobe contains the primary
The parietal lobe is in the dorsal aspect of motor cortex, or M1, which is directly anterior
the brain, and immediately anterior to the occipital to the central sulcus. M1 contains neurons that
lobe. The anterior-most (front) end of the parietal control movement of the body. For example, if
lobe is bordered by the central sulcus, and the you were to activate the dorsal most part of M1 in
ventral border is the lateral fissure. a person, you would see motor activity in the leg.
The sense of touch is complex. With our The frontal lobe also carries out the “higher
skin, we are able to detect light touch, temperature, order” functions of the brain. Our personality is
pain, vibration, and many other modalities. This influenced by the frontal lobe - an injury to these
ability to sense different tactile properties of things brain structures can result in a radical change
in the world around us with our body is one of in a person’s behavior. Frontal lobe allows us to
the major functions of the parietal lobe. Another do mental math, to hold a string of letters in our
closely related sense, proprioception, the ability head to be repeated backward, and to suppress
to identify where parts of your body are located, socially unacceptable actions.
Clinical connection: Phineas Gage

The mid-1800s saw an expansion
of industry in the United States. The most
reliable and quickest way to move goods
and people was with the railways that were
starting to zig-zag across the growing
country. The factor slowing down railway
expansion was terrain: land had to be
relatively flat for the tracks to be laid down.
Terraforming mountains was a dangerous
ordeal, and in the years before TNT, a
relatively safe explosive was developed,
work accidents were a risk that these
Figure 2.8 Phineas Gage with the tamping rod (left)
demolition workers faced.
and a drawing of the injury (right).
2-9
Phineas Gage was one of those workers. In the green mountain hills of Vermont, Gage was
putting explosive powder into a crack in a mountain to clear land for a new railway. As Gage packed
the explosive using a three-foot-long metal rod, a spark accidentally ignited the blast prematurely,
causing the tamping iron to rocket cleanly through Gage’s skull.
Miraculously, Gage survived the blast. Within a month, he had made an almost complete
recovery. Gage was talking excitedly with his doctors, he was eating voraciously, and even reported
experiencing no pain. While the doctors noticed that his entire frontal lobe had been destroyed, it
was his friends who noticed the dramatic change in his personality: whereas he was once a friendly
man, adored and respected by his coworkers, the new Gage was irreverent, generally unlikable,
and prone to using profanity at the most inappropriate times. The pre-injury Gage was a shrewd
businessman who followed through with his plans, but Gage now was unreliable and at times,
acted almost animalistically. Because of the injuries to his frontal lobe, his friends described him as
being “no longer Gage.”
Spinal cord
Dorsal
It is sometimes easy to think of (Superior)
neuroscience as a focused study of the brain:
How does activity of the brain contribute to
behavior? In what ways does the brain change Rostral Caudal
in disease? Why do the cells of the brain behave (Anterior) (Posterior)
the way they do?
The truth is there are many parts of the
body that also fall under the broad study of Ventral
neuroscience. For example, the automatic knee- (Inferior)
jerk reflex that a clinician examines when they tap
on your patellar tendon is a test of the nervous Rostral
system. The reflex is driven by sensory neurons (Anterior)
that detect muscle stretch, motor neurons that
cause the kicking response, and interneurons
that prevent the opposing muscle from acting. We Ventral Dorsal
(Inferior) (Superior)
have neural circuits that provoke changes in the
activity of our internal organs, from the beating of
our heart to the digestion of food, and the study
Caudal
of these systems is certainly part of neuroscience (Posterior)
as well.
Moving posterior from the brainstem is Figure 2.9 Unlike other mammals like dogs or
the other organ of the central nervous system, cats, humans walk upright, giving us a “hooked”
a long, thin structure of nervous tissue called nervous system.
the spinal cord. It functions to carry information
2-10
both upwards towards the brain, and downwards
towards the body’s other organs and muscles.
It can also process sensations and form an
appropriate motor response in the absence of Cervical
brain input. The spinal cord originates roughly at
the level of your neck and runs down to the small
of your back, giving it a length around 44 cm
(17.5 inches). The diameter of the spinal cord is
not uniform all the way down, being ~13 mm (0.5 Thoracic
inches) at its widest and ~6.5 mm (0.25 inches)
in diameter at the thinner areas (slightly smaller
than the diameter of a pencil.)
The spinal cord is housed within a series of
bones, called the vertebral column. Although the
spinal cord itself is continuous, it can be divided Lumbar
based on the overlying vertebrae. A combination
of a letter and a number is used to identify each
section of the spinal cord, the letter corresponding
Sacral
to the vertebral section and the number referring
to the number of bones down from the previous
section (the smaller numbers are more anterior,
larger numbers more posterior). Branching off Figure 2.10 The names of the regions of the
from each section of the spinal cord are two pairs vertebral column, the bones that protect the
of nerves, the afferent (incoming to the CNS) spinal cord.
sensory nerve roots which branch from the dorsal
side of the spinal cord, and the efferent (outgoing same areas. Sections C3 through C5 innervate
from the CNS) motor nerve roots which branch the diaphragm, so an injury at this level or higher
from the ventral side of the spinal cord. These two can quickly lead to death since the person may
branches meet and extend away from the spinal stop breathing. The spinal cord is at the widest
cord. After merging, they are called the spinal diameter at the cervical area, as it has a swelling
nerves, and humans have 31 pairs of these. that corresponds to the many inputs and outputs
Moving from anterior (top) to posterior to the arms.
(bottom), the four regions of the spinal cord are:
2. Thoracic
1. Cervical There are 12 pairs of spinal nerves that
The cervical region corresponds to the make up the thoracic area of the spinal cord.
upper 8 pairs of spinal nerves. Nerves that exit These regions innervate the middle trunk area,
through the cervical region innervate the muscles the intercostal muscles between the ribs, and
in the neck, shoulders, arms and hands. Afferent abdominal muscles. Branches off the spinal
nerves detect somatosensory inputs from these nerves in the thoracic areas are responsible
2-11
for changing the activity of the various internal around the genital organs and the dorsal aspects
organs during a fight-or-flight response (more on of the legs, like the buttocks and the back of the
the autonomic nervous system in section 2.2). thighs. There are also parasympathetic nerves
that come from the sacral region, and these
3. Lumbar innervate the colon, bladder, and genital organs
There are 5 pairs of lumbar spinal (again, more on the autonomic nervous system in
nerves. These pathways carry motor command 2.2).
information to the hips, thighs, and knees . Since information must pass through the
Afferent lumbar inputs detect sensory information anterior regions of the spinal cord to reach the
from the ventral side of the legs, such as the top posterior parts of the body, the more anterior an
of the thigh or the shin bone. As in the cervical injury, the more parts of the body that are affected.
region, the lumbar region has a swelling that The disease that affected former U.S. President
increases the diameter of this section of spinal Franklin Delano Roosevelt likely damaged
cord compared to the thoracic or sacral areas. posterior spinal cord structures, which explains
why function of his legs was lost while function of
4. Sacral his arms were left intact. However, the injury actor
At the posterior-most end of the spinal cord
is the sacral region, which consists of 5 pairs of
nerves. Sacral spinal nerves control flexing of the Figure 2.12 Cross-section (transverse) of the
toes. These nerves detect sensory information spinal cord showing a few anatomical features
(top). Section of spinal cord stained with LFB,
which dyes myelin in blue, which is why white
matter looks more blue than gray matter (bottom).
Dorsal
horn
Lateral Central
horn canal
Ventral
horn
White
matter
Gray
matter
Figure 2.11 Drawing of the spinal cord and the

connecting spinal nerves.
2-12
Christopher Reeves sustained while horseback Another feature that is seen across all
riding destroyed his spinal cord at the anterior- levels of the spinal cord are the entry points for
most level of C1, causing complete paralysis and the afferent sensory nerves and the exit points
lack of sensation from the neck down. for the efferent motor nerves. Somatosensory
Unlike in the brain, there is basically only information arrives into the spinal cord from the
one truly meaningful projection of the spinal cord, dorsal side. Most of the sensory neurons have
and that is by cutting sections in the transverse their cell bodies outside of the spinal cord in a
plane. These sections are parallel to the ground large clump of nervous tissue close to the dorsal
if the spinal cord was oriented vertically, like a side called the dorsal root ganglion. On the
person standing up. Sometimes, this projection is other hand, efferent motor nerves exit the spinal
also called a cross-section. cord on the ventral side.
No matter which level of the spinal One of the main differences across
cord you look at, all cross-sections have a few different sections of the spinal cord is the ratio
similarities. Most notably, the inner portion of of white matter to gray matter. In general, the
a section has a butterfly-shaped structure of ratio leans towards more white matter at the
gray matter surrounded by a border of white anterior regions of the spinal cord compared to
matter. Gray matter contains mostly cell bodies the posterior parts of the spinal cord.
while white matter contains mostly pathways The CNS ends at the spinal nerves.
of communication. Therefore, the ascending The remaining nerves that affect the muscles
sensory tracts and descending motor tracts run and beyond are the beginning of the peripheral
along the outer portions of a spinal cord section. nervous system.
Dorsal root
Dorsal root ganglion
Sensory
nuclei
Motor
nuclei
Ventral root
Figure 2.13 Cross-section of the spinal cord showing the dorsal root ganglion, the clump of cell bodies
from the incoming sensory neurons.
2-13
2.2 Peripheral nervous system (PNS)
The PNS functions as the intermediary shoulder muscles are proximal to the nerves that
between the CNS and the rest of the body, project to the hand muscles.
including the skin, internal organs, and muscles Another pair of anatomical terms that
of our limbs. is useful in describing the nervous system
When talking about the PNS, another pair is contralateral and ipsilateral. When the
of anatomical words will be introduced, proximal vertebrate nervous system evolved, there was
and distal. A part of the body that is more proximal a preference for a “crossed system,” one where
is something that is in close proximity to the CNS, the left half of the brain generally controlled and
whereas something that is distal is farther away, received information from the right half of the
or more distant, from the CNS. For example, body, and vice versa. This type of communication
the efferent nerves that project to the neck and is called a contralateral connection. Most parts
of the nervous system have this contralateral
organization, where stuff on the left side of our
Contralateral Contralateral
Ipsilateral Ipsilateral vision first goes into the primary visual cortex of
the right brain, physical sensations on the left
hand first goes into the somatosensory cortex
of the right brain, and so on. The opposite of
Proximal contralateral is ipsilateral, and you would use this
word to describe a part of the body that is on the
same side as that half of the nervous system. For
example, the right hand is ipsilateral to the right
hemisphere of the spinal cord.
The PNS can be divided into three main
branches:
Distal
1. Somatic nervous system

The somatic nervous system represents
all the parts of the PNS that are involved with
the outside environment, either in sensing the
environment or acting on it. For example, the
nerves that detect pressure or pain on the foot
are part of the afferent somatic nervous system.
We also think of the PNS as the branch that sends
signals to our skeletal muscles. The nerves that
Figure 2.14 Anatomical language used in innervate the muscles of the legs as we run are
describing relationships from parts of the nervous part of the efferent somatic nervous system.
system. The somatic nervous system is also called the
2-14
“voluntary nervous system” since it is used to a threat, either perceived or real. All of these rapid
cause muscle movement related to intentional bodily responses result in the body preparing to
actions. attack or defend itself. Increased respiration allows
the body to take in more oxygen, and dilation of
2. Autonomic nervous system blood vessels in the muscles allows that oxygen
The autonomic nervous system to get to the muscles, which is needed for muscle
encompasses all the branches of the PNS that activation.
deal with the internal environment. As with the Now, consider a completely opposite
somatic nervous system, the autonomic nervous scenario. You’ve just gorged yourself on a huge
system is comprised of nerves that detect the dinner of deep dish pizza, Italian beef sandwiches,
internal state as well as nerves that influence bacon cheese fries, and tiramisu for dessert. You
the internal organs. The body carries out all would probably feel relaxed, satisfied, and more
sorts of functions and responses unconsciously than a little sluggish. A different physiological
without any intentional control. It can do so by response is happening, a behavior called the
sending signals to smooth muscles and glands. rest-and-digest response. These physiological
The signals that cause us to sweat when it is hot, changes are driven by the other main branch
our pupils to dilate when it is dark, and our blood of the autonomic nervous system, called the
pressure to adjust when we stand up too quickly parasympathetic nervous system.
are all driven by the nerves of the autonomic Both the sympathetic nervous system
nervous system. and parasympathetic nervous systems influence
Imagine what would happen to your body the internal organs simultaneously. At all times,
if you, while walking through the quad, turned the heart is getting signals from the sympathetic
a corner and encountered a huge feral tiger, nervous system which increase heart rate,
somehow set free from the Lincoln Park Zoo. You and signals from the parasympathetic nervous
would notice a sudden fear response: your heart system which decreases heart rate. However,
rate would skyrocket, you would start breathing this seesaw-like balance can shift quickly in
more rapidly, and your body temperature might either direction, such as inducing a sympathetic
increase. Furthermore, your body will undergo response if a fearful stimulus is encountered, like
additional reflexive responses that you might the runaway tiger.
not even notice: your pupils will dilate, the The sympathetic and parasympathetic
bronchioles in your lungs will dilate, and your nervous systems differ anatomically as well. The
liver and kidneys will start to activate a variety of nerves that drive the sympathetic response branch
enzymes. All of these responses happen within off the spinal cord at the thoracic and lumbar
seconds of seeing the tiger. levels, so sometimes we can use thoracolumbar
This set of physiological changes to a to describe the site of origin. The nerves form a
threat is sometimes called the fight-or-flight chain of many clumps of cells that run alongside
response, which is driven by one of the two the spinal cord, called the sympathetic
branches of the autonomic nervous system, the ganglion. On the other hand, parasympathetic
sympathetic nervous system. The sympathetic drive originates predominantly in the cervical
nervous system activates when we are faced with spinal cord, with some signals originating in
2-15
Sympathetic Target Sympathetic Parasympathetic
ganglia organs effect effect
Spinal
cord Eye Pupillary dilation Pupillary constriction
Lacrimal gland ↓ secretion ↑ secretion
Mucous membranes
Oral glands ↓ saliva production ↑ saliva production
Heart ↑ heart rate ↓ heart rate
Respiratory system Dilate bronchi Constrict bronchi

Stomach ↓ activity ↑ activity
Abdominal blood Vasoconstriction Vasodilation

vessels
Liver ↑ glucose utilization ↓ glucose utilization
Pancreas ↓ activity ↑ activity

↑ norepinephrine
Adrenal gland
release
Small intestine
↓ motility ↑ motility
Large intestine
Kidney + bladder Inhibit urination Stimulate urination
Gonads + genitalia ↑ Muscle ↑ blood flow

constriction
Figure 2.15 Diagram showing innervation of different organs by the sympathetic and parasympathetic
nervous systems and the corresponding effect. Note that the adrenal gland does not have
parasympathetic activity.
the sacral areas. The parasympathetic nervous 3. Enteric nervous system

system usually receives signals from several The internal organs that carry out digestive
cranial nerves. CN X, also called the vagus functions, such as the esophagus, stomach, and
nerve innervates multiple bodily organs in the intestines, are surrounded by a dense mesh of
midsection of the body (vagus comes from the neurons that regulate their activity. Consisting
same root word as vagrant, appropriate since this of half a billion nerve cells, this net of neurons
nerve wanders all around the body.) cause the digestive tract to increase or decrease
the rate of these processes depending on the
body’s demands.
2-16
The enteric nervous system receives Cranial nerves
signals from both the sympathetic and
parasympathetic nervous systems, and functions Many sensory and motor nerves originate in
without our conscious knowledge. Historically, the spinal cord, but there are 12 pairs of nerves
these digestive functions have been classified that exit from the brain. These cranial nerves
as part of the autonomic nervous system, but can control motor functions, carry out general
these responses do not share the same reflex or specialized sensory functions, or both. The
pathway, and the enteric signals can work entirely cranial nerves usually deal with parts related to
independent of the vagus nerve, for example. the head, but not exclusively.
Table 2.16 The twelve cranial nerves and their function.
Cranial Nerve Function Description
CN I Olfactory nerve Sensory Sense of smell
CN II Optic nerve Sensory Sense of vision
CN III Oculomotor nerve Motor Control of extraocular muscles which allow move-
ment of eyeballs; constriction of pupils; changing of
lens shape
CN IV Trochlear nerve Motor Control of the superior oblique muscle of the eye
that moves the eyeball down and lateral
CN V Trigeminal nerve Sensory + motor Tactile and pain sensory information from the face
and mouth; Control of muscles used in chewing
CN VI Abducens nerve Motor Control of the lateral rectus muscle of the eye that
moves the eyeball outward laterally
CN VII Facial nerve Sensory + motor Control of the muscles that allow for facial expres-
sions; Taste sensation on the anterior 2/3rds of the
tongue
CN VIII Sensory Detection of sound information and head positional
Vestibulocochlear nerve (vestibular) information
CN IX Glossopharyngeal Sensory + motor Detection of somatic sensory in the middle ear and
nerve posterior 1/3rd of the tongue; Taste sensation on
the posterior 1/3rd of the tongue; Controls the stylo-
pharyngeal muscle that allows swallowing;
CN X Vagus nerve Sensory + motor Control of the internal organs by autonomic nervous
system using parasympathetic activity
CN XI Accessory nerve Motor Control of the sternocleidomastoid and trapezius
muscles of the neck and shoulders
CN XII Hypoglossal Motor Control of the muscles of the tongue
nerve
2-17
2.3 Support structures of the nervous system
Although we mostly think about nerve cells as non-neuronal structures, but are still critically
being the main characters of the nervous system, important in allowing the nervous system to do
there are many other anatomical features that what it needs to do.
play important supporting roles. These are often
Brain circulation and cerebral blood flow

Anterior
Like every other organ in the body, the
communicating
brain requires oxygen and nutrients to function. artery Anterior cerebral
Middle
In humans, this function is accomplished by the cerebral artery artery
blood that is pumped around the body using a
network of blood vessels called the circulatory
system. The brain has a very high demand for
oxygen and nutrients: at only 2% of total body Posterior
weight, it receives about 15% of total cardiac communicating
artery Posterior
output.
cerebral
Oxygenated blood moves anteriorly
artery
through the aorta into the brain via two different
Basilar
pairs of arteries, the vertebral arteries and
artery
the internal carotid arteries. The left and right
vertebral arteries merge into a single basilar
artery, and along with the left and right internal
carotid arteries, feed into a loop-like circular blood Vertebral
artery
vessel called the circle of Willis. According to
one theory, the circle of Willis is an anatomical
redundancy that allows an organism to maintain
cerebral blood flow even if one part of the arterial
system is narrowed or blocked. From here, the
circle of Willis has paired “exit” arteries that
distribute blood to different areas of the brain:
the anterior cerebral arteries provide blood to
dorsomedial cortical structures and deep brain
structures, and the posterior cerebral arteries
provide blood to the occipital lobe. The other
major arteries are called the middle cerebral
arteries which branch off the internal carotid Figure 2.17 Diagram of the circle of Willis (top)
artery and deliver blood to the lateral cortices. and an angiogram (bottom) showing the structure
in real life.
2-18
Clinical connection: Stroke
Stroke is an extremely common, life- Ischemic stroke
threatening medical condition that results in
a loss of blood flow to the brain. According
to 2016 statistics from the World Health
Organization, stroke is the second highest
cause of death worldwide. The number one Hemorrhagic stroke
risk factor for stroke is high blood pressure.
There are two common types of
strokes that a person may experience. More
than 80% of all strokes are ischemic strokes
(pronounced is-keemik), which happens when
normal blood flow is interrupted, causing cell
death by deprivation of brain tissue of oxygen Figure 2.18 Diagram illustrating the two main
and nutrients. Generally, this type of injury types of stroke and the effect on blood flow to
can happen when a blood clot forms, travels the brain
through the circulatory system and gets lodged
in a tiny brain blood vessel, thus blocking the
passage of blood. for providing blood to specific areas of the brain,
The other 20% of strokes are it is possible to diagnose the specific area where
hemorrhagic strokes, which results from the stroke is happening based on the presentation
a burst blood vessel that causes bleeding of symptoms. For example, if the middle cerebral
into the brain. The presence of uncontrolled artery blood is occluded by an ischemic stroke,
blood inside the brain causes an increase in the left hemisphere motor cortex will lose blood
intracranial pressure, which can be lethal. flow. Because of the contralateral organization of
Many brain cells may die since they cannot the descending motor pathway, the patient may
take up oxygen directly from the blood. therefore present with paralysis or weakness in
Additionally, blood has dramatically different the right half of the body.
properties than the normal solution which It is vitally important to correctly diagnose
the brain cells live in, and this can cause the and differentiate between the two types of strokes.
neurons to trigger a self-destruction program. An ischemic stroke may be treated with injection
Generally, hemorrhagic stroke is more deadly of a “clot-busting” drug, a substance that helps
than ischemic stroke. the body break down the offending blockage.
Because the different blood vessels of However, these clot-busters could make the
the brain’s circulatory system are responsible bleeding from a hemorrhagic stroke even worse.
2-19
Blood-brain barrier (BBB)
It is important for oxygen and nutrients from stroke, epilepsy, and Alzheimer’s disease,
to pass from the blood into the brain tissue. just to name a few. It is still unknown what role
Small blood vessels outside of the brain, such the disruption of the BBB plays in brain disorders.
as the capillaries in the fingertips, have very The exclusive nature of the BBB can be a
thin walls, sometimes the width of a single cell, double-edged sword. It is difficult to deliver a drug
and are therefore highly permeable to gases. into the brain from the blood stream if that drug
These vessels can either contain tiny holes or is unable to pass through the BBB. For example,
large protein structures that physically transport the current gold standard pharmaceutical
substances across the blood vessel. On the treatment for Parkinson’s disease is to increase
other hand, it is also advantageous to separate the brain’s levels of dopamine. However,
toxins and foreign pathogens in the bloodstream dopamine does not pass through the BBB. To get
from getting into brain tissue. The blood-brain around this, physicians give the BBB-permeable
barrier (BBB) is an anatomical adaptation that substance L-DOPA, which the brain is able to
selectively transports substances necessary for convert into dopamine. Many other therapeutic
normal biological function, while simultaneously drugs do not cross the BBB, so researchers are
excluding potentially harmful invaders from the developing methods using electromagnetic fields
brain. The BBB physically surrounds blood vessels to temporarily weaken the barrier, or surround the
in the brain. It is made up of endothelial cells and drugs in nanoparticles, which are so small that
a type of glial cell called an astrocyte. The BBB is the body cannot identify as foreign.
injured in all variety of medical disorders, ranging
Figure 2.19 The blood-brain barrier separates blood vessels from the brain tissue. Peripheral blood
vessels do not have such an anatomical adaptation.
Peripheral blood Brain blood

vessel vessel
Nucleus Astrocyte
Neuron
Fenestration Endothelial
cell
Blood vessel
Intracellular Tight junction

gap
2-20
The ventricles and cerebrospinal fluid (CSF)
In a coronal section of the brain, it is very inside the skull. Without CSF, the brain weighs
common to see large symmetrical “holes” near almost 1.5 kg (~3 lbs). Cells and blood vessels
the medial aspect. These spaces are called at the ventral base of the brain would be crushed
ventricles.The human brain has a total of four under the weight of the brain itself. But when the
ventricles in the brain. The two very large paired brain is surrounded by CSF, it weighs less than
ventricles, one in each hemisphere, are the lateral 50 grams, almost two orders of magnitude lighter!
ventricles. They are connected medially into the CSF is also found in a tightly-regulated
third ventricle, which extends to the posterior membranous sac called the meninges (more
aspect of the brain. From here, an aqueduct that about it below) that encases the brain. In fact,
runs ventrally extends into the fourth ventricle more than 80% of the CSF in the body exists in
before continuing into the central canal, a this space outside the brain. This liquid serves
narrow space that runs all the way through the as a form of “cushioning” that protects the brain
length of the spinal cord along the midline. The from rapid he ad movements. If it weren’t for this
entire ventricular system is entirely connected. physical protection, the inertia of head movement
The ventricles are filled with a liquid called may cause your brain to smash against the inside
cerebrospinal fluid (CSF). CSF is basically of the rigid skull if you move your head too quickly.
a high salt water solution (sodium ions at 140 The CSF layer allows the head to withstand
mM and chloride ions at 110 mM). Because of some sloshing of the brain, but a movement that
the high osmolarity of CSF, it is a very buoyant is too abrupt can cause a traumatic brain injury, a
solution. Like a fully grown person who can float condition that we will return to in chapter 15.
easily on the surface of the extremely salty Dead CSF can also function as a way to wash
Sea, CSF allows the brain to remain “floating” impurities out of the brain. The volume of CSF in
Figure 2.20 The ventricular system consists of several interconnected chambers filled with cerebrospinal
fluid (CSF).
Lateral ventricles
Interventricular
foramen
Third ventricle
Cerebral aqueduct
Fourth ventricle
Central canal
2-21
Clinical correlation: Hydrocephalus
A common condition affecting the brain of about 1 in 200 newborns and a small number of
adults is hydrocephalus, historically called “water on the brain.” In patients with hydrocephalus, the
volume of CSF increases, which elevates intracranial pressure, causing symptoms such as fever,
stiff neck, headache, seizures, or altered mental status. In adults, the skull is rigid and unmoving.
But in newborns with hydrocephalus, the plates of the skull are not completely fused together. Often,
these children will have a bulging parts on the skull and an expansion of the forehead. Increased
CSF volume can happen in a couple ways. The clearance of CSF may fail while production remains
normal, or the entrance to the central canal in the spinal cord may be narrowed or blocked by a
tumor, leading to an increase in the volume in the brain. A common treatment for hydrocephalus
is to surgically implant a shunt, which is a hollow tube that runs from the ventricle down into the
abdominal space, which allows for drainage thus decreasing intracranial pressure.
Flattened gyri
Narrow sulci
Enlarged
ventricles
Enlarged
head size
Healthy child Child with hydrocephalus
Figure 2.21 Hydrocephalus is one of the most common birth defects, affecting around 0.1% of
births in the United States. It can also affect adults. Hydrocephalus can be deadly.
the typical human body is about 150 mLs, a little each day. Since the CSF is in close association
more than half a cup. Because there is frequent with the neurons, cellular waste materials get
turnover of CSF, the material gets absorbed dissolved into CSF, which can then be degraded
back into the body regularly. Each day, the body and broken down outside of the brain.
produces about half a liter of CSF, so the brain
cycles through the entire volume a few times
2-22
Meninges
The brain is a squishy internal organ the adult body (if you took a piece of printer paper
housed inside the skull. If there weren’t some and fold it in half four times, that should give you
protective buffer separating the soft brain matter an idea of how thick the dura mater is in the adult
from the rigid bone, the jelly-like brain would be human). The dura mater is physically attached
smashed up against the inside of the skull and to the inside of the skull with highly resilient
get injured as the head moves around. The connections found at the sutures between the
meninges are a series of protective membranes plates of the cranium. The name originates from
that minimize this kind of damage. They surround Latin meaning tough mother.
the brain and extend all the way down the spinal 2. Arachnoid mater. The arachnoid mater
cord. Think of the meninges as an organic type is the middle layer of the meninges. The fibers
of “bubble wrap” that encases a fragile nervous are very delicate and resemble a spider web,
system. which is where the name comes from. Within this
There are three types of membranes that space, there are protrusions that allow for CSF
collectively make up the meninges. From the to drain into sinuses, which allow for recycling of
outside-most layer to the innermost, they are: soluble substances. Most of the CSF in the brain
1. Dura mater. The dura is made of thick, exists underneath this layer in the subarachnoid
fibrous material, and can get to be 0.8 mm thick in space.
Figure 2.22 The meninges are a series of protective membranes that surround the CNS.
Veins
Skull
Arachnoid mater Dura mater

Subarachnoid Subdural space
space
Pia mater
Cerebral cortex
2-23
3. Pia mater. The pia mater is the third
layer of the meninges. It is very fragile and in direct
contact with the surface of the brain, and closely
follows the sulci and gyri. The name means pious
mother.
Clinical correlation: Meningitis

Inflammation of the meninges is a
potentially deadly condition called meningitis.
Exposure to infectious agents like viruses
or bacteria such as Neisseria meningitidis
that leaks from the blood into the meninges
is a common cause of the inflammation.
When the meninges are inflamed, the brain
gets compressed from all sides, increasing
intracranial pressure, producing many of the
same symptoms seen in hydrocephalus: fever,
stiff neck, headache, seizures, and altered
mental status. The N. meningitidis bacteria
and the viruses are highly transmissible in
close contact, but vaccinations are highly
effective at minimizing the infection rate. As
with bacterial infections, broad-spectrum
antibiotics are effective at treating the
infection.
DePaul University.
2-24
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2-25
Editor: Katie Willis, PhD (University of Oklahoma)
For the majority of human history, the

only way we were able to study the structure of
the brain was with crude, butcher-like methods.
Wait for a person to die, saw a giant hole in the
top of the skull, take the brain out, and slice it
into pieces to see if there was some correlation
between the way the brain looks and the way they
died. With these methods, only major changes in
gross anatomy could be observed, such as that
resulting from severe birth defects or trauma.
Brain analysis methods were enhanced
by the scientific adoption of light microscopy.
Naturalists in the mid 1600s such as Antonie van
Leeuwenhoek, Jan Swammerdam, and Robert
Hooke began looking at biological substances up
close, and the brain proved to be a complex and
interesting sample of tissue.
A major advancement in the study of
neuronal morphology came about in the late
1800s. The Italian anatomist and biologist Camillo
Golgi identified a shortcoming with the cellular
Figure 3.1 A microscope image of a single Golgi
analysis techniques of the time: structures in
stained neuron (top) and a slice of Golgi stained
the CNS were impossible to distinguish from
brain (bottom).
one another. The cells in the brain were so
densely packed together, that it became difficult
to identify which cellular material belonged to now known as a “Golgi stain.” (Despite being
which cell. Golgi came up with a new technique more than a hundred years old, we currently don’t
using a silver compound that caused the silver to know the mechanism by which the silver stain is
precipitate inside the cell membranes. However, taken up into the neurons, or what determines
not every cell took up the silver. Instead, only why certain cells take the stain and others don’t.)
a small fraction of neurons, maybe 1% or even Because of the great contrast between cell and
less, were completely stained in black, which background, every single part of the neuron was
stood out remarkably well against the light yellow completely filled, allowing Golgi to do drawings of
background of the surrounding tissue. This the morphology of this nervous tissue. Based on
reaction, initially called the “black reaction,” is his staining results, Golgi supported the idea that
3-2
the parts of the nervous system are all one very shared Nobel Prize in Physiology or Medicine
large, physically connected network. This idea in 1906 for their accomplishments in helping
was known as the reticular theory. to understand “the structure of the nervous
About 10 years later, the Spanish system.” Even though Cajal’s neuron doctrine
neuroanatomist Santiago Ramon y Cajal repeated was adopted widely by scientists, the elucidation
some of Golgi’s staining experiments with other of this organization would not have been made
sections of nervous tissue. Looking at similar possible without Golgi’s development of the
darkly-filled neurons, Cajal arrived at a different silver stain. The sharing of this prestigious award
conclusion: the nervous system is not a giant was ironic because of the many disagreements
net, but rather a series of individual units that are between the two scientists. Cajal commented on
separated from one another physically. This idea their relationship, saying:
came to be known as the neuron doctrine.
Both Golgi and Cajal were awarded the “What a cruel irony of fate of pair, like Siamese
twins united by the shoulders, scientific
Figure 3.2 Camillo Golgi (left) and Santiago adversaries of such contrasting character!”
Ramon y Cajal (right) were both awarded the joint
Nobel Prize in Physiology or Medicine in 1906. Cajal’s neuron doctrine was eventually given
more support with the aid of modern techniques,
like electron microscopy, that are capable of
physically seeing the distance between two
neurons. The neuron doctrine represents our
current understanding of how the nervous system
is organized, and this chapter is focused on
describing the anatomical features of the nervous
system at the cellular level.
3-3
Chapter 3 outline
3.1 Characteristics of neurons

3.2 Cellular anatomy of neurons
3.3 Cellular functions of glia
3.1 Characteristics of neurons

The main units of the nervous system or lipid membrane, consists of a sheet of several
are cells called neurons. Although neurons do individual molecules called phospholipids, which
have a variety of adaptations that make them consist of two hydrophobic (water-fearing) tails
unique from other types of cells in the body, and a hydrophilic (water-loving) end. These
they are still cells. Therefore, they contain all of phospholipids arrange themselves into a bilayer
the basic features of a typical mammalian cell. with the hydrophilic tails touching each other and
For example, they are made up of an aqueous the hydrophilic sides facing the cytoplasm and
cytoplasm bounded by a cell membrane. This the extracellular space, which are both mostly
cell membrane, also called a plasma membrane water. Because of the chemical properties of
the cell membrane, it is very
effective at keeping ions and
Figure 3.3 The cell membrane is made up of a lipid bilayer, which
charged molecules separated,
consists of organized phospholipids.
while allowing small molecules
Cell like water and oxygen across
Extracellular space the cell.
They also have all the
Cell membrane
Nucleus organelles that you would see in
Intracellular space other cell types, like a nucleus
and mitochondria.
The number of neurons
in the adult human brain,
Lipid bilayer according to our current best
estimate, is close to 86 billion.
This number was calculated
using a revolutionary technique,
Proteins the isotropic fractionator or
Phospholipid
“brain soup” developed by
Hydrophilic head Brazilian neuroanatomist
Suzana Herculano-Houzel. To
Hydrophobic tail
put this number in context, we
3-4
have about 37 trillion cells in the whole body, so neuron can go from -70 mV to +45 mV and back
neurons in the brain make up about 0.2% of all to -70 mV in as quickly as two milliseconds!
cells in the body. Neurons are not the only electroactive cells
Below are some unique characteristics in the body. Our lives depend on cells in the heart
that neurons have in common. that are also capable of changing in potential, as
they respond to rhythmic electrical impulses that
Neurons are electroactive drive our heartbeat. This is why being struck by
The inside of most cells have a negative lightning may cause your heart to desynchronize
electrical charge compared to the solution outside in activity, and why a shock from a defibrillator
of the cell. This difference between the electrical can electrically “kick-start” the heart back to a
charges is called the membrane potential, or meaningful pattern.
transmembrane potential. When a neuron
is at rest, the amplitude of this charge may be Neurons are specialized for rapid communication
somewhere between -50 millivolts (mV) and -90 Many cells are capable of sending and
mV. Often times, we say that in general the cell receiving chemical signals across long distances
rests at around -70 mV. Membrane potential is and time scales. But neurons are able to
abbreviated as Vm. communicate with a combination of electrical
and chemical signals in a matter of milliseconds.
Additionally, the shape of neurons and the
organization of the neurons on a microscopic
level make them effective for sending signals
in a very specific direction. Many neurons have
an incoming receiving end and an outgoing
sending end. The placement of one neuron next
to the correct partner is very important, and many
chemical signaling systems are in place to ensure
-70 mV that the developing nervous system is properly
wired together.
Figure 3.4 Compared to the extracellular space,
the voltage of the neuron is generally negative. Neurons are “forever” cells
We are constantly replacing non neuronal
Most neurons do not spend their entire cells. For example, the cells in our bones replace
lives at -70 mV. Instead, neurons have special themselves frequently at a rate of about 10%
proteins embedded in their cell membranes that each year. Our body makes new skin cells to
allow for charged ions, such as sodium or chloride, replace the dying skin cells on the surface so
to move into or out of the cell. When a net positive that we have a “new” skin every month. The cells
charge enters into the cell, the Vm becomes more along the inside of our stomachs, exposed to very
positive. Likewise, when net negative charge harsh acidic conditions, get replaced about every
enters the cell, the membrane potential becomes week. About 100 million new red blood cells are
more negative. The membrane potential of a created every minute!
3-5
On the other hand, the mature nervous ...But, neurons can change
system generally does not undergo much Even though new neurons are not created
neurogenesis, the creation of new neurons. in most areas of the brain, neurons still have the
The neurons that we have after development capability to change in their structure and function.
are the ones that we will keep until we die, and Some of these changes, such as physical
this permanence of neuronal count makes them changes to the structures of the input sites of the
different from almost every other cell of the body. neurons, are believed to last for a lifetime. We use
However, the idea of adult neurogenesis is a the word plasticity to describe the ability for the
topic of debate among neuroscientists, since brain to alter its morphology (derived from Greek
some areas like the olfactory system and the plastikos, meaning “capable of being shaped or
hippocampus display new nerve cell production. molded” - think of plastic surgery, where a person
changes their physical appearance; see chapter
13, Leaning and Memory).
Also, neurons do have the capacity to
repair themselves to some extent. Neurons of the
PNS may get injured or completely destroyed as
a result of trauma to the body. Afterwards, those
injured neurons can regrow to connect once
again with their original partner. This regrowth
seems to depend on a few chemical signals that
the body produces, such as nerve growth factor
and brain derived neurotrophic factor. However,
this process is often very slow, and does not
Figure 3.5 The handle of George Washington’s always successfully restore the nervous system
axe breaks and is soon replaced. Later, the to the way it was pre-injury.
head breaks as well. Is the axe still George
Washington’s axe? This paradox is similar to the
cells of our body, which are replaced frequently -
with neurons being the exception.
3-6
3.2 Cellular anatomy of neurons
Synapse Dendrites Figure 3.7 The dendrites are the highly branched
input sites of the neuron. They are named
because of their resemblance to trees.
Along the dendrites of some neurons, it is

Axon possible to see tiny protrusions of cell membrane
Soma
that stick out from the main dendrite. These
bumps are called spines. Spines can roughly
be classified based on their approximate shape;
thin, mushroom, and stubby being some of the
more easily recognizable forms. A spine may be
about 100 nm in diameter, making it smaller than
Figure 3.6 The basic anatomy of a neuron.
the wavelength of visible light, with a total volume
The main function of neurons is to of about 0.1 femtoliter - one ten-quadrillionth of a
use changes in electrical properties in order liter!
to communicate with connected cells. This Chemical signals released by another
communication usually moves in one direction, cell are received by the dendritic spines, and
and we will use this pathway as an outline for so each spine may represent an input site of
discussing the anatomical structures of the communication. Some cells, like a pyramidal
neurons. neuron in the hippocampus, may have more than
30,000 spines, indicating that one cell may detect
Dendrites information from several incoming cells.
Information first enters the neuron through We believe that spines are one of the
the dendrites, the branch-like extensions that most important sites where the nervous system
protrude from the cell body. The word dendrite is able to change. For example, neurons change
originates from the ancient Greek word “dendro-”, shape after exposure to various environmental
meaning “tree” (think of rhododendron). conditions, such as stress or exposure to drugs.
Dendrites look like the branches of a tree: they Tiny changes to the surface of the neuron at the
reach outward away from the center of the cell level of dendritic spines is an example of plasticity.
body, generally getting thinner the farther away Dendritic plasticity is thought to underlie the
you look. reason that we can learn new facts or maintain
3-7
Filopodia Long thin Thin Stubby Mushroom Branched
Length Length Length Length:width Width 2 or more heads

>2 μM <2 μM <1 μM ratio <1 μM >0.6 μM
Figure 3.8 Tiny extensions of the cell membrane on dendrites are called spines. They can be classified
based on their shapes and sizes.
memories about our childhood over long periods microns in diameter.

of time. Some set of tiny, submicroscopic The cell body contains many of the
changes to the morphology of dendritic spines organelles that are essential for the production
may represent a single complex memory that you of proteins that the neuron needs. Many of these
form. organelles are not unique to neurons, and can
A neuron does not need spines for be found in other cell types. The most apparent
receiving information or for plasticity to take place. organelle visible under high magnification (400x)
Many cells lack spines, but are still capable of is the nucleus, which houses DNA and other
permanently changing. The input site may be genetic material. From our understanding of the
anywhere along the dendrite, or even at the cell central dogma of molecular biology, this DNA is
body, the “center” of the neuron. transcribed into a string of single-stranded genetic
code called messenger RNA (mRNA), which is
Cell body (soma) exported out of the nucleus. This mRNA is then
Information that arrives through the many used as a guide for the synthesis of proteins.
dendrites of a neuron eventually filters into the The next step of protein creation depends
cell body, or the soma, of the neuron. Somata on organelles that are adjacent the nucleus.
(plural of soma) vary in size across different Physically continuous with the membrane that
types of neurons, the largest somata belonging surrounds the nucleus is a folded membranous
to the Betz cells of the motor cortex with an area organelle called the endoplasmic reticulum
upwards of 100 microns in diameter: about the (ER). Attached to the ER are several ribosomes,
size of a single grain of salt. On the opposite end which are the molecular machines that read the
of the spectrum, granule cells of the cerebellum mRNA and translate that code into proteins. The
are so densely packed so that they make up Golgi apparatus are layers of folded plasma
more 70% of all neurons in the brain, maybe 4 membranes that function in transport. They
3-8
are found near the nucleus, although small Inhibitory
protrusions of these organelles may reach into input
Excitatory
the other parts of the neuron. input

Excitatory
input
DNA
mRNA Axon
Axon hillock
Figure 3.10 The axon hillock acts as an integration

center that sums all the excitatory and inhibitory
Figure 3.9 Like non-neuronal cells, DNA is housed inputs, and decides on a binary output called the
in the nucleus (purple). DNA is transcribed into action potential.
mRNA and exported out of the nucleus, where it
called the axon hillock. With respect to signal
can be translated into protein.
transduction, the axon hillock works as the
Axon integrative center of the neuron. It is responsible
The axon is the main output extension for deciding whether to pass a signal onto the next
of the neuron. While neurons only have a single cell. The cell membrane of the hillock performs a
axon extending from the cell body, this axon can complex set of “cellular arithmetic” that weighs all
branch several times after exiting the soma. In of the incoming signals: excitatory, inhibitory, and
branching, an axon from a single neuron is able modulatory signals. After all of the calculations
to communicate with many other neurons at have been performed, the membrane either
the same time. Axons are usually thinner than sends a signal or not.
dendrites, some being only a micron in diameter. At the end of each branch of the axon is a
Several axons can bundle and travel together; small swelling, which is called the axon terminal
these are nerves. Axons can be very long; the or terminal bouton. The terminal is the part of the
longest axon in the human body is part of the neuron that is specialized for the production and
sciatic nerve that runs from the posterior end release of the neurotransmitters that are used for
of the spinal cord down the leg to control the communication between neurons. One subarea
muscles of the big toe. of specific interest in the axon terminal is a small
The first section of the axon, the junction patch of membrane called the active zone.
between the cell body and the beginning of Embedded in the cell membrane at the active
the projection, is a patch of axonal membrane zone is a variety of proteins that are important for
with very unique characteristics. This section is the process of neurotransmitter release.
3-9
Anterograde
transport
Microtubules
Retrograde
transport
Vesicles
Figure 3.12 Diagram of an axon terminal, showing

microtubules and vesicles.
proteins that can carry other proteins along the

microtubules. When substances are transported
away from the cell body, it is called anterograde
Figure 3.11 Neurons (green) extend a single axon transport, while the process of moving proteins
from the soma, which can branch extensively. towards the cell body is retrograde transport.
Another important organelle that is found
along the length of the axon are neurofilaments.
Inside the axon These organelles are made up of several different
Most of the proteins synthesized in proteins that serve as a cellular “scaffolding” that
neurons are created in the cell body very close helps keep the structure of the axon intact. Mature
to the nucleus, where the mRNA that is exported neurons can be very dense with neurofilaments,
from the nucleus is able to easily interact with the which increases the diameter of the axon.
rough endoplasmic reticulum and the ribosomes. Within the terminal are a number of
But, some of these proteins are needed far vesicles, small spherical “packages” made of
away from the cell soma, at the axon terminal, cell membrane that are coated in special proteins.
for example. Neurons need some system of Within these vesicles are the molecules that the
transport system that can move newly created neurons use for chemical communication. When
proteins to where they need to go. Inside the the action potential travels down the axon and
length of the axon runs an organelle called reaches the axon terminal, the cell membrane
microtubules, which function like a molecular changes in electric charge, and this causes
railway for proteins. The cells use motor-like vesicles to fuse with the inner membrane of the
3-10
neuron. During fusion, the vesicular membrane
merges with the cell membrane at the axon
terminal, causing the contents of the vesicle to
be released outside the cell.
Outside the axon

Some neurons have a special modification
surrounding their axon called a myelin sheath.
Electrical synapse Chemical synapse
Myelin is comprised of several tightly-wrapped
layers of cell membrane that encompasses a short Figure 3.14 Electrical synapses physically share
section of the axon. Myelin might be wrapped as cytoplasm (left) while chemical synapses use
many as 250 or 300 times around a single section neurotransmitters to communicate (right).
of axon. Myelin does not extend fully enclose the
entire length of the axon from soma to terminal,
but rather surrounds short sections at a time. The Synapse
spaces of exposed axon between each section of The synapse is the physical distance that
myelin are called nodes of Ranvier. On average, separates two neurons. In agreement with Cajal’s
these nodes are about 1 micron long. neuron doctrine, the nervous system is not made
Myelin serves a few functional purposes. up of a single cell with a giant, shared cytoplasm,
Myelin increases the speed by which an electrical but rather a series of neurons in close proximity,
signal is transmitted. Some of the most heavily separated by a gap of extracellular space.
myelinated axons are able to send signals up This distance between two cells
to 120 meters per second (almost 270 miles can vary depending on the nature of the synapse.
per hour, faster than a Formula 1 racer.) Myelin An electrical synapse may be less than 5
also increases the effective thickness of the cell nanometers apart. Cells connected by electrical
membrane along the axon. In doing so, myelin synapses share cytoplasm but have two separate
acts as an insulator that causes signals to more cell membranes. On the other hand, a chemical
reliably be passed down the axon. synapse is a larger distance, about 15 - 40 nm
across. Adjacent neurons connected
Figure 3.13 Myelin sheaths are made up of layers of cell by chemical synapses do not share
membranes that surround small sections of axons. The cytoplasm.
nodes of Ranvier are the exposed sections of axons between
the myelin.
Axon hillock Myelin sheaths
Soma Nodes of Ranvier Axon terminal

3-11
Clinical connection: Multiple sclerosis While MS has the potential to be debilitating
Multiple sclerosis (MS) is a disease and painful, the disease itself is not necessarily
that results from destruction of myelin in the lethal, and MS only decreases life expectancy
CNS. When myelin is damaged, signals do by 5-10 years on average. People with MS
not reliably propagate from the brain to the are just as likely to die from natural causes as
body, from the body to the brain, or between much as a neurotypical person.
areas of the brain. MS damages myelin at One of the leading theories about the
both descending and ascending neurons, so cause of MS is a faulty immune system. A
a person with MS might experience muscle normally functioning immune system identifies
weakness, poor balance, and muscle spasms and destroys foreign pathogens. Sometimes,
(efferent motor neurons) as well as numbness this system makes a mistake, and the immune
and pain (afferent motor neurons). It can also response recognizes normal parts of the body
affect neuronal signaling in the brain, causing as being a “foreign object”, causing the body
symptoms such as cognitive impairment, to destroy itself. This is called an autoimmune
vision loss, and changes in affect leading to disorder. In the case of MS, it is believed that the
depression. immune system identifies and targets myelin
Multiple sclerosis is a common for destruction, leading to demyelination.
neurological disorder that affects some Although immunosuppressants may slow the
2.5 million people worldwide. MS typically progression of MS, these drugs increase the
presents in adulthood, usually between 20- risk of a person developing an illness that a
50 years old. Unfortunately, there is currently healthy immune system would be able to
no known cure for MS. Therapy is focused on prevent.
either slowing the progression of the disease,
helping patients recover after an attack, or
decreasing the severity of the symptoms.
Immune
cells
Neuron
Injured
myelin
Healthy
myelin
Figure 3.15 Multiple sclerosis is a disease resulting from the destruction of myelin, which hinders
the ability for neurons to communicate properly.
3-12
Classifications of neurons In addition to classifying neurons based
Neurons have a wide variety of shapes on their morphology, neurons can also be divided
and can be divided roughly into three different based on their functions.
classes depending on their morphology. In order
of increasing morphological complexity, they are: 1. Sensory
Sensory neurons are the afferent neurons
1. Unipolar cell that are responsible for obtaining information
Unipolar cells have a single cellular about either the outside world or the internal
extension coming off the soma that acts as both environment and passing that information
the receiving and the sending end. Unipolar cells towards the CNS. Sensory neurons can detect
are very common among invertebrates; humans a variety of stimuli, ranging from photons of
do not have unipolar neurons. light (visual system) or chemicals floating in the
air (olfactory system), to carbon dioxide levels
2. Bipolar cell in the blood (chemoreceptors) or stretching of
A bipolar cell, as can be implied from the the muscles (spindle receptors). Since they are
name, has a single dendrite and a single axon. highly specialized for detecting different types of
They are not very common, but can be found in stimuli, sensory neurons have a large variety of
human sensory systems, such as in the eye or in shapes and structures.
the signaling pathway connecting the ear to the
brain. 2. Motor
Motor neurons, or motoneurons, carry
3. Multipolar cell signals from the CNS to the body. There are two
Multipolar neurons have several dendrites main types of motor neurons. Somatic motor
and one single axon. These cells are the most neurons control skeletal muscle movement,
common among all the neurons in the human such as flexing or extending the muscles of the
nervous system. Most drawings of neurons you arm. They release neurotransmitter directly onto
will see in this book are multipolar cells. muscles. Autonomic motor neurons, on the other
hand, release neurotransmitter onto a clump of
Figure 3.16 Neurons can be classified based on neurons outside of the CNS called the autonomic
their morphology. ganglion, which then signal to the smooth muscle,
cardiac muscles, or glands.
Unipolar Bipolar Multipolar
neuron neuron neuron
3. Interneuron
Interneurons exist as a relay between
the sensory or motor neurons and the CNS, or
between each other. They represent a very broad
class of neurons, and make up an important part
of reflex circuits, such as the knee-jerk response.
3-13
The above classifications are only a rough Sensory Motor Interneuron
guideline for separating neurons. As with most neuron neuron
biologists, neuroscientists enjoy classifying cells
based on their properties. It is almost always
preferable to use the most specific name possible
in identifying neurons. Many cells have been
identified based on the way they look (chandelier
cells), some named on the neurotransmitter
released (cholinergic interneurons), some named
by where they are found (cerebellar granule cell),
and yet others named based on the person who
discovered them (Purkinje cells).
Figure 3.18 Neurons can also be classified based
on their function.
Visualizing the synapse as 50 picometers - more than a 10,000,000x

The original microscopes that van magnification!
Leeuwenhoek used to visualize cells and Using EM, you are able to get
microorganisms relied on the transmission ultrastructural resolution of the synapse. In two
of light to see objects up close. For us to be adjacent neurons, EM allows you to distinguish
able to see objects, light needs to bounce off the boundaries of both neurons, and to clearly
the intended target. Light particles travel in a see the synapse in between. You can also see
wave, and if the object we intend to visualize the vesicles contained in the axon terminal,
is smaller than the wave, then the wave sometimes in the middle of fusion.
would pass right over the object. The shortest
wavelength of visible light is around 380
nanometers, so light microscopy is limited to
visualizing objects in the micrometer or larger
range - a 2,000x magnification with the best
possible lenses.
In the early 1950s, a group of scientists
developed a technique called electron
microscopy (EM). In EM, a beam of electrons
is aimed at a sample in a vacuum, and the
reflection of those electrons can be collected
and detected with a computer. Since electrons Figure 3.17 Electron microscope image
have a much shorter wavelength than visible showing a synapse at ultrastructural resolution
light, you are able to resolve objects as small (less than 100 nm).
3-14
3.3 Cellular functions of glia
Although most of neuroscience is
concerned with understanding the functions of
neurons, there are other cells in the nervous
system that are just as interesting. These
cells are grouped together under the umbrella
classification of glia. Historically, when these
non-neuronal cells were visualized under the
microscope, the histologists and anatomists had
no idea about their function. They were seen
all around the neurons, so the assumption was Figure 3.19 Astrocyte labeled by staining the
that these cells were structural elements, a sort protein GFAP (left). Astrocytic endfeet are closely
of living glue that held the nervous together. associated with blood vessels as part of the
Today, we know that these glia serve all variety blood-brain barrier (right).
of functions; unfortunately the misnomer “glia,”
derived from the Latin word for glue, is still used function in maintaining the blood-brain barrier.
to describe these non-neuronal components of Astrocytes are also very closely associated
the nervous system. We estimate that the brain with synapses. Astrocytes have a very dense
has roughly an equal number of glial cells and expression of proteins on their cell surface that
neurons—86 billion of each. can transport molecules of the neurotransmitter
There are many different classes of glia, glutamate, for example, inside the astrocyte. By
but we will focus on five types. acting as a glutamate “sponge,” astrocytes are
able to decrease the strength of a glutamate
1. Astrocytes signal. Through a similar uptake mechanism,
Astrocytes are named for their characteristic astrocytes can also affect the extracellular
star-shaped morphology. Astrocytes have a concentration of ions such as potassium, which
dense expression of the protein glial fibrillary then has an influence on cellular excitability.
acidic protein (GFAP), and this protein is often Because of these interactions between astrocytes
used as a marker for differentiating astrocytes and neurotransmission at the synapse, we use
from other cell populations. the phrase tripartite synapse to refer to the
One of the main functions of astrocytes in three components of a synapse: The presynaptic
the brain is to help maintain the blood-brain barrier. neuron, the postsynaptic neuron, and the
At the end of the extensions of the astrocyte are astrocyte.
protrusions called “endfeet.” These endfeet are Astrocytes also synthesize and produce
often wrapped around the endothelial cells that a variety of trophic factors, which are helper
surround the blood vessels. The endfeet release molecular signals that serve several different
important biological compounds that allow the functions. For one, trophic factors signal to
endothelial cells to remain healthy as they neurons that the neuron should continue to live,
3-15
Presynaptic
Astrocyte
neuron
Postsynaptic neuron
Figure 3.20 Astrocytes can modify communication

between two neurons and are therefore part of
the tripartite synapse.
or that specific synapses should be maintained.

Figure 3.21 Oligodendrocytes are capable of
They help guide the neurons as they reach out,
myelinating multiple axon segments at once.
forming synapses where appropriate.
3. Schwann cells
2. Oligodendrocytes Schwann cells are named after the German
Oligodendrocytes only exist in the CNS. biologist who first described these glial cells. He
Their name is derived from their morphology. found that there are cells that are wrapped around
Oligo- refers to “a small number” (think oligarchy, the axons of nerve cells that project towards
a government ruled by a few people), and muscles - myelin. These Schwann cells can only
dendro- refers to “tree” (like a rhododendron). be found in the PNS.
Each oligodendrocyte has a few branches that The main action of Schwann cells is to
reach away from the cell body. provide a section of myelin sheath for PNS
The main function of the oligodendrocytes neurons, and in this way, they function similarly
is to add a layer of myelin around the axons of to the oligodendrocytes. Schwann cells produce
nearby CNS neurons. A single oligodendrocyte is only a single section of myelin, compared to
able to myelinate up to 50 segments of axons. As oligodendrocytes, which myelinate multiple
cells that produce myelin, they are responsible for sections.
increasing the conduction speed of nearby neurons Schwann cells also function in the
as they send signals. When the oligodendrocytes regeneration of injured axons. When nerves in
begin myelinating, they are able to produce the PNS are damaged after trauma, Schwann
almost 3 times their weight in membrane per day. cells rapidly mobilize to the site of injury. Here, the
By maturity, the oligodendrocyte supports cell remaining loose myelin hinders the regeneration
membrane that is 100 times the weight of the cell. process, and the Schwann cells destroy the extra
Due to the need to support such large amounts of cellular membranes. Schwann cells also produce
myelin, it’s estimated that they have the highest signaling molecules that guide the injured axons
metabolic rate of any type of cell in the brain. to the correct targets, which helps the axon
regrow.
3-16
Axon
Schwann cell
nucleus
Myelin
Figure 3.23 Microglia (green) are much smaller

than neurons (red). They are neural immune
Figure 3.22 Schwann cells myelinate a single cells that exhibit morphological changes when
segment of an axon in the PNS (top). They also performing cellular cleaning.
contribute to regeneration of injured nerves
(bottom). down the inside of the spinal cord.
4. Microglia Ependymal cells produce CSF. In total, the
Microglia are a bit different from the other body can make about half a liter of CSF each day
glial cell populations. For one, microglia are (a little more than two cups.) The ependymal cells
more immune cells rather than neural. They act are part of a structure called the choroid plexus,
as cellular scavengers that travel throughout the the network of blood vessels and cells that form a
brain and spinal cord. It is estimated that microglia boundary between the blood and the CSF.
make up 10-15% of all cells in the brain.
As immune cells, microglia identify and Figure 3.24 Ependymal cells line the inside of the
destroy clumps of proteins, dead / dying cells, or ventricles and produce cerebrospinal fluid.
foreign pathogens that enter into the brain. After
an injury to the CNS, like a traumatic blow to the Ventricular space
head, microglia rapidly react to the area of the
insult. The marker Iba1 is often used to identify
when microglia are reacting to an injury.
5. Ependymal cells
Along the inside of the ventricles are a
lining of glia called the ependymal cells. These
ependymal cells are columnar with small finger-
like extensions called cilia that extend into the
ventricles and into the central canal that runs
3-17
Image credits
Cover: Dana H. Simmons, Ph.D. dana-simmons.com
3.1 https://upload.wikimedia.org/wikipedia/commons/6/6d/GolgiStainedPyramidalCell.jpg
https://upload.wikimedia.org/wikipedia/commons/1/1a/Human_hippocampus_2.5x.jpg
3.2 https://upload.wikimedia.org/wikipedia/commons/5/57/Camillo_Golgi_nobel.jpg
https://upload.wikimedia.org/wikipedia/commons/3/30/Cajal-Restored.jpg
3.3 https://upload.wikimedia.org/wikipedia/commons/5/5f/Cell_membrane_detailed_diagram_
simplified_ca.svg modified by Austin Lim
3.4 https://svgsilh.com/9e9e9e/image/2040692.html modified by Austin Lim
3.5 https://pixabay.com/photos/axe-old-lumberjack-blade-1008981/
3.6 https://upload.wikimedia.org/wikipedia/commons/0/0a/Anatomy_of_a_Neuron_with_Synapse.png
modified by Austin Lim
3.7 https://upload.wikimedia.org/wikipedia/commons/7/74/Dendritic_arborization_patterns_2.png
https://upload.wikimedia.org/wikipedia/commons/9/90/Submerged_Albizia_Saman_in_the_Mekong_
at_sunset_%28close-up_view%29.jpg
3.8 https://upload.wikimedia.org/wikipedia/commons/6/6e/Geometric_characteristics_of_dendritic_
spines.png modified by Austin Lim
3.9 https://upload.wikimedia.org/wikipedia/commons/f/fb/MRNA-interaction.png modified by Austin
Lim
3.11 Image courtesy of Connor Maltby
3.12 https://upload.wikimedia.org/wikipedia/commons/8/86/201704_microtubule.svg modified by
Austin Lim
3.15 https://upload.wikimedia.org/wikipedia/commons/2/2a/Multiple_Sclerosis.png modified by Austin
Lim
3.16 https://upload.wikimedia.org/wikipedia/commons/9/92/Neurons_uni_bi_multi_pseudouni.svg
3.17 https://upload.wikimedia.org/wikipedia/commons/6/6c/Synapse_neuro-neuronale.png
3.19 https://upload.wikimedia.org/wikipedia/commons/5/56/Human_astrocyte.png
https://upload.wikimedia.org/wikipedia/commons/3/34/Astrocytes_Wrapping_around_Blood_Vessel.
png
3.21 https://upload.wikimedia.org/wikipedia/commons/2/2e/Oligodendrocyte_illustration.png
3.22 https://upload.wikimedia.org/wikipedia/commons/5/52/CeluladeSchwann.jpg
https://upload.wikimedia.org/wikipedia/commons/0/03/Analysis_of_
development_%281955%29_%2817549733973%29.jpg modified by Austin Lim
3.23 https://upload.wikimedia.org/wikipedia/commons/0/0b/Microglia_and_neurons.jpg
3.24 https://upload.wikimedia.org/wikipedia/commons/c/ca/Glial_Cell_Types.png modifed by Austin
Lim
DePaul University.
3-18
4-1
One of the interesting properties of neurons one part of a neuron to send signals over long
is that their cell membranes are electroactive, distances – hence, the analogy of electrical wires
meaning that they are sensitive to electrical running overhead. In this chapter, we will go
charge. Neurons are capable of changing the into depth describing the molecular and cellular
electrical potential of their membranes, which components that contribute to the electrical
makes them a very dynamic population of cells. properties of a neuron, both at rest and during an
These changes, which can happen on the scale action potential.
of milliseconds, provide a rapid method for
Chapter 4 outline
4.1 Ion channels

4.2 The electrochemical gradient
4.3 The Nernst equation
4.4 The action potential
4.5 Movement of action potentials
4.1 Ion channels

The cell membrane that separates the proteins embedded in the cell membrane.
inside of the cell from the outside is a very effective These transmembrane proteins are huge
boundary. It is described as being selectively protein complexes that span the entirety of the
permeable, which means that some molecules membrane, with an outer side and an inner side.
are able to travel across the membrane easily, In the middle of the protein is a pore, which is
other molecules have an intermediate ability essentially a “tunnel” that allows molecules
to cross, and other molecules are completely and ions to pass across the cell membrane.
incapable of passing. Generally, gases and These proteins are called ion channels. These
molecules of water are able to pass through channels are passive since they do not use any
the cell membrane easily. Large molecules cellular energy to move ions. Rather, they simply
like glucose, and charged molecules like ions provide easy passage for ions. It may be useful to
or amino acids, are unable to pass across the think of an ion channel as a “cellular door.”
membrane. One important feature of ion channels
Most cells of the body, including is their ability to distinguish ions based on
neurons, have specialized transmembrane their chemical properties. For example, some
4-2
Gases Hydrophobic Small polar Large polar Charged
molecules molecules molecules molecules
Steroids Water Glucose Ions

ethanol
O2
-
H2
CO2 +
Figure 4.1 Selective permeability of molecules across the cell membrane.
channels are selective for Na+, while preventing

Closed Open
the passage of all other ions. Each ion channel
configuration configuration
has special molecular characteristics that allow
certain types of ions to pass through the pore
while excluding other ions. Some features that
allow for distinction between ions include:
1. Pore size. The molecular shape of an
ion channel can exclude larger diameter ions if
it is small enough, restricting the ability for the
large ion to enter the pore – in the same way that
a ping pong ball cannot pass through a narrow
diameter of a straw.
2. Electrical charge. Ion channels can
Figure 4.2 Ion channels (purple) are also prevent certain ions from passing through
transmembrane proteins that can be open, based on the electrical charge. The inside of the
allowing charged ions to cross the cell membrane pore is lined with charged amino acids, and their
through a molecular “tunnel” called the pore. charge allows only certain types of ions to pass.
4-3
For example, sodium channels have several categorize ion channels into four major classes
negatively-charged glutamate residues inside based on their opening and closing conditions.
the pore. Because of this, negatively-charged 1. Leak channels are persistently open.
ions like chloride will be repelled by the negative You can think of these leak channels as revolving
charges, but the positively-charged sodium ions doors that are never locked. Neurons usually have
will be attracted to the inside. several leak channels, such as a leak channel for
potassium (K+) and a leak channel for chloride
(Cl-) ions. These two ions are at equilibrium,
flowing back and forth across the cell membrane,
Na+ K+ and they help contribute to the properties of the
neuron at rest.
2. Voltage-gated ion channels are
sensitive to the electrical potential of the
surrounding membrane. Their ability to open
Figure 4.3 Ions dissolved in water are surrounded and close depends on the electrical charge of
by a shell of water molecules. The potassium ion the membrane. Many of them, such as voltage-
is larger, and the water molecules are farther gated sodium (Na+) channels, remain closed at
apart, making the attraction weaker than in the negative potentials (resting condition) and only
sodium ion. open at positive potentials (action potential).
3. Ligand-gated ion channels open in
3. Hydration shell. Selectivity based on response to binding certain molecules (ligands),
charge and small size is a simple task, but how such as neurotransmitters. These types of ion
can it be possible for an ion channel to allow larger channels are also called ionotropic receptors,
ions to pass while excluding smaller ions? This is and these will be described in much more depth
possible because it is energetically favorable to in chapter 5.
allow an ion that has been stabilized sufficiently 4. The fourth class of ion channels is a
by the properties of the amino acid residues lining catch-all category that includes a wide variety of
the pore. channels that are used by the sensory systems.
This process is related to the observation They open and close in response to unique stimuli
that a shell of water molecules surrounds each depending on what they are able to sense. For
charged ion in solution. To pass through the pore, example, some open and close depending when
water molecules must be separated from the ion. they are moved physically, such as a distortion
The potassium ion has diffuse hydration shell, and or stretch. We have these in our ears (hair cells,
so it is easier to separate water from a potassium chapter 8.1), in our skin (Pacinian corpuscles,
ion compared to a sodium ion. The passage of chapter 8.3) and in our muscles (Golgi tendon
potassium becomes more energetically favorable organ, chapter 10). Photoreceptors in our eyes
compared to passing a sodium ion, causing these have ion channels that close in response to
pores to be selective. being hit by photons of light, and this activity is
Like doors, different types of ion channels necessary for us to be able to see in both brightly
open and close under different conditions. We can and dimly lit environments.
4-4
4.2 The electrochemical gradient
Without ion channels, ions do not cross the a negative potential, movement of charged ions
cell membrane and therefore stay either outside will change as well. In this case, the electrical
or inside the cell. But when an ion channel is gradient now attracts negatively charged ions
present and open, ions can move across the cell into the cell while pushing positively charged ions
membrane, depending on the specific conditions out of the cell.
inside and outside the neuron. There are two
different forces that act on ions once an ion 2. Chemical gradient
channel is open: the electrical gradient and the The chemical gradient refers to the natural
chemical gradient. process by which a high concentration of a
substance, given enough time, will eventually
1. Electrical gradient diffuse to a lower concentration and settle evenly
The electrical gradient refers to the over the space.
electrical forces acting on charged molecules,
“pulling” opposite charges together while also
“pushing” like charges away from one another -
just like the polarity of magnets.
At rest, the interior of the cell has a negative
charge, about -70 mV. Because of these negative
charges inside the cell, the electrical gradient Figure 4.5 The chemical gradient describes the
causes positively charged ions to be attracted to same forces acting on ions as diffusion, where
the inside of the cell. At the same time, negatively ions move from areas of high concentration to
charged ions will be repelled out of the cell. low concentration.
The voltage of the neuron (Vm ) can deviate
significantly from -70 mV, reaching potentials as You can think of the chemical gradient as
high as +40 mV. When the Vm changes, the force similar to the way people behave when they exit
exerted by the electrical gradient changes as well. a full elevator. People don’t want to be so close
If the cell now has a positive potential instead of to each other inside a cramped space. Once the
doors open, people scatter quickly, going
Figure 4.4 The electrical gradient describes the forces to where they can have more personal
acting on ions as they follow the rules of magnetism in space. They move from an area of high
physics - “opposites attract, and similar charges repel.” concentration to low concentration.
Molecules behave the same way.
+ - - + Unlike the electrical gradient,
the chemical gradient is unaffected
by biological movement of ions. In
-70 mV +40 mV other words, the distribution of ions
across the membrane does not change
4-5
significantly. The number of ions that flow across and Na+ is now able to pass across the cell
the cell membrane is so minute that the relative membrane, the electrical gradient causes the
distribution of ions across the cell membrane sodium to move into the cell.
essentially does not change. We also know that the concentration of
These two forces are collectively called the sodium outside the cell (written as [Na+]o, where
electrochemical gradient. In order to accurately the brackets indicate concentration and the
predict the forces acting on a given ion, you need “o” refers to “outside”) is high compared to the
to know 1) the charge of the ion and 2) the relative concentration of sodium inside the cell (written
concentrations of ions across the membrane. as [Na+]i) by roughly an order of magnitude.
Therefore, when that sodium-permeable ion
Take a look at the following two examples : channel opens, Na+ will move from the area of
1. Sodium (Na+) movement across the high concentration to low concentration, causing
membrane Na+ to move into the cell.
Consider the positively-charged ion, Given that both the electrical and chemical
sodium (Na+). Because it has a positive charge, gradients are in favor of moving Na+ into the cell,
it is electrically attracted to the inside of the cell, opening a sodium channel causes a net flow of
which has a negative charge at rest. Therefore, Na+ ions into the cell.
when a sodium-permeable ion channel opens
Extracellular
+ +
+ +
+
+ +
+ +
+
-70 mV
+
Intracellular
Figure 4.6 When a sodium channel opens (purple), sodium ions (orange) are acted on by two forces.
They have a positive charge, which is attracted to the negatively-charged inside of the cell (electrical
gradient). They are at a higher concentration outside the cell, which causes them to move to the inside
of the cell with the lower concentration (chemical gradient).
4-6
2. Potassium (K+) movement across the membrane voltage can, you could imagine there
membrane exists some Vm where the flow of ions moving
Just like with sodium, we can use our in are exactly equal to the flow of ions moving
knowledge of potassium’s charge and the out. In this case, the two forces acting on the
distribution of K+ ions across the membrane in ion oppose one another perfectly, resulting in
order to predict the forces acting on K+ ions when a dynamic equilibrium (This process is called
a potassium channel is open. “dynamic” because there is a constant movement
We know that the inside of the cell is of ions going in and going out, and yet it is at an
negative and K+ has a positive charge, so the “equilibrium” because there is no net movement
electrical gradient causes K+ to be attracted into of charge: the charge moving in is balanced by
the cell. We also know that the inside of the cell the charge moving out.) This exact value of the
has a relatively high concentration of K+ ions Vm is called the equilibrium potential for the
compared to the outside of the cell; therefore the ion, which is also abbreviated Ex where x is the
chemical gradient pushes K+ out of the cell. ion of interest. The equilibrium potential differs for
Since the ion concentrations across the each ion, and is described in Table 4.1.
membrane do not change significantly, but the
Extracellular
+
Electrical gradient
-70 mV
Chemical gradient +
+ +
+ + +
+
+
+ +
Intracellular
Figure 4.7 When a potassium channel opens (blue), potassium ions (green) are acted on by two
opposing forces. They have a positive charge, which is attracted to the negatively-charged inside of
the cell (electrical gradient). At the same time, they are at a higher concentration inside the cell, which
causes them to want to move outside of the cell (chemical gradient). This process is at equilibium.
4-7
Ion Abbreviation Concentration outside [X]o Concentration inside [X]i
Sodium Na+ 140 mM 15 mM
Potassium K+ 5 mM 150 mM
Chloride Cl- 120 mM 10 mM
Calcium Ca2+ 1 mM 100 nM = 0.1 µM
Magnesium Mg2+ 2 mM 0.5 mM

Miscellaneous anions A- 20 mM 100 mM
Table 4.8 Charged ions are unequally distributed across the cell membrane. Typical concentrations of
ions in a mammalian neuron.
4-8
4.3 Calculating Ex and the Nernst equation
Even though the equilibrium are closer to 310 K. This term is included in
potential (Ex) for each ion can be determined the equation since all biological processes are
experimentally, it is also possible to calculate Ex temperature dependent, especially those at the
using a mathematical equation called the Nernst level of molecular machinery.
equation. By understanding the Nernst equation, z is the electrical charge of the ion. For
you can predict the direction that ions will move sodium and potassium, z is +1, for chloride or
when an ion channel opens given various monovalent anions z is -1, and for divalent cations
conditions. The Nernst equation is as follows: like calcium and magnesium, z is +2. This term
is essential since the Nernst potential is used to
predict the direction of ion movement based on
the charge of the ion. This value represents the
influence exerted by the electrical gradient.
Equation 4.9 The Nernst equation calculates the F is the Faraday constant which has a
reversal potential for a given ion x. value of 96,485 Coulombs / mol.
[x]o and [x]i represent the concentration
Ex is the equilibrium potential. As a
of ion x outside the cell and inside the cell,
potential, it has units in volts, usually measured
respectively. Their units are generally in mM, but
in millivolts. When a cell’s membrane potential
these units cancel out in the equation. These
is exactly at this Ex, the ion is at equilibrium:
values represent the forces acting on the ions by
ion movement into the cell is matched by ion
the chemical gradient.
movement out of the cell. Ex is sometimes also
The Nernst equation has many complex
called the reversal potential, because once the
constants and terms, so neuroscientists often
cell membrane crosses from this potential, the
use the back-of-the-envelope equation as a
net movement of the ions reverses directions.
shortcut for quickly calculating the equilibrium
This value is also called the Nernst potential in
potential. This shortcut equation condenses down
honor of Walther Nernst, the Nobel prize-winning
the R and F constants, turns the natural log into a
German chemist who first developed the formula
base 10 logarithm, and assumes the calculations
to describe electrochemical reactions.
are done at physiological temperature. The
R is the ideal gas constant. It has a value
shortcut formula can be written as:
of 8.314 J / K * mol. The R term is included in the
equation because it is a way to convert between
the number of molecules and the energy that
these molecules exert.
T is the temperature in Kelvin (to convert
from Celsius into Kelvin, add 273 to the Celsius Equation 4.10 The “back-of-the-envelope”
value. C + 273 = K). Usually, room temperature equation is a shortcut to estimate the reversal
is around 293 K, and biological temperatures potential for an ion x.
4-9
The Nernst equation is able to calculate Under these conditions, the permeability for K+
the reversal potential for individual ions assuming (pK) is 1, pCl is 0.55, and pNa is 0.04. Therefore, the
that the appropriate ion channels are open. resting membrane potential Vm will be closest to a
However, in neurons, not all ion channels are combination of EK and ECl, since these two terms
opened or closed at the same time. In a neuron dominate the GHK equation. Just as a reminder,
at rest, usually Na+ does not enter into the cells the resting membrane potential is around -70 mV,
since sodium channels are closed. K+ ions , on and EK is around -80 mV while ECl is around -60
the other hand, are often moving through leak mV.
channels all the time. Chloride channels are However, during an action potential
generally open as well, but they pass less current (described in section 4.4), permeability for
at rest than potassium channels do. sodium increases significantly. As pNa rises, the
A formula called the Goldman-Hodgkin- membrane potential will shift closer towards ENa,
Katz equation (GHK equation) combines the which is +55 mV. The GHK equation provides
Nernst potentials of three relevant ions (Na+, a mathematical explanation for how movement
K+, and Cl-) into a single equation that, when of Na+ across the membrane causes the cell to
evaluated, gives us the value of the membrane become more positive.
potential Vm.
The GHK equation is written as:
Equation 4.11 The Goldman-Hodgkin-Katz equation is used to

calculate the membrane potential given permeability of ions and their
concentrations across the cell membrane.
When you analyze the GHK equation, you

will notice that it is essentially a combination of the
Nernst equations for the equilibrium potentials
for the three ions. The GHK equation also
introduces a new term, the value p which stands
for permeability: the ability for an ion to cross the
membrane through ion channels. Permeability
itself does not have a unit.
It is easier to think of permeability as the
“weight” of each equilibrium potential. The higher
the permeability for a given ion, the closer the Vm
is to the Ex for that ion. For example, consider the
value of the GHK equation for neurons at rest.
4-10
4.4 The action potential
The action potential is a short-lasting
Membrane potential (mV)

Depolarization
(1 or 2 milliseconds), temporary change in
-65 mV
membrane potential that can travel down the
length of the axon. Action potentials are the main
method of communication that neurons use, -70 mV
and each action potential triggers the release
of neurotransmitters at the axon terminal of a
Hyperpolarization
chemical synapse. Action potentials are all-or- -75 mV
nothing responses, meaning that only a large
change in potential will be able to pass the signal Figure 4.12 When the neuronal membrane
forward, but a small, sub-threshold change in Vm potential becomes more positive above the resting
will not. Sub-threshold changes in Vm are called membrane potential, we call it depolarization.
graded potentials. When the membrane potential becomes more
During an action potential, the membrane negative, we say it is hyperpolarized.
potential deviates from the resting membrane
potential of around -70 mV (this value can range of ions, predominantly sodium and potassium,
from -90 mV to -50 mV, depending on the type across the cell membrane through voltage-gated
of neuron) to positive potentials. When Vm ion channels. An action potential takes place in 5
goes from negative to a more positive potential, steps, some of which overlap in duration.
this change is described as a depolarization.
Likewise, when Vm changes to a value that is Suprathreshold
more negative, it is called a hyperpolarization. +50 mV depolarization
The action potential has a very characteristic
Membrane potential (mV)
shape: a rapid depolarization, followed by a

prolonged hyperpolarization, before repolarizing
0 mV
and slowly returning to the resting membrane
potential over the next few milliseconds.
Cells regularly receive many inputs at
once. To trigger an action potential, the sum of -50 mV Threshold
the inputs must be sufficiently depolarizing to
-70 mV
bring the Vm to a value that is more positive than Subthreshold
the action potential threshold. For an average depolarization
-100 mV
neuron, the action potential threshold is around
-55 mV. Anything less than the action potential
threshold will fail to send the signal forward. Figure 4.13 If the depolarization exceeds the
The change in membrane potential seen action potential threshold, roughly -55 mV, the
in an action potential is driven by the movement neuron will fire an action potential (green).
4-11
1. Depolarization from incoming which are called excitatory post synaptic
neurons potentials (EPSPs), while release of inhibitory
Presynaptic neurons that release neurotransmitters cause small hyperpolarizations,
neurotransmitters onto dendrites cause a small or inhibitory post synaptic potentials (IPSPs).
amount of ion movement via postsynaptic ligand- These PSPs are characterized by a fast but
gated ion channels. These small deviations in small rising phase where the Vm changes quickly
membrane voltage are called postsynaptic followed by a slower decay phase where the Vm
potentials, or PSPs. Release of excitatory resets back to resting potential.
neurotransmitters causes small depolarizations Usually, a single EPSP only causes a
small amount of depolarization that isn’t sufficient
for bringing Vm above the threshold potential.
Reaching the threshold often requires multiple
EPSPs. Multiple EPSPs are added together in
one of two ways: spatial summation and temporal
summation. Spatial summation happens when
two small EPSPs from two adjacent inputs are
triggered. Temporal summation occurs when
multiple EPSPs from the same input occur close
together in time. Each individual EPSP has a
normal decay period, and adding a second EPSP
during that decay period causes the two to add
Figure 4.14 Activation of excitatory inputs (left) together, which may now be large enough to bring
causes depolarization, while activation of inhibitory Vm above the action potential threshold. When a
inputs (right) can cause hyperpolarization. large enough total depolarization of membrane
potential reaches the soma, an action potential is
initiated at the axon hillock.
0 mV
-50 mV Threshold
-70 mV
Figure 4.15 Spatial summation is the addition of signals from two inputs adjacent to each other (left).
Temporal summation is the addition of two signals close together in time (right).
4-12
2. Opening of voltage-gated Na+ Na+ movement across the cell membrane into the
channels cell causes the Vm to depolarize to very positive
At rest, the voltage-gated ion channels are potentials. The peak of the action potential can
almost all closed. But as the Vm depolarizes, the reach +40 mV.
channels are more likely to open. At this point,
we use our understanding of the electrochemical 3. Opening of voltage-gated K+ channels
gradient to predict the movement of Na+ ions. Embedded in the cell membranes are
The positively charged sodium ions are drawn other voltage-gated channels that are selective
to the negative potential on the inside of the for K+ rather than Na+. Like the voltage-gated Na+
cell, and the ions move from the area of high channels, these K+ channels begin to open when
concentration (outside the cell) to an area of lower the cell starts to depolarize, allowing K+ ions to
concentration (inside the cell). Both forces are in move across the cell membrane.
favor of Na+ entering the cell when the voltage- When the cell has depolarized to about
gated sodium channels open, and this movement +40 mV, we can use our knowledge of the
of positive charges into the cell causes further electrochemical gradient to make predictions
depolarization. about what happens to K+ ions. The positive
+ +
Closed state Open state Inactivated state

Resting membrane potential Small depolarization Large depolarization
Very low conductance High conductance No conductance
Figure 4.16 Voltage-gated Na+ channels have a molecular structure that allows the channel to
temporarily change structure in response to membrane voltage. A small depolarization to -50 mV causes
the channels to open, while a large depolarization above -30 mV causes the channels to inactivate,
blocking further sodium currents.
4-13
potential inside the neuron repels the K+ ions
(electrical gradient), and the relatively high Clinical connection: Chronic pain
concentration of K+ inside the cell pushes K+ Nociception is a complex sensation that
out of the cell (chemical gradient). In total, the nervous system detects rapidly. Pain is the
both of these forces act on the K+ ions to perception that the body is experiencing some
leave the neuron. Movement of positive kind of injury or noxious stimulus, so pain triggers
charge carriers out of the cell makes the a reflex that causes the person to withdraw from
interior of the cell (and Vm) more negative. the painful stimulus, which decreases the severity
K+ movement through the voltage-gated of the damage. Pain can also create memories
potassium channels causes the cells to that discourage people from future contact with
become more negative than the resting pain-inducing situations.
membrane potential. When we experience a noxious stimulus,
that information is sent towards the central
4. Inactivation of voltage- nervous system by means of action potentials.
gated Na+ channels And in most cases, the detection of pain is a
Voltage-gated Na channels have
+
healthy, protective sensation.
a very complex molecular structure. In There are, however, some people with a
addition to having a pore through which dysregulation in their somatosensory systems
ions can move across the cell membrane, that cause them to experience pain even in the
they have an inactivation gate that can absence of injurious stimuli, a condition called
block the flow of sodium ions. When the cell allodynia. Although we still don’t understand what
membrane reaches a positive potential, the causes allodynia, it is known that some change in
inactivation gate closes, thus preventing voltage-gated sodium channel properties causes
further movement of excitatory, depolarizing an increase of excitability of pain-sensing neurons
Na+ ions. is increased.
These voltage-gated Na+ channels
undergo the inactivation process very
rapidly, often times faster than a millisecond. milliseconds to deactivate.
When these K+ channels deactivate, the
5. Deactivation of voltage-gated hyperpolarizing current stops, which causes the
K+ channels membrane potential to gradually return to the
In this last step of the action potential, theequilibrium of resting potential.
main current flow is an outward current as the
positively-charged K+ ions are driven out of the In summary, you can also think of the
cell through voltage-gated K channels by the
+
shape of the action potential as consisting of
electrochemical gradient. When positive charges three phases.
leave the cell, the interior once again becomes 1. Depolarization. The upwards deflection
more negative. (-70 mV to +40mV) of the action potential that
Unlike the voltage-gated Na channels,
+
lasts for half a millisecond. Vm becomes more
the process of deactivation is much slower. positive because of Na+ ions that enter the cell
On average, it may take these channels a few through the voltage-gated sodium channels. At
4-14
Depolarization Repolarization Afterhyperpolarization
0 mV
-50 mV
-70 mV
Voltage-gated
Na+ channels
Closed Open Inactivated Closed
Voltage-gated
K+ channels
Closed Opening Open Deactivating
Figure 4.17 Voltage-gated ion channels open, inactivate, and deactivate at different times during the
action potential.
this step, the voltage-gated potassium channels 3. Afterhyperpolarization. The slow

also start to open. return back to the resting membrane potential
2. Repolarization. The rapid downwards (-70 mV to -80 mV and back to -70 mV ) that can
deflection (+40 mV to -70 mV), also lasting for last for a few milliseconds. This return back to
about half a millisecond. Here, the voltage-gated the equilibrium of the resting state is due to the
sodium channels have almost all inactivated, and gradual deactivation of voltage-gated potassium
positively-charged K+ ions are being driven out channels.
of the cell through the voltage-gated potassium Ions moving across the membrane
channels. As positive charges leave the cell, Vm change the membrane potential. The best way
becomes more negative. to think about the change in Vm in response to
4-15
able to move across the cell membrane, the
Randomness in ion channel properties membrane potential shifts towards ENa, which
Voltage-gated ion channels do not follow is a depolarization. During the repolarization
a precise “if-then” flowchart in determining when phase, when the voltage-gated K+ channels
to open, inactivate, or deactivate. Rather, ion open, the potential across the cell membrane
channels are very probabilistic in nature. For now shifts towards the equilibrium potential for
example, consider as a voltage-gated sodium K+, which is close to -80 mV.
channel changes from the closed state to the The steps of the action potential can
open state. A single channel like this might show also be thought of in mathematical terms by
probabilistic behavior as follows: at -70 mV, there examining the variables of the GHK equation.
is a 0.1% chance to open. At -30 mV, there is now a As permeability for a given ion increases, it
50% chance to open. At +20 mV, there is a 99.9% shifts the balance of Vm more heavily towards
chance to transition to the open configuration. the equilibrium potential of that specific ion. So,
Likewise, these channels also transition during the depolarization phase of the action
from the open state to the inactive state on a potential when the voltage-gated sodium
probabilistic basis as well, with the greatest channels open, the permeability term for
probability of inactivating at depolarized sodium (pNa) increases to as high as 20, which
potentials. causes Vm to move towards ENa (+55 mV).
100% And during the repolarization phase, voltage-
gated potassium channels open, while the
80% voltage-gated sodium channels are inactived.
Probability of opening
When this happens, pK increases, pNa drops to

zero, and as a result, the Vm shifts towards the
60%
equilibrium potential for potassium (-80 mV).
In the moments following the beginning
40%
of an action potential, there is a time window
where a second action potential cannot be
20%
fired. This time window, about half a millisecond
in duration, is called the absolute refractory
0%
period. On a molecular level, the absolute
-100 -80 -60 -40 -20 0 20
refractory period exists because the voltage-
Membrane Potential (mV)
gated sodium channels are inactivated,
Figure 4.18 Opening of voltage-gated ion which prevents them from being able to pass
channels is probabilistic, with a greater likelihood any more inward excitatory current. The
of opening at depolarized potentials. absolute refractory period may last for up to a
millisecond.
ion movement is to consider the equilibrium A few milliseconds after the end of the
potential of each individual ion that is moving. absolute refractory period begins a phase called
For example, ENa is +55 mV. When a voltage- the relative refractory period. During this
gated sodium channel opens and Na ions are
+
phase, it is more difficult to fire an action potential
4-16
compared to the resting condition. At the level of
the receptors, the relative refractory period exists
for two main reasons. First, only some of the
voltage-gated sodium channels have “reset” from
their inactive state. Second, many of the voltage-
gated potassium channels are still in the open
state, which allows the movement of K+ ions,
causing the neuron to rest at a more negative
potential. Also, increased movement of K+ ions
hinders depolarization, as the GHK equation
demonstrates, since potassium movement
pulls membrane potential closer towards the
equilibrium potential for K+. This relative refractory
period lasts as long as the afterhyperpolarization,
and therefore exists on a gradient: the sooner
after the repolarization phase of the first action
potential, the more difficult it will be to reach
threshold for a second action potential.
4-17
4.5 Movement of the action potential
Up to this point, we have only considered is the next section of membrane. When they do
a single piece of cell membrane and how it so, the next patch of the membrane becomes
responds during an action potential. For an depolarized. This depolarization causes the next
action potential to travel from the axon hillock set of channels to open, which results in even
to the axon terminal, this temporary change in more sodium influx. From here, the process
Vm must physically move down the length of the repeats down the axon. The action potential is a
axon. The ability for the action potential to travel chain reaction that starts at the axon hillock and
is made possible because the Na+ ions that enter doesn’t stop until the axon terminal.
through voltage-gated sodium channels are not An action potential is like a wave. It only
restricted to the cytoplasmic volume beneath moves in one direction, and there are two main
the ion channels. These Na+ ions behave just reasons why:
like any other substances that are in an area of 1. First, sodium ions move down their
high concentration: they move towards areas of concentration gradient. The Na+ ions that enter
low concentration. As Na+ rushes into the cell, through a voltage-gated sodium channel are less
they follow the chemical gradient and quickly likely to want to move in the reverse direction,
move toward areas of low concentration, which since this area currently has a relatively high Na+
Voltage-gated Na Voltage-gated Na
channels open channels closed
Na+
Na+
Na+
Node of Ranvier
Schwann cell
Axon hillock
Synapse
Saltatory conduction
Figure 4.19 Movement of an action potential down a myelinated axon relies on saltatory conduction.
4-18
Analgesia and motor signaling
A trip to the dental office sometimes
requires an injection of an analgesic like
lidocaine before the dentist performs any
otherwise-painful procedures. On a molecular
scale, lidocaine is an inhibitor of voltage-gated
sodium channels. By blocking these channels,
lidocaine prevents action potentials from
traveling up the afferent pathway, preventing
incoming sensory inputs from the teeth and
gums from reaching the central nervous system.
When these signals are blocked, we don’t feel
any drilling.
Just as incoming signals can be inhibited
through voltage-gated sodium channel
inhibitors, so can outbound signals – sometimes Figure 4.20 Pufferfish and other species likely
with deadly consequences. Through evolution, evolved a symbiotic relationship with bacteria that
nature came across a variety of voltage-gated produce the deadly TTX to prevent predation.
sodium channel inhibitors that function as
poisons to prevent predation. Because the efferent pathway is used to signal components of the
motor system, blocking downward signals can lead to paralysis. One family of fishes, the pufferfish,
may have a very high concentration of a deadly voltage-gated sodium channel inhibitor called
tetrodotoxin, or TTX. This toxin is produced by a bacteria that live symbiotically in pufferfish
organs. Ingestion of TTX prevents neurons from communicating. One efferent signaling pathway,
the phrenic nerve, signals the diaphragm to move up and down. Without proper medical treatment,
people exposed to doses as small as 1 milligram of TTX can die of respiratory failure in hours.
Despite these tremendous risks, pufferfish is a delicacy in Japan. The dish, called fugu, can
cause numbness of the lips and even a mild intoxication.
concentration. Instead, they will move towards The role of myelin

the area with a low concentration of ions, which Previously, in discussing the cellular
is the forward direction. anatomy of the neurons, we described myelin,
2. Secondly, the previous patch of layers of lipid that are sometimes thickly wrapped
membrane is in the absolute refractory period, around the axon of the neuron. Myelin increases
which makes it impossible for an action potential to conduction velocity, the speed at which an
travel backwards. During this time, many voltage- action potential travels down the length of the
gated sodium channels are still inactivated, and axon. Myelin works by physically blocking leak
most voltage-gated potassium channels are potassium channels in the cell membrane.
open. By covering these channels, positive charges
4-19
become unable to exit the cell, which causes the
signal to move more rapidly.
A myelinated axon still requires some
influx of sodium ions for the signal to travel,
however. This influx occurs at the nodes of
Ranvier, the unmyelinated segments of the
axon. These areas are very dense with voltage-
gated sodium channels. Because the changes
in electrical charge are detected at intervals,
we sometimes say that the signal is passed by
saltatory conduction (saltare is the Italian word
for “jump”).
In this chapter, we described the molecular
and cellular underpinnings of the action potential,
the main method of signaling that the nervous
system uses for communication. In the following
chapter, we will explain how neurons talk to
one another using those electrical signals
in combination with chemical signals called
neurotransmitters.
DePaul University.
4-20
Title page: Image by pasja1000 from Pixabay, Image by TeroVesalainen from Pixabay
4.4. OpenStax / CC BY (https://creativecommons.org/licenses/by/4.0) https://commons.wikimedia.org/
wiki/File:Openstax_college-physics_22.5_magnet-pole-attraction.jpg
4.5 (diffusion fig BruceBlaus [CC BY 3.0 (https://creativecommons.org/licenses/by/3.0)]
4.18 Correa AM, Bezanilla F. Gating of the squid sodium channel at positive potentials: II. Single channels
reveal two open states. Biophys J. 1994 Jun;66(6):1864-78. doi: 10.1016/S0006-3495(94)80980-4.
PMID: 8075324; PMCID: PMC1275912.
4.19 https://commons.wikimedia.org/wiki/File:Propagation_of_action_potential_along_myelinated_
nerve_fiber_en.svg modified by Austin Lim
4.20 https://upload.wikimedia.org/wikipedia/commons/4/4e/Pufferfish_%28Butete%29.jpg
4-21
Editor: Monica Javidnia, PhD (University of Rochester)
Previously, we described the electrical differences between synapses.

properties of a single neuron. A lone neuron A lone neuron can send action potentials
can send action potentials as a means of as a means of communication, but cells become
communication, but cells become much more much more interesting when they have partners to
interesting when they have partners to talk to. talk to. The nervous system of the worm C. elegans
The nervous system of the worm C. elegans is is only 300 neurons, and yet it is complex enough
only 300 neurons, and yet it is complex enough to engage in moderately intricate behaviors like
to engage in moderately intricate behaviors like responding to repellant or attractant odors, social
responding to repellant or attractant odors, social feeding, and long-term learning. The human brain,
feeding, and long-term learning. The human brain, with its 86 billion neurons, can engage in these
with its 86 billion neurons, can engage in these behaviors and so many more - only because of
behaviors and so many more - only because of communication between the different neurons in
communication between the different neurons in the brain.
the brain. In this chapter, we will focus on the
In this chapter, we will focus on the molecular-level features of communication
molecular-level features of communication between neurons, starting from the anatomical
between neurons, starting from the anatomical differences between synapses.
Chapter 5 outline
5.1 Electrical vs. chemical synapses

5.2 Properties of vesicles
5.3 Receptors
5.1 Electrical vs. chemical synapses
The synapse is not a part of the structure Electrical synapses

of a neuron, but rather the site of close proximity Electrical synapses are the simpler of
between two communicating neurons. There the two types of synapses. In an electrical
are two main types of synapses: electrical and synapse, the main driver of communication
chemical. between two neurons is a change in potential,
and the carrier of charge is almost always an
5-2
Connexon
Connexin monomer
Cell membrane
Extracellular space
Channel
Figure 5.1 An electrical synapse exists between two closely-connected neurons. Cytoplasm passes
between the two neurons through a protein complex called a connexon.
ion. The electrical synapse simply means that interact closely with each other and form the gap
the cells share their cytoplasm with an adjacent junction, which is the structure that connects
cell. Electrical synapses are what Camillo Golgi neurons electrically.
imagined when he proposed the reticular theory Neurons that are connected by electrical
of nervous system organization. Oftentimes an synapses are remarkably close to each other.
entire network of many hundreds of neurons is The synaptic gap between the two electrically
connected by these synapses. connected neurons is about 3.5 nanometers.
Imagine two neurons that are connected by Logically, the neurons must be close since the
an electrical synapse. First of all, both of them are hemichannels are like a physical “bridge” between
complete cells on their own. Each one contains the two cells.
a complete plasma membrane surrounding
the neuron, a nucleus, and all the individual
organelles needed to carry out that cell’s basic
life processes. Electrical synapses share the
cytoplasm between the two connected cells, so
ions, ATP, and larger signaling molecules and
proteins are able to move between the two cells.
For this to happen, there exists a specialized
physical channel between the two that allows for
the passage of cytoplasm called a connexon
or hemichannel. Each hemichannel itself is
made up of six transmembrane proteins called
connexins (you can remember the difference
Figure 5.2 Electrical synapses are similar to a
between the channel and the individual protein
skybridge that physically connects the cytoplasm
because proteins often end with the letters -in).
between two neurons.
When two connexons contact each other, they
5-3
Electrical synapses are capable of
passing information bidirectionally. This means Clinical connection
that a signal does not always move sequentially Charcot-Marie-Tooth (CMT) disease
from the presynaptic cell to the postsynaptic Charcot-Marie-Tooth (CMT) disease is a rare
cell. Rather, ions and signaling molecules are genetic disorder that damages parts of the
free to move through the connexons in either peripheral nervous system including the motor
direction. Also, each cell within an electrically- nerves, resulting in muscle weakness and
coupled network can receive inputs at any difficulty with walking, and the sensory nerves,
of the cells, making it able to detect several causing some to experience abnormal sensations
signals at once - the same way a huge satellite such as tingling or pain in their extremities.
dish can detect more signals than a small dish. These symptoms are characteristic of signal
Electrical synapses likely evolved transduction failure resulting from deficits in
because of evolutionary pressures that myelin. One type of connexin protein, called
selected for speed. These synapses can pass Cx32, is heavily expressed in Schwann cells, the
signals as fast as electrical charges can move glia that produce myelin in the PNS. Mutations in
through an electrolyte-rich fluid like cytoplasm, the gene that codes for Cx32 are associated with
which is almost instantaneous. Therefore, an the X-linked form of CMT disease, and knocking-
escape reflex that is made up of communication out the gene in experimental mice cause the mice
across electrical synapses is advantageous to express similar symptoms as human CMT.
for animals that need to escape predators. For
example, crayfish exhibit a reflexive abdominal
flexion response when exposed to threatening
stimuli, causing the animal’s body to dart away
from a threat within a fraction of a millisecond.
Comparing across the phylogenetic tree,
electrical synapses are often found in less
complex organisms, including arthropods
such as insects and crustaceans, where such
reflexes are likely more critical for survival. Figure 5.3 People with CMT disease often have
Another advantage of electrical abnormally shaped feet.
synapses is that they can form a large network
of interconnected neurons with synchronized
activity. For example, neuroendocrine cells in connecting inhibitory interneurons allows the
the hypothalamus are connected by electrical network to send an immediate “shut-down” signal
synapses. When the “go” signal arrives, all under specific circumstances.
the cells depolarize at once, which can result
in the massive release of hormones into the Chemical synapses
bloodstream. A network can also cause sudden, At a chemical synapse, a signaling
powerful inhibition. Like an angry mob of people molecule is released by the presynaptic cell to
chanting, a network of electrical synapses influence the postsynaptic cell. These signaling
5-4
Presynaptic Motor
neuron neuron
Synaptic
vesicle Synaptic
vesicle
Muscle Receptor
Chemical
synapse
Receptor
Postsynaptic
neuron
Figure 5.4 Chemical synapses are the site of close interaction between two neurons (left) or a motor
neuron and a muscle fiber, which is called the neuromuscular junction (right).
molecules, generally called neurotransmitters, Because of the complexity of the signals

are synthesized or stored by neurons. After that chemical synapses can convey, evolutionary
being released, these neurotransmitters diffuse development through time has allowed for a
randomly across the synapse, where they are tremendous variety of responses. Chemical
able to affect nearby neurons once the chemical synapses allow for fine-tuning of neural networks,
binds to its corresponding receptor. giving these nervous systems a larger range of
Since chemical synapses do not rely on a possibilities. The nervous systems of “higher”
direct physical protein “tunnel” to connect the two organisms like humans tend to have several
neurons, the distance between the two cells can chemical synapses since these signals are likely
be much larger. On average, a chemical synapse necessary for complex behaviors and cognition.
is a distance of about 20-40 nanometers, roughly Many chemical synapses exist between
a thousand times smaller than the diameter of a the axon of one neuron and the dendrite of
human hair. another neuron. One specific type of chemical
A chemical synapse can pass a variety synapse refers to the space between a motor
of signals, depending on the neurotransmitter neuron and muscle tissue, and this is called the
and the receptor. For example, some signals neuromuscular junction, or NMJ. When the
are directly excitatory and allow positively chemical signaling molecule acetylcholine (ACh)
charged cations to enter the neuron causing is released by the presynaptic motor neuron, it is
depolarization. Other signals are hyperpolarizing, detected by receptors that are expressed on the
and therefore inhibitory. And yet other signals are muscle. The release of ACh causes contraction
much more complex, inducing changes in protein of the muscle.
expression that can modify cellular excitability
over the course of minutes or hours.
5-5
5.2 Properties of vesicles
Types of vesicles
Molecules of neurotransmitters are often Electron microscopy
stored in synaptic vesicles before being released. Electron microscopy is a technique
Synaptic vesicles are tiny spheres of lipids just that allows for the imaging of subcellular
like the cell membrane. These vesicles can be structures that are on the order of
roughly characterized into one of two classes: nanometers, such as synapses, small
vesicles, and large dense core vesicles.
1. Small vesicles. These vesicles have a diameter
of 40 nanometers and a volume of about 30 cubic
microns. Given the size of neurotransmitters,
we can estimate at somewhere on the order of
thousands to tens of thousands of molecules of
neurotransmitter can be stored in each vesicle.
Small vesicles store most of the neurotransmitters
we most often think of, including glutamate, GABA,
dopamine, and norepinephrine, for example.
Small vesicles are almost always exclusive found
in the axon terminals.
2. Large dense-core vesicles. These vesicles Fig 5.5 Electron microscope image
are much larger than small vesicles, with a range showing small vesicles (cyan) and large
of diameter from 100 to 250 nanometers. They dense core vesicles (magenta).
store peptides such as dynorphin or enkephalin,
which have chemical structures much larger than membranes, with one side facing the intracellular
the other neurotransmitters. Since these peptides space and other facing the inside of the vesicle.
are packaged into their vesicles near the nucleus, Their main function is to take molecules of
large dense-core vesicles can be found in the cell neurotransmitter from the intracellular space of
bodies and all along the axons in addition to the the axon terminal and pump them into vesicles.
axon terminal. Many of the vesicular transporters are
named based on the neurotransmitters that they
Loading of vesicles are capable of recognizing and transporting.
Vesicles need to be filled with molecules of Some have a single substrate, such as vesicular
neurotransmitter before release into the synapse. GABA transporters (VGAT) which move GABA,
In small vesicles, filling is only made possible vesicular glutamate transporters (VGluT) which
through the action of giant transmembrane move glutamate, and vesicular acetylcholine
proteins called vesicular transporters. These transporter (VAChT) which moves acetylcholine
are protein complexes that span the vesicular into vesicles. Others recognize a broad class
5-6
of neurotransmitters, such as the vesicular an area of high concentration to low concentration,
monoamine transporters (VMATs), which are energy is generated. The vesicular transporters use
responsible for moving monoamines such as this energy to push neurotransmitter in. Because
dopamine and serotonin into the vesicles. H+ ions move opposite of the neurotransmitter
Vesicular transporters are able to function molecules, vesicular transporters are called
because the interior of the vesicle is highly acidic antiporters. Transporters have slightly different
compared to the interior of the cell. Vesicles stoichiometries, as it requires two protons to
have a high concentration of H+ ions (protons) move a single molecule of dopamine, while
because of the action of the transmembrane the energy from a single proton is sufficient to
enzyme vesicular ATP-ase, or v-ATP-ase. transport GABA or glutamate.
These membrane-embedded proteins utilize the
molecular energy contained in ATP to concentrate Location of vesicles
H+ ions in the intravesicular space. For each Synaptic vesicles can be found in one of
molecule of ATP used, one proton gets pumped three places at the axon terminal.
into the vesicle.
Vesicular transporters pump molecules 1. Readily releasable pool (RRP). These
of neurotransmitter against their concentration vesicles are located close to the cell membrane
gradients, which is an energetically difficult task. at the axon terminal. In fact, many of them are
To have enough energy, the vesicular transporters already “docked,” meaning that their coat proteins
use the high intravesicular concentration of H+ to are already interacting closely with the proteins
move molecules of neurotransmitter across the on the inside of the cell membrane. When the
vesicular membrane. When a proton moves from depolarizing charge of an action potential reaches
Fig 5.6 Synaptic vesicles in the axon terminal get filled by the action of two different vesicular transporter
proteins. The v-ATP-ase uses energy to pump H+ into the vesicle against it’s concentration gradient
(left). Then, a vesicular transporter such as vGluT use the movement of H+ down it’s concentration
gradient to increase intravesicular concentration of neurotransmitter (right).
Axon Terminal
Synaptic vesicle
Glu
H+ H+
ATP ADP
5-7
the terminal, these vesicles at the RRP are the Release of vesicles
first ones that fuse with the cell membrane and At a chemical synapse, the process of
release their contents. neurotransmitter release is very tightly regulated.
If there were no mechanisms to control the release
2. Recycling pool. These vesicles are of chemicals at the synapse, nerve cells would
the ones that have been depleted due to release. deplete their entire stock of neurotransmitter. The
They are currently in the process of being refilled signals that trigger muscle contraction at the NMJ
or reloaded with neurotransmitter. They are would cause constant muscle tension. All sorts of
farther from the cell membrane, and the protein brain signals would be active, and over-excitation
machinery is not primed for release, so it requires would cause toxicity. Needless to say, regulated
a more intense stimulation to release the contents control of neurotransmitter release is a normal
of these vesicles. and essential part of nervous system function.
Regulation of release depends on several
3. Reserve pool. These vesicles are the proteins that are important parts of the process.
farthest from the surface of the cell membrane, These proteins are often embedded within cell
and most vesicles are held in this reserve pool. membranes of the vesicles or the neuronal
For these neurons to be released, very intense membrane.
stimulation is required. Reserve pool vesicles
may not even be recruited for release under 1. V-SNAREs are the proteins expressed
physiological conditions. on vesicles (v for vesicle). Synaptobrevin
and synaptotagmin are two specific
Fig 5.7 Axon terminals contain hundreds of vesicles roughly
v-SNARE proteins that are involved
divided into three categories.
during synaptic release.
Axon Terminal
2. T-SNAREs are proteins
Reserve pool expressed on the cytoplasmic side of
the axon terminal. The inside of the
cytoplasm is the “target” for the vesicle
Recycling pool
(The t in t-SNARE). Syntaxin and
Readily releasable synaptosomal nerve-associated protein
pool (RRP) 25, or SNAP-25 for short, are t-SNAREs
that function during vesicular fusion.
Fig 5.8 v-SNARE proteins interact with t-SNARE proteins to allow for vesicular fusion and release of
neurotransmitter.
Synaptotagmin
Syntaxin
SNAP-25
5-8
Clinical connection: Botulism Healthy NMJ
Botulism is a deadly condition that Vesicle
results from exposure to the spores produced Acetylcholine
by the bacteria Clostridium botulinum. Toxic
spores can be found in the soil, contaminated Synaptobrevin
foods, or water. The toxin itself is one of the Synaptotagmin
most potent agents known to man - exposure
to concentrations as low as 2ng/kg is lethal.
The most common symptoms include muscle SNAP-25
weakness or paralysis, especially the muscles Botulinum toxin-exposed NMJ
of the face or the limbs. For about 5% of
people who develop botulism, death results
from paralysis due to respiratory failure.
Botulinum toxin is known to selectively
cleave the proteins that comprise the SNARE
Botulinum toxin
complex. There are a few specific types
of botulinum toxin with slightly different Fig 5.9 Botulinum toxin selectively cleaves
intracellular targets, but the result is the same vesicular fusion proteins, preventing
on the molecular level: prevention of vesicular acetylcholine from being released at the NMJ.
fusion eliminating neurotransmitter signals.
Despite being one of the deadliest by paralyzing the muscles. Botulinum toxin is
toxins so far identified, millions of people also used medically for conditions resulting
pay to have a preparation of toxin called from excessive neurotransmitter release, such
“Botox” injected into their face. For most, the as muscle spasms, excessive sweating, or
injection of botox is a cosmetic procedure migraine.
that can reduce the appearance of wrinkles
Fusing of vesicles capable of detecting elevated levels of Ca2+ in the

The last step of neurotransmitter release axon terminal. As it turns out, an elevation of Ca2+
is the fusing of the cell membrane. In order to in the intracellular space is the “go ahead” signal
release their chemical contents into the synapse, that causes neurotransmitter release.
vesicles need to fuse with the cell membrane. As The concentration of intracellular calcium,
the vesicular membrane merges with the interior generally in the range of 100 nM, is much lower
of the neuronal membrane, the contents of the than the concentration outside the cell. Embedded
vesicle become exposed to the extracellular in the cell membrane of the axon terminals
space. Only then are the neurotransmitters are transmembrane proteins called “voltage-
capable of activating receptors. gated calcium channels” or VGCCs. As their
One of the key proteins required for name suggests, they function very similarly to
vesicular fusion is the vesicle-embedded the voltage-gated sodium channels described
V-SNARE synaptotagmin. This protein is in previous chapters: they are large protein
5-9
complexes that normally remain closed, but when tighter together, it causes the vesicle membrane
the surrounding neuronal membrane becomes to approach the inside of the cell membrane,
depolarized, they physically change conformation which results in vesicular fusion.
and open up, allowing ions to move across the Vesicles are capable of fusing in at least
cell membrane. These VGCCs selectively pass two different ways.
only Ca2+ ions. The electrochemical gradient 1. Full fusion. A vesicle that undergoes
causes these Ca2+ ions to enter into the cell. full fusion experiences total exocytosis. The
As the change in membrane potential vesicular membrane becomes completely
travels down the length of the axon (the action integrated with the cellular membrane, and all of
potential), it causes a depolarization at the the neurotransmitter spills into the synapse.
terminal, triggering calcium entry via the VGCCs. 2. Kiss-and-run. This method of
Ca2+ at the terminal binds with synaptotagmin. neurotransmitter release is incomplete fusion.
The v-SNAREs and the t-SNAREs interact with The vesicle only partly connects with the interior
one another in the presence of Ca2+, forming a surface of the cell membrane, and only a limited
molecular structure called a SNARE complex. number of neurotransmitter molecules are able to
The SNARE complex looks a lot like two twist enter the synapse via diffusion.
ties that are wound tightly together. As they twist
Fig 5.10 Synaptic vesicles either fuse completely (left) or partially in kiss-and-run (right).
Full fusion Kiss-and-run
5-10
5.3 Receptors
Receptors are proteins that are capable Receptors are classified into one of two
of sending a signal to change the function or main categories.
activity of a neuron. Most receptors that function 1. Ionotropic receptors. Physically,
in neurotransmission are large transmembrane ionotropic receptors are transmembrane proteins
proteins. On the extracellular surface is a with a large-diameter pore through which ions
specific series of amino acid residues called can pass. These channels only open when a
the active site. The active site, also called the molecule of chemical binds to the active site on the
orthosteric site, is shaped to allow molecules of extracellular side of the protein. These chemicals
neurotransmitter to bind to the receptor. are also called ligands, and so ionotropic
receptors are also called ligand-gated
Fig 5.11 Ionotropic receptors (top) allow ion ion channels. Once a neurotransmitter
movement after receptor binding, while metabotropic activates the ionotropic receptor, ions will
receptors (bottom) trigger second messengers to move based on the electrochemical gradient
induce signaling. for that ion. As a result of ion movement, the
cell’s membrane potential will change. For
Neurotransmitter
Neurotransmitter released from synapse example, nicotinic acetylcholine receptors
bound to receptor are ligand-gated sodium channels, so when
these receptors are activated by a ligand
Ion like acetylcholine, sodium ions enter into the
cell causing depolarization and excitation.
Ionotropic receptors are able to
induce a change in membrane potential
very rapidly, on the scale of milliseconds.
Due to the nature of the amino acid
residues that make up the pore of ionotropic
receptors, they can be very selective for
certain ions. For example, negatively
charged residues lining the inside of the
pore repel negatively charged Cl- ions while
allowing positively charged cations to pass
through the channel.
2. Metabotropic receptors. These
receptor complexes cause the cell to
change its metabolism in a way that leads
to either excitation or inhibition. Ions do
Second not pass through these receptors. Instead,
G protein
messenger metabotropic receptors use the actions of G
proteins, proteins which induce changes in
5-11
neuronal excitability through the action of second inner surface of the cell membrane. Functionally
messenger signaling molecules. speaking, these G proteins are capable of binding
Physically, metabotropic receptors are to molecules of guanosine triphosphate (GTP)
transmembrane proteins that contain 7 alpha- or guanosine diphosphate (GDP). Chemically
helix motifs that pass through the cell membrane. similar to ATP, GTP can function as a source of
The N-terminus of the protein is extracellular, and energy. G proteins themselves exhibit catalytic
the protein “weaves” back and forth across the activity of GTP. This means that they are capable of
cell membrane, resulting in a protein with three breaking down GTP into the less-energetic GDP.
extracellular loops and three intracellular loops. When GTP is bound to the GPCR, the receptor
Because of this shape, these receptors are also is active. When this molecule is hydrolyzed into
called seven-transmembrane receptors, or GDP, the receptor becomes inactive.
7-TM receptors. Some G proteins are heterotrimeric,
Another name for these receptors is meaning that they are made up of three different
“G protein-coupled receptors”, or GPCRs. subunits, alpha, beta, and gamma. The GTP
Metabotropic receptors are physically linked to binding sites and catalytic sites are found on the
proteins called G proteins, which exist on the alpha subunit, the largest of the three subunits.
Fig 5.12 GPCRs signal via activation of the G protein attached to the intracellular side of the receptor.
5-12
Usually, the alpha subunit becomes soluble after PKA is a kinase, an enzyme that is
activation, while the beta / gamma complex stays phosphorylates other proteins. The addition of
embedded in the neuronal membrane. The G a phosphate group onto a protein changes its
alpha subunit exists in different varieties. properties dramatically. PKA phosphorylates
protein targets that increase cell excitation.
Gαs. When a neurotransmitter activates a For example, one target of PKA activity is the
GPCR coupled with the Gαs protein, the Gαs protein intracellular side of certain glutamate receptors.
is excitatory (The “s” stands for stimulatory). Phosphorylation causes these receptors to stay
Binding of a ligand to the active site of open longer than normal when they are activated
Galphas-coupled GPCRs results in increased by a molecule of glutamate. This means that
activity of the enzyme adenylate cyclase (AC). a single molecule of glutamate causes more
AC itself is an enzyme that creates a second excitation (passes more depolarizing current into
messenger, a molecule called cyclic AMP the cell) in the presence of increased PKA activity.
(cAMP). Elevated levels of cAMP activate an Targets of PKA activity also include the
enzyme called protein kinase A (PKA). intracellular store of glutamate receptors. When
phosphorylated, these receptors are trafficked to
Fig 5.13 GPCRs that are coupled with Gαs are the neuronal membrane. An increase of receptors
excitatory through adenylate cyclase signaling. at the postsynaptic side leads to increased
excitatory neurotransmission over a period of
G protein coupled minutes and hours, representing one form of
receptor Glutamate receptor
plasticity.
An even longer-term action of PKA is
its ability to change the transcription of various
genes, which can trigger the synthesis of
Adenylate cyclase
proteins. Some genes downstream of PKA activity
include the structural protein actin, important for
cAMP morphological changes in neuronal structure, or
ion channels which change neuronal responses
to neurotransmitter release.
PKA
Gαi. A GPCR that is coupled with Gαi
causes a decrease in excitability. In many ways,
Gαi proteins serve the opposite function as Gαs
proteins - the “i” stands for inhibitory.
Whereas activation of Gαs increases
Target genes the action of AC, Gαi proteins decrease AC
activity. Therefore, Gαi activation decreases
the intracellular concentration of cAMP, in turn
Nucleus decreasing PKA activity. Given the function of PKA
as a kinase that increases cellular excitation as
5-13
described above, decreased PKA activity inhibits potassium channel conductance.
cellular activity through multiple mechanisms, While the alpha subunits carry out a large
some of which include decreased current through part of GPCR-mediated changes in cellular
glutamate receptors, decreased trafficking of excitation, the beta and gamma subunits also
glutamate receptors to the presynaptic neuronal affect excitability. The beta and gamma subunits
membrane, and decreased transcription of certain are bound together as a dimer, but they separate
genes. from the alpha subunit once the GPCR becomes
activated. The beta-gamma complex can also
Gαq. Generally, Gαq is an excitatory G function as a signaling molecule.
protein. Gαq uses a different signaling pathway Compared to ionotropic receptors,
compared to the PKA pathway that is downstream metabotropic receptors affect neuron activity on a
of Gαs or Gαi. Gαq protein activation leads to activity slower time scale, on the range of milliseconds to
of the enzyme phospholipase C (PLC). seconds, and possibly even longer depending on
On a biomolecular level, PLC acts the downstream mechanisms that are activated.
on the phospholipid membrane molecule
phosphatidylinositol 4,5-bisphosphate (PIP2). Presynaptic receptors
PLC is a hydrolytic enzyme, and it breaks PIP2 In the discussion of receptors, it is common
into two separate second messenger molecules: to think of receptors as being expressed at the
the soluble inositol triphosphate (IP3) and the dendrites, embedded within the postsynaptic
membrane-embedded diacylglycerol (DAG). One membrane. However, not all receptors are
of the functions of IP3 is to liberate Ca2+ from located here. Some receptors are presynaptic,
intracellular stores, which elevates intracellular meaning they can be found at the axon terminal.
Ca2+ levels, depolarizing the cell and activating Presynaptic receptors are often inhibitory and
calcium-dependent processes, which are often serve a self-regulatory function. Presynaptically-
excitatory. DAG activates protein kinase C expressed receptors that respond to the same
(PKC), an enzyme with substrates that increase neurotransmitter that is released are called
neurotransmitter release probability or decrease autoreceptors.
Fig 5.14 Gαq signals using PLC, which then produces two signaling molecules, IP3 and DAG.
5-14
As described previously, neurotransmitters Na+ to move into the cell. Ionotropic glutamate
are the substances that are released at chemical receptors are generally subdivided into three
synapses, and they are the signaling molecules classes, named after exogenous chemicals that
that allow neurons to communicate with one can activate the receptor. AMPA receptors are
another. To date, scientists have identified Na+ channels, but some also allow Ca2+ entry.
more than 100 neurotransmitters. Here, we will NMDA receptors allow both Na+ and Ca2+ to pass
describe six classical neurotransmitters, their across the membrane. When the cell is at rest,
receptors, and their actions. Additionally, three NMDA receptors also have a large magnesium
atypical neurotransmitters will be introduced. ion in the pore that blocks ion movement through
One important note to keep in mind as the channel. The third category of ionotropic
you think about neurotransmitters: the effect glutamate receptors is called kainate receptors,
that a neurotransmitter has on a cell depends on which are similar to AMPA receptors.
the receptor. In other words, a neurotransmitter The metabotropic glutamate receptors
molecule can either excite or inhibit a neuron (mGluRs) signal using different G proteins. There
depending on the composition of receptors are a total of 8 of these mGluRs, classified into
that are present. For example, glutamate is three groups, called Group I, Group II, and Group
excitatory at most synapses in the nervous III. Group I are excitatory GPCRs which signal via
system. Glutamate exerts excitation by activating Gq, while Group II and Group III are inhibitory via
ionotropic glutamate receptors, which are the Gi signal transduction pathway.
ligand-gated cation channels. However, at one One theory proposes that excess signaling
particular synapse in the eye, glutamate activates by glutamate can lead to neuronal death, a
a metabotropic glutamate receptor that causes phenomenon called excitotoxicity. Of the
cellular inhibition.
Fig 5.15 Glutamate is the main excitatory
Glutamate neurotransmitter in the nervous system, acting at
Glutamate (Glu) is the main excitatory different categories of receptors, three of which
neurotransmitter used by the nervous system. are shown below.
Glutamate is the same as the amino acid glutamic
Glutamate
acid. There is more glutamate per volume of
brain tissue than any other neurotransmitter.
Glutamatergic neurons are identified by the
AMPA NMDA mGluR
presence of the vesicular glutamate transporter
(vGluT). Mg2+
Glutamate can activate both ionotropic
and metabotropic receptors. Ionotropic glutamate
receptors are all ligand-gated cation channels,
which makes them excitatory since they allow
Na+ Na+ Ca2+
5-15
various glutamate receptors, the NMDA receptor The main action of GABA as an inhibitory
is most strongly implicated in contributing to neurotransmitter is to activate one of three main
excitotoxicity, since uncontrolled elevated classes of receptors, called A, B, and C. GABAA
levels of calcium can be deadly for neurons. receptors are ligand-gated chloride channels,
Excitotoxicity is observed in a variety of disease so activating these ion channels causes Cl- flux,
states ranging from neurodegenerative disorders which opposes the ability for the cell to reach
such as Parkinson’s disease, Alzheimer’s action potential threshold. GABAB and GABAC
disease, and multiple sclerosis, but also in injury receptors are both metabotropic receptors that
such as concussion or stroke. inhibit neuronal activity through the action of the
Gi protein.
GABA + glycine A neurotransmitter that is similar to GABA
Gamma-aminobutyric acid (GABA) is the is glycine. Another small amino acid, glycine is
main inhibitory neurotransmitter in the brain. mostly used by neurons of the spinal cord and
According to one estimate, about 25% of neurons brain stem. Glycine is also inhibitory , and acts at
in the brain are GABA-ergic. Chemically speaking, glycine receptors, which are ligand-gated chloride
GABA is remarkably similar to glutamate. In channels.
fact, GABA is synthesized from glutamate in
a single step by the enzyme glutamic acid Dopamine
decarboxylase (GAD). GAD is often used as a Dopamine (DA) is a biogenic amine
biochemical marker for the presence of GABA- derived from the amino acid tyrosine through
ergic neurons. Many interneurons use GABA as the action of several enzymes. One in particular,
their chemical signaling molecule. tyrosine hydroxylase (TH), is the main marker
that is used for identifying dopamine-producing
Fig 5.16 The inhibitory neurotransmitter GABA is neurons. Unlike glutamate or GABA, dopamine-
synthesized from glutamate by the action of GAD. producing neurons are not widely abundant in
the brain. Instead, there are generally only a few
patches of neurons that produce dopamine, most
of which are found in the midbrain. Two areas
include the ventral tegmental area and the
substantia nigra.
There are five classes of dopamine
receptors, named D1 through D5. All of them are
Glutamatic acid metabotropic receptors. D1 and D5 are generally
decarboxylase (GAD)
excitatory receptors, while D2, D3, and D4 are
inhibitory receptors.
Since Roy Wise’s theory proposed in
the 1960s, DA has been known in pop culture
as the “pleasure neurotransmitter” because of
its involvement in the processing of reward and
motivation. For example, if we use microdialysis
5-16
Frontal in the substantia nigra pars compacta
cortex Striatum
Substantia (SNpc) degenerate, as in Parkinson’s
nigra (SN) disease, a person develops the trademark
symptoms: difficulties with motor control,
resulting in a resting tremor, postural
instability, and bradykinesia (slowness
Nucleus of movement). Reversing the dopamine
accumbens (NAc)
deficiency by introducing an exogenous
Ventral tegmental
source of dopamine is our current gold
area (VTA) Hippocampus
standard of treatment for PD.
Fig 5.17 Brain dopamine is synthesized in two major
midbrain nuclei, the VTA and SN, labeled in green. Serotonin
Serotonin (5-HT) is a
(a technique to measure the concentration of neurotransmitter that is derived from the dietary
chemicals) in the nucleus accumbens, dopamine amino acid tryptophan. The enzyme tryptophan
levels spike in response to all sorts of pleasurable hydroxylase is the first step of serotonin
or rewarding stimuli: food, water, sex, sugar, and biosynthesis and is often used as a marker to
exposure to drugs of abuse. However, we now identify serotonergic neurons. As with dopamine,
know that dopamine is much more complex there are only a few areas of the brain that
than once believed. One theory suggests that synthesize serotonin, the major one being the
dopamine elevation serves as a “learning signal” Raphe nucleus in the brain stem.
that causes us to pay attention to salient stimuli Receptors for serotonin have a wide variety
in the environment. of actions. We have identified seven major families
DA is also needed for normal motor of 5-HT receptors, which are designated by the
control. When dopamine-producing neurons number and subclasses which are designated by
a letter. For example, the 5-HT2A receptor
Fig 5.18 Levels of dopamine in the NAc rise when is metabotropic and excitatory via Gq
animals lever press for delicious foods, denoted in red. signaling, while the 5-HT5 receptor is
inhibitory via Gi signaling. Most of them
400%
are metabotropic receptors; only the
350%
5-HT3 receptor is ionotropic.
300%
Dopamine efflux
Serotonin is heavily implicated

250% in the regulation of mood and complex
200% behavioral conditions. One of our most
effective strategies for treating depression
150%
is the administration of a drug such as
100%
fluoxetine, which acts as a selective-
50%
serotonin reuptake inhibitor (SSRI).
Pharmacologically, fluoxetine increases
Time
5-17
Clinical correlation: Parkinson’s disease (PD) and L-DOPA-induced dyskinesia (LID)
Parkinson’s disease is a debilitating neurodegenerative disorder that affects as many as 1%
of all people aged 60 or older. Generally, PD is lethal within 16 years. By the time a patient presents
to the clinic with motor dysfunction, they have already lost almost 60-80% of dopamine-producing
neurons in this area!
For decades, clinicians have been using the biochemical
precursor to dopamine, L-DOPA, to treat the symptoms.
However, after chronic exposure to L-DOPA, the drug becomes
less effective and has a shorter duration of therapeutic action.
Worse still, frequent treatment can lead patients to develop
hyperkinesias, an abnormal excess of movements. This
iatrogenic disorder is called L-DOPA induced dyskinesia
(LID).
Biomedical engineers have developed a promising non-
drug approach to treating PD called deep brain stimulation.
A small stimulating device is surgically implanted into the
subthalamic nucleus of the brain. When this brain area is
stimulated, neural circuits are recruited which restores normal
motor control.
Aromatic amino acid

decarboxylase (AADC)
L-DOPA Dopamine
Fig 5.19 Patients with PD have characteristic changes in gait as a result of low dopamine (top).
The current best pharmacological therapy is levodopa administration, which is the biochemical
precursor to dopamine (bottom).
synaptic levels of serotonin by preventing Acetylcholine

reuptake, and for some people, this has a moderate Acetylcholine (ACh) is a small
ability to reverse depression. Serotonin signaling molecule that is made by the enzyme choline
is also a target for drugs that treat anxiety, post- acetyltransferase (ChAT), which chemically
traumatic stress disorder, obsessive-compulsive bonds a molecule of acetyl-CoA with a molecule
disorder, schizophrenia, and more. of choline. The presence of ChAT in a neuron is
used as a biochemical marker for neurons that
produce acetylcholine.
5-18
ACh was the first neurotransmitter nicotine in addition to acetylcholine. These
discovered and chemically isolated, a feat which ionotropic receptors are ligand-gated sodium
earned two researchers the shared Nobel Prize channels and are therefore excitatory. On the
in Physiology or Medicine in 1936. One of the two other hand, the metabotropic receptors are called
scientists, a German pharmacologist named Otto muscarinic acetylcholine receptors (mAChRs)
Loewi, stimulated the vagus nerve connected to since they are activated by the chemical
an isolated frog heart, which caused the heart muscarine found in some species of mushrooms.
rate to slow down. When he put the surrounding MAChRs can be coupled with either Gs or Gi, so
solution on top of another heart, he observed they can be either excitatory or inhibitory.
that the second heart also slowed down, despite ACh is the main neurotransmitter that the
having no physical connection to the first heart. nervous system uses in order to communicate
From this, he concluded that a chemical released with the muscles at the neuromuscular junction
by the vagus nerve is able to decrease heart rate. (NMJ). Here, ACh is released by motor neurons,
This chemical was first called Vagusstoff, the where it activates nicotinic acetylcholine receptors
German word meaning Vagus substance. Today, on muscle cells, causing them to constrict, or
we know it as acetylcholine. flex. On the other hand, muscarinic acetylcholine
ACh is able to act at ionotropic and receptors are located in the heart, and their
metabotropic receptors, and activity at both activation causes a decrease in heart rate (as
receptor classes is essential for normal function. Otto Loewi demonstrated with the isolated frog
The ionotropic receptors of the nervous system heart preparation.)
are called nicotinic acetylcholine receptors In the central nervous system, ACh is
(nAChRs) because they can be activated by involved in a wide variety of processes, including
attention and learning. One of the first
Fig 5.20 An electron microscope image of the neuromuscular theories to explain the symptoms of
junction showing vesicles (T, top) forming a synapse with Alzheimer’s disease looked at a loss
the muscle cell (M, bottom). Acetylcholine is the main of ACh-producing neurons in the basal
neurotransmitter used in muscle control at the PNS. forebrain that become more severe
as the disease worsens. It has since
been demonstrated that Alzheimer’s
disease is more complex than this
early hypothesis.
Norepinephrine
Norepinephrine (NE) is a
neurotransmitter that is synthesized
from a molecule of dopamine
by the enzyme dopamine beta-
hydroxylase. Norepinephrine-
producing cells are localized in the
pons of the brain stem, a structure
5-19
called the locus coeruleus. The locus coeruleus beta-agonists are used as bronchodilators for
is very small, but these neurons send projections asthma.
widely throughout the brain. Norepinephrine also functions in
the brain to modulate behaviors including
Fig 5.21 Norepinephrine in the brain is synthesized by alertness and attention.
small populations, but these cell bodies project widely
across several other areas. Atypical neurotransmitters
Although we generally think of
Frontal
Thalamus neurotransmitters as neurochemicals that
lobe
function as described above, there are a
Cingulate gyrus
few atypical neurotransmitters that don’t
quite fit the mold of the other chemical
Hippocampus signals.
Amygdala Neuropeptides
Locus coeruleus Neuropeptides are a class of large
Lateral tegmental signaling molecules that some neurons
NE cell system synthesize. Neuropeptides are different
To spinal cord
from the traditional neurotransmitters because
Outside of the brain, we think of of their chemical size. Monoamines like DA, NE,
norepinephrine as being responsible for triggering or 5-HT have a molecular weight around 150-
the sympathetic nervous system response of the 200, while one of the smaller neuropeptides,
body, the “fight-or-flight” reaction that prepares enkephalin, has a molecular weight of 570. One
the body for physical activity in times of fear or of the largest, dynorphin, has a molecular weight
acute stress. These norepinephrine-producing greater than 2,000. Because of their large size,
nerve cells reside in the sympathetic ganglia, a neuropeptides have to be packaged in dense-
clump of nerve cells that run parallel to the spinal core vesicles very close to the site of production
cord, one on each half of the body. These neurons near the nucleus rather than in clear vesicles right
project out towards the internal organs. at the terminal.
Receptors for NE are classified into
two main categories, alpha or beta. There are
subtypes within each category, giving us five
major receptors for NE: alpha-1, alpha-2, beta-
1, beta-2, and beta-3. All five of these receptors
are metabotropic, and some are excitatory while
others are inhibitory. Our internal organs express Fig 5.22 Enkephalin, one of the smaller
these noradrenergic receptors. Clinically, the neuropeptides, is very large compared to other
“beta blockers” are a class of drugs that inhibit neurotransmitters. Enkephalin is an agonist for
beta-adrenergic receptors; the resulting action is both δ and μ opioid receptors.
a decrease in blood pressure. Conversely, some
5-20
Neuropeptides such as enkephalin and
dynorphin are agonists at a class of receptors Cannabinoid
called the opioid receptors. These opioid receptor
receptors fall into four main types. The three
Presynaptic
classical opioid receptors are named using Greek neuron
letters: δ (delta), μ (mu), and κ (kappa), and the
fourth class is the nociceptin receptor. All of these
receptors are inhibitory metabotropic receptors Neurotransmitter
which signal using the Gαi protein.
These receptors are expressed in several
brain areas, but expression is particularly heavy
Receptors
in the periaqueductal gray, a midbrain area that
functions to inhibit the sensation of pain. Drugs Postsynaptic
neuron
that activate the opioid receptors, like morphine,
Endocannabinoid
oxycontin, or fentanyl, are the most effective
clinical treatments that we know of for acute pain.
Unfortunately, these same drugs also represent Fig 5.23 ECBs are synthesized from the
a tremendous health risk, as opioid drugs can postsynaptic cell membrane and signal through
be lethal in overdose and have a high risk of presynaptic cannabinoid receptors
substance use disorder.
ECBs activate one of two receptors, CB1 and
Endocannabinoids (eCBs) CB2. Both of them are inhibitory metabotropic
The eCBs are a class of lipid- receptors that couple with Galphai. Generally,
based neurotransmitters. They are unusual CB1 receptors are found in the nervous system,
neurochemicals in a few ways. Instead of while the CB2 receptors are found elsewhere in
sending information from the axon of one neuron the body, such as in the immune system.
to the dendrite of the next neuron (anterograde The eCB system is widely used by various
signaling), eCBs allow the postsynaptic dendritic systems in the body. It is estimated that eCB
component to communicate with the presynaptic receptors are the most abundant GPCRs in the
axon terminal. Since they communicate whole body.
information in the “opposite” direction of classic These substances were named because
neurotransmitter signaling, eCBs are called they are endogenous chemicals that are
retrograde signaling molecules. Secondly, eCBs functionally similar to compounds found in plants
are not packaged into vesicles and released by of the genus Cannabis. One reason cannabis is
fusion processes. Instead, eCBs are synthesized used is because of its ability to interact with our
de novo, meaning they get created right when eCB receptors.
they needed and used at that moment. The two
most well-characterized eCBs in humans are Nitric oxide
called 2-AG and AEA. The nervous system is capable of signaling
via the gas nitric oxide (NO). This gasotransmitter
5-21
is not stored in vesicles but rather is synthesized receptor for NO is an intracellular receptor called
as it is needed. NO is formed when the amino soluble guanylate cyclase (sGC). SGC works
acid arginine is degraded by the enzyme NO through a signaling pathway that is different from
synthase (NOS). other metabotropic receptors so far described.
Because NO is a gas, it easily permeates SGC is linked with the signaling molecule cyclic
across cell membranes. Therefore, the receptors GMP (cGMP), which activates protein kinase
for NO do not need to be transmembrane proteins G. PKG can either be excitatory or inhibitory,
expressed on the cell surface. Instead, the depending on the intracellular components.
Chapter summary called receptors. Upon binding a molecule of

Neurons communicate with one another neurotransmitter, these receptors physically
in a variety of ways. Anatomically, neurons are change shape, resulting in ion flow across
separated by a small extracellular gap called the membrane (ionotropic receptors) or a
the synapse. This synapse may directly connect change in the activity of intracellular signaling
the intracellular cytoplasm, as in an electrical molecules (metabotropic receptors). Binding
synapse. Alternatively, the gap may be much of neurotransmitter changes the excitability of
larger, and chemicals that get released and neurons.
diffuse across the synapse in order to signal We have so far identified more than
to the following neuron. These chemicals, the 100 neurotransmitters. Many of them are small
neurotransmitters, are stored in vesicles, tiny molecules that are packaged in vesicles, which
spheres that are located in the presynaptic axon then diffuse from the presynaptic neuron to the
terminal. The release of these chemicals is very postsynaptic neuron, such as acetylcholine,
closely regulated, and neurons have several glutamate, or GABA. However, there are some
mechanisms that regulate vesicular fusion. atypical neurotransmitters such as neuropeptides,
Following release, the neurotransmitters endocannabinoids, and nitric oxide that have
diffuse across the synapse and can bind to different methods of communication.
the active site on transmembrane proteins
DePaul University.
5-22
Cover: Image found at https://www.hippopx.com/en/people-letters-envelope-pen-dip-pen-writings-ink-62437
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5.5 Tao C-L, Liu Y-T, Zhou ZH, Lau P-M and Bi G-Q (2018) Accumulation of Dense Core Vesicles in Hippocampal Synapses
Following Chronic Inactivity. Front. Neuroanat. 12:48. doi: 10.3389/fnana.2018.00048
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Austin Lim
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5.17 https://upload.wikimedia.org/wikipedia/commons/d/de/Dopamine_pathways.svg modified by Austin Lim
5.18 Data from K.N. Segovia, M. Correa, J.D. Salamone, Slow phasic changes in nucleus accumbens dopamine release
during fixed ratio acquisition: a microdialysis study, Neuroscience, Volume 196, 2011, Pages 178-188, ISSN 0306-4522,
https://doi.org/10.1016/j.neuroscience.2011.07.078. Reprinted with permission 2/15/2020
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sketch_1886.svg
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section%29.jpg
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5-23
6-1
Claire Sun (Mount Sinai)
Editor: Katie L. Willis, Ph.D. (University of Oklahoma)
Most of the information you learn in simultaneously.

neuroscience textbooks were discovered by There are three major components that
people who applied the scientific method to can be described for some of the techniques:
systematically answer a research question. 1. A description of how the method
In order to come to their conclusions, these works. Each of these methodological strategies
neuroscientists used a variety of techniques, rely on using the knowledge from other fields of
borrowed from biology, medicine, chemistry, study and applying that knowledge to a question
physics, engineering, psychology, and many other about the nervous system. Knowing how the
academic disciplines. Neuroscience researchers methods work allow us to decide what types of
use the wide range of scientific methodological data can be collected and when each method will
strategies to answer: “How does the nervous be appropriate to use.
system work?” 2. Some of the main advantages of
In this chapter, we will describe a few of the technique. Not every method is applicable
the methods that are used to ask and answer for studying every question. Instead, it would be
questions in neuroscience. These methods can beneficial for neuroscientists to choose the most
be divided roughly into four major categories: appropriate strategy for a particular research
Imaging anatomy, imaging function, imaging cells, question given the circumstances.
and finally manipulating the nervous system. 3. Some shortcomings or limitations of
Within each of these categories, the techniques the technique. As above, no strategy is perfect.
will start with the “big picture” view, and by the Methods that look at the “big picture” aren’t able
end of each section we zoom down to the level of to look at microscopic level detail. There are
molecules and genes. limitations for every technique and being aware
Just a minor caveat about these of these limitations inform us about caveats in
techniques. Many of these strategies can be interpreting data.
used independently, but some may be used Although almost all these techniques can
be used in either humans or non-humans, some
techniques are best adapted for humans and
others for non-humans. Using a technique on a
inappropriate species can lead to poor results. For
example, humans can lay still for tens of minutes
Figure 6.1 Being able to zoom in allows us to see at a time during an imaging scan session, while
small details, but information from the big picture rats or mice will not be able to do this simple
is missing. behavior (without restraint or anesthesia). Before
6-2
About resolution volume. Electron microscopy (described in
Many of the imaging techniques are 6.3.1) offers the highest spatial resolution of
concerned with resolution. Resolution in the imaging techniques.
neuroscience is very similar to resolution in Temporal resolution refers to the
digital photography or computer monitors. A ability to distinguish two events in time
picture taken in high resolution contains more from one another. Temporal resolution is
information than one in low resolution, and can measured in units of time. Functional imaging
therefore be more valuable. Imaging strategies techniques with high temporal resolution, such
consider two different types of resolution, as electrophysiology, can differentiate two
spatial and temporal. signals as close together in the hundreds of
Spatial resolution refers to the ability microseconds range.
to differentiate two points in space from each
other. An imaging method with high spatial Stimulus
resolution means that two signals very close
together can be identified as two different
signals instead of one. Spatial resolution
is usually measured in units of distance or Increasing
Detected temporal
signal resolution
Increasing spatial resolution Time
Figure 6.2 Methods with higher spatial Figure 6.3 Methods with higher temporal
resolution are better for identifying the location resolution are better for precisely detecting
of different parts of the image. Precisely when a signal occurs. With low temporal
identifying the parrot’s beak in the leftmost resolution techniques (top of detected signals),
image (low resolution) is difficult, but is easy in two discrete events spaced apart by time
the rightmost image (high resolution). appear as one event.
getting started with our list of research methods, that leads to the development of therapies that
we should ask ourselves “Is it better to study the prevent, cure, or otherwise improve the quality
question in humans or in non-human animals?” of patient’s lives. And while curing diseases in
non-human animals is the purpose of veterinary
The case for human subjects medicine, curing humans is the primary end goal
The main reason we conduct studies in of biomedical research, and that goal is only truly
humans is to understand the human nervous met by testing on humans. A cure developed for
system. It is knowledge of the human condition rodents might give us a clue about the human
6-3
case, but without seeing how well it works in macaque monkeys. The closer we move towards
humans, the therapy won’t save human lives. the human, the more similarities the model
Humans are great at following directions organism shares with us. Of the commonly used
without much training, unlike non-humans - as model organisms, macaque monkeys are the
anyone who had tried to house train a puppy can non-humans that are most similar to humans.
attest. We can follow simple sets of directions We share 93% of our genetic material with
that untrained non-humans find difficult, such macaques, but we still have different metabolic
as “lie still”. During functional activity scans, we and physiological processes, and our behaviors
can perform extremely complex higher-order
cognitive tasks, such as “imagine that we give
you 20 dollars, and we will take away a dollar Genetic
Model
similarity to
when you answer a question incorrectly” organism
humans
(rats and chimpanzees have no concept of
currency). We can describe our feelings in
C. elegans
writing and self-report on our symptoms,
both of which are tasks that are impossible
in non-humans.
Fruit fly
Believe it or not, recruiting human
(Drosophila
subjects for neuroscience or psychology melanogaster)
studies is usually cheaper than studying that
same question in nonhuman animal models.
Collecting data from undergraduates is Mouse
(Mus musculus)
sometimes free, since many are required
to participate in some number of hours of
psychology studies to pass introductory Rat
(Rattus
level classes. Although the cost per patient norvegicus)
differs depending on the nature of the study,
many patients get paid as little as $10 an
hour. On the other hand, housing colonies of Macaque monkey
mice, rats, or monkeys gets very expensive, (Macaca mulatta) 93%
very quickly.
The case for non-human subjects

Human 99.9%
But, it is often impossible to test
(Homo sapiens)
every question in humans. Instead of always
studying humans, scientists often use non-
human model organisms, the most common Figure 6.4 A short list of animal models that are often
organisms being the worm C. elegans, fruit used in neuroscience research and their genetic
flies (Drosophila melanogaster), zebrafish similarity to humans. Humans are 99.9% genetically
(Danio rerio), song birds, mice, rats, and identical to other humans.
6-4
are much different from theirs. to brain damage (these experiments aren’t
Ethical constraints prevent us from done very frequently in nonhumans anyway.)
performing experiments that may cause physical Invertebrates, such as worms and fruit flies
or psychological harm if performed in humans. are not heavily regulated by ethics oversight
We would never conduct a test on humans to committees, allowing scientists to conduct a
assess what concentration of neurotoxin leads wider set of experiments on these animals.
Experimental preparations These preparations have the opposite

Performing an experiment in an intact, strengths and weaknesses of in vivo
living organism, whether human or nonhuman, preparations. They allow for extremely good
is described as an in vivo (Latin meaning control over variables, but the results are
“within life”) preparation. The main strength less reliable in translating to a therapy. The
of this strategy is that the data collected here regulations on these experiments are much
are more predictive of the human condition, more lax compared to in vivo experiments;
which is one of the main goals of biomedical most of the regulatory guidelines are to protect
research. However, the in vivo preparation has the experimenter rather than the patient or the
challenges, because thousands of variables experimental subject.
within a living system are uncontrolled or still Falling in between these two
unknown. There are also very strict ethical preparations is an ex vivo experiment. In
limitations on the nature of experiments that this kind of experiment, a section of the living
can be done in vivo. organism is taken, such as a slice of brain,
On the other hand, an in vitro (Latin a tissue biopsy, or a detached frog leg. The
meaning “within glass”) preparation is an strengths and limitations of these experiments
experiment performed on cultured cells or are somewhere in between that of the other
isolated molecules of DNA, RNA, or protein. two preparations.
in vivo ex vivo in vitro
Increasing control over variables

Decreasing ability to predict therapeutic potential
Decreasing strictness of ethical regulations
6-5
Nonhuman animals perform all kinds of meaning that most patients in psychology studies
behaviors that humans never experience. These are Western, Educated, and from Industrialized,
behaviors are unique to nonhumans and can only Rich, and Democratic countries. One study
be studied in nonhumans of course. We will never estimates that about 96% of psychology studies
be able to understand flying (birds) or slithering use WEIRD subjects, whereas these people
(snakes) as a means of locomotion by studying are only 12% of the total global population. This
humans. creates a bias in sample selection, since WEIRD
One thing that makes human studies people perform differently on behavioral tasks
difficult is how weird we are. We all come from compared to others. Even our susceptibility to
very different backgrounds, bringing our own visual illusions is affected by our WEIRD-ness.
set of experiences, flaws, and biases into every
research study. Your current mood and mind state
can alter behaviors profoundly - just ask any one
who gets “hangry.” In nonhuman studies, many
of these variables are closely monitored. When
we raise model organisms in the lab, almost Figure 6.5 Many WEIRD people are susceptible
every aspect of their life is controlled, from their to the Muller-Lyer illusion, and we perceive the
food source, living conditions, and their day- lower line to be longer than the top line even
night cycles, which eliminates several sources of though they are the same length.
variability that affect human studies.
Another factor that makes human studies
challenging is that we are WEIRD: The acronym
6-6
Chapter 6 outline
6.1 Imaging brain activity

6.2 Imaging brain function
6.3 Imaging the cells of the nervous system
6.4 Changing nervous system activity
6.1 Imaging brain activity

The earliest methods of analyzing nervous
system anatomy were crude: manual dissection of
the brain post-mortem (after death). In the 1860s,
these methods received attention clinically with
the studies conducted by French neurologist and
surgeon Paul Broca. One of Broca’s patients,
nicknamed “Patient Tan,” had severe language
deficits and was only able to say “tan.” Broca
performed an autopsy after Patient Tan died, and
observed a very localized injury in his brain that
was likely the cause of Tan’s language deficits.
At the same time, a pseudoscientific
fad was gaining in popularity. Franz Gall, a
German neuroanatomist, published a treatise
describing phrenology, the belief that we can
predict personality traits based on the shape of
a person’s head and the bumps on the outside
of the skull. According to Gall, behaviors such as
romanticism, individuality, and cautiousness are
a result of differences in brain anatomy that push
the skull outwards.
Today, we know that phrenology is a fad
unsupported by the rigorous methodology of Figure 6.6 Drawing of Patient Tan’s brain after
science. But there was a valuable lesson that Broca’s autopsy (top). Tan’s language disorder
emerged from phrenology which still persists was likely a result of the highly localized damage
in part today. Both phrenology and Broca’s to a region of his left hemisphere. Chart showing
observation support localization of function, the localization of different behaviors according
the idea that specific areas of the brain are to the pseudoscience practice of phrenology
important for certain functions. Today, we also (bottom).
6-7
think about the connections between two areas the X-rays get blocked. When an X-ray passes
as being important for healthy brain activity. The unimpeded, it causes the film to darken. But,
techniques discussed below were developed wherever the X-rays are blocked, the film remains
to allow scientists to see some aspect of the white. Therefore, material that is more dense
anatomy of the nervous system, either gross (such as bone) appears as white, less dense
anatomical differences or connectivity. material (such as the air surrounding the body or
CSF) appears dark. Other tissue are some shade
6.1.1 Computerized tomography scan of gray in between.
(CT scan or CAT scan) The CT scan is essentially a three-
dimensional X-ray that revolves around the
Example questions answered: person as they move through the scanner.
“Does the patient have a brain tumor, and where Instead of using radiographic film, the CT scan
is the brain tumor located?” uses a computer that detects the passage of
“Are the meninges intact?” X-rays, located directly across the emission
source of the X-ray. Instead of a flat, two
The CT scan relies on X-ray technology dimensional-image, the CT scan uses an X-ray
that was developed in 1895. X-rays are high gun that revolves around the person’s body as
energy beams of electromagnetic radiation that they advance slowly through a large circular
are capable of passing through many physical hole. The computer is then able to compile the
objects. Traditional two-dimensional X-rays, such
as those used to image a broken bone or tooth
decay, use radiographic film to detect where
Figure 6.8 The patient lies on a table that moves

through the middle of the CT scanner.
series of two-dimensional images and turn them

into a three dimensional reconstruction that can
be used to see the brain from any projection. CT
scans give us a spatial resolution of about 0.5
Figure 6.7 In X-ray images, dense materials mm. CT scans are generally used clinically to
(bone) appear as brighter while less dense assess diagnostic changes over several days
smaterials (air) appear as black. (such as before and after tumor removal or to
6-8
determine if an intracranial bleed has healed), so for a rapid diagnosis of anatomical structures.
temporal resolution is not a major consideration. However, X-rays are highly mutagenic.
As an anatomical analysis that can easily Prolonged exposure to X-rays dramatically
identify tissues of different density, it is great increases the risk of developing various cancers,
for identifying and diagnosing particular brain since X-rays interfere with the process of DNA
conditions. Brain tumors can be visualized in a replication. It is estimated that the radiation
CT scan, since they are identified by an increase exposure in a single head CT scan is similar
in tissue density compared to normal brain tissue. to the background exposure of X-rays in a few
Hydrocephalus, an abnormal and potentially months. When a CT scan is prescribed, the
deadly expansion of the CSF-filled ventricles, can diagnostic information gained from a CT scan
be quickly identified by this analysis. Meningitis, is more important than the risks from increased
an inflammation of the meninges, may present as radiation exposure.
increased contrast in the CT scan.
The big advantage of the CT scan is that 6.1.2 Diffusion tensor imaging (DTI)
it is noninvasive. You can use a CT scan in order
to diagnose and identify the cause of a condition Example questions answered:
while a person is still alive, and hopefully work “Is the volume of the white matter tract medial
towards developing an intervention. longitudinal fasciculus important for normal
It is also a relatively quick technique. A full language processing?”
head CT scan takes only minutes, which allows “Does spinal cord compression cause neurological
deficits?”
While a CT scan is great for detecting gross

anatomical anomalies like tumors or intracranial
bleeding, it has a difficult time with subtle
anatomical changes like differences between
gray matter and white matter tracts. A technique
for identifying these differences was proposed in
1994, called diffusion tensor imaging (DTI).
DTI quantifies white matter because of
the morphological features of white matter. More
specifically, DTI uses MRI technology (see section
6.2.3 for more information) to detect and quantify
the movement of water molecules, which moves
differently in gray matter than white matter. A single
molecule of water in the middle of a cup can move
in any direction with equal probability. This type
of motion is called isotropic diffusion. However,
Figure 6.9 What do you notice that is abnormal the movement of a water molecule in biological
in this CT scan? tissue is not completely random, largely because
6-9
premise that anisotropic diffusion is observed in
white matter tracts.
DTI can give spatial resolution on the
order of millimeters. It is generally not used for
monitoring changes over time, so temporal
resolution is not a major consideration.
Axonal projections are directional, with the
soma at one end and the axon terminal at the
other. One of the shortcomings of DTI is that it
Figure 6.10 Diffusion tensor imaging can be cannot give us information about the directionality
used to visualize tracts of white matter, indicated of the axonal projections.
by different colors.
6.1.3 CLARITY
the brain is made up of heterogeneous tissue.
White matter is very different from gray matter. A
Example questions answered:
water molecule is more easily able to diffuse along
“Do neurons in layer 5 of motor cortex send
the same direction as a tract of white matter, but
axonal projections into the spinal cord?”
has a difficult time moving perpendicularly across
such tissue. The difference in molecular motion
The methods described above only provide
is called anisotropic diffusion. DTI uses the
rough anatomical information, and therefore have
Figure 6.11 In isotropic diffusion (top), a single limits to their value. CLARITY is a revolutionary
particle is able to move in any direction randomly. anatomical technique that gives microscopic
However, in anisotropic diffusion (bottom), a single level analysis. First published in 2013, CLARITY
particle is more likely to move along a certain was developed at Stanford by the lab of Dr. Karl
pathway, aligning with the cellular architecture. Deisseroth. The value behind CLARITY is that
we are now able to visualize connectivity in the
Example Example brain at a microscopic level, giving us amazing
condition movement spatial resolution at the order of a microns.
of a single One of the problems with visualizing the
particle structures of the brain at a microscopic scale
is that cells have a lot of membrane, which is
mostly made up of lipids. Instead of letting light
Isotropic diffusion pass unimpeded, lipids refract light in somewhat
unpredictable ways. Even cytosol has all sorts
of particles floating around in it that cause light
to bend and bounce around. These lipids and
other cellular particles prevent light from passing
Anisotropic diffusion through nervous tissue, minimizing our ability to
use transmitted light to see the brain.
6-10
In CLARITY, the brain is first flushed with Unlike the CT scan, CLARITY can’t be
chemicals that form a gel matrix that surrounds applied in an intact living organism. CLARITY is
every cellular structural component, from the an extremely destructive process that destroys
spines on the dendritic arbor all the way to tissue. The surrounding gel matrix is like a mold
the axonal terminals. Then, using a chemical of a hand. You can see all the anatomical features
detergent, the cellular lipids get solubilized of the hands - fingers, wrinkles, nails, and so on.
and washed away while the gel matrix remains But the mold is just an image, unable to function.
unaffected. This allows us to now see the “mold” The mold of the hand cannot grip things, cannot
that remains around where the cell membranes feel things, and does not have any bones /
used to be. By washing away the light-deflecting tendons / muscles. In using CLARITY, all function
lipids, we can now see where the connections is destroyed.
were, causing the brain to appear transparent.
Figure 6.12 With CLARITY, a whole animal brain (left) can be made transparent (middle), allowing for
visualization of individual cellular structures (right).
6-11
6.2 Imaging brain function
Anatomical analyses are certainly a

meaningful way to study aspects of the nervous
system. But being able to measure and record
brain function is important for answering different
types of questions. After all, the brain of a
recently deceased person might look identical
anatomically to that of a living person, but they
would exhibit significantly less function.
6.2.1 Electroencephalography (EEG)

“At what times of the night does the sleeping brain
exhibit synchronized neuronal activity?”
“How does brain activity change when a person
is having a seizure?”
The electroencephalogram (EEG) is

one method by which we can observe electrical
activity of the brain. When neurons send action
potentials, several charged ions move across
cell membranes, which causes a change in the
electrical charge of the adjacent area. Some of
these charges are very large, especially when
several millions of neurons are sending action
potentials at the same time. These currents
produced by neurons of the outer surface of Figure 6.13 The electroencephalogram (EEG)
the brain (cortex) can be so large, that they are is a noninvasive measure of neuronal activity
detectable outside the skull at the surface of the (top). The information gathered (bottom) reflects
head. The EEG works by recording these changes changes in electrical potential measured at the
at different areas of the brain. The technique was scalp.
first used in the 1920s by psychiatrist Hans Berger,
who invented the technique. The theory behind the To perform an EEG, a gel is applied onto
EEG is the same used in an electrocardiogram, small patches of the scalp. This gel is basically
or ECG, to detect the electrical activity of heart a sodium chloride gel that acts as a conductor,
cells. allowing the currents to be picked up by a series
of adhesive electrodes. EEG systems used in
6-12
hospitals for diagnosis or in laboratories for EEG is also useful for the diagnosis of
research studies may have anywhere between a variety of brain disorders that are a result of
20 to 128 electrodes. Each electrode is sensitive aberrant cortical neural activity. The most well
enough to detect voltage deflections as small known of these is epilepsy. In epilepsy, when
as 10 microvolts. Each electrode is placed on a person has a seizure, it is believed that large
a specific area of the scalp, and the information masses of neurons are sending action potentials
from each electrode runs into a computer. From across the cortex, producing very large signals
there, the computer can then perform calculations that can be detected by scalp electrodes.
to determine which cortical areas to the brain Migraine, a debilitating condition, may be due
exhibit what patterns of activity. to waves of unusual neural activity that sweep
EEG software is capable of examining across the cortex. Other applications of EEG may
the rapidly-fluctuating electrical potentials and include helping diagnose Alzheimer’s disease,
dissecting out the several components buried depression, and possibly ADHD.
within the complex signals. From one waveform, The EEG has great temporal resolution.
it can pick out high frequency components called Because it is detecting changes in currents, it
beta waves (between 13 and 30 Hz), low frequency is capable of sampling in the range of 10,000
components called delta waves (between 0 and 4 Hz, meaning that for each electrode, 10,000
Hz), and all frequencies in between. data points can be collected per second. Since
The EEG is a noninvasive functional action potentials happen on the time scale of
analysis method. Nothing permanent is done to milliseconds, being able to calculate changes in
the person when they get an EEG because it electrical potentials at such speeds gives us the
is only detecting information. Wearing a cap of ability to assess brain activity very precisely.
electrodes may be annoying, but it is a harmless But, the EEG has poor spatial resolution,
procedure. Because of the experimental set up only detecting signals that originate in the outer
for EEG, there are many cases where using an most layer of the brain. More electrodes increase
EEG is preferable. The EEG is a standard part spatial resolution, but even at 128 electrodes, an
of a polysomnogram, a series of tests that can EEG only has spatial resolution to the level of
be done to evaluate sleep disorders. In fact, our about 7 cubic centimeters.
best and most reliable characterization of the
phases of sleep rely on brain activity measures
as recorded by an EEG (Chapter 13). Relatedly, 6.2.2 Positron emission tomography
EEGs are also used clinically when a person is (PET scan)
under anesthesia as a tool to evaluate their level
of unconsciousness. Example questions answered:
Not only is the EEG noninvasive, but it “Which areas of the brain decrease in activity
is also relatively cheap - at least in comparison when a person experiences mild cognitive
to many of the other methods described in this impairment?”
chapter. It does not require heavy equipment and “Do drug-dependent people have a high density
is mobile. All the machinery needed to run an of opioid receptors?”
EEG can be contained within a backpack.
6-13
The positron emission tomography
(PET) scan is an application of nuclear medicine
best known for its applications in the medical
setting for the diagnosis of cancer. Before the PET
scan, a radioactive compound called a tracer is
injected into the bloodstream. This tracer is a
compound where an atom is substituted with a
radioactive isotope, such as tritiated hydrogen
(3H) or fluorine-18. The PET scanner itself is a
large circular device that looks similar to the CT
scanner. The tracer is chemically unstable, and
it spontaneously emits positrons. When those
positrons interact with the electrons of nearby
molecules, two gamma particles are emitted in
perpendicular directions. These gamma particles
are then detected by the PET scanner as the
person moves through the machine.
A common tracer that is used for imaging
brain function is fluorodeoxyglucose-F18, or
FDG. FDG is a radioactive analog of glucose,
one of the main sources of cellular energy. Highly
Fluorodeoxyglucose-F18
(FDG) Figure 6.15 The positron emission tomography
(PET) scanner (top) is quiet compared to the CT
scan or MRI. It can generate data sets (bottom)
that visualize the approximate location of highly-
energetically demanding tissue (yellow and
orange), such as a brain tumor.
metabolically active areas of the body take FDG

into the cells. Energetically demanding areas
e+ - of the brain require more energy to do their
e
γ γ
functions (the same reasons that tumors, rapidly-
reproducing patches of tissue, appear very bright
Figure 6.14 When a positron (e+) emitted by in PET scan analyses). In order to produce the
the tracer compound (FDG) interacts with energy needed for increased neuronal activity,
nearby electrons, gamma rays (γ) are emitted at the brain changes perfusion levels by dilating
perpendicular angles which are detected by the blood vessels in order to bring more glucose to
PET scanner (gray boxes). those areas. Therefore, when an area of the brain
6-14
increases in energetic demand, that change can CT scan. A person is exposed to radioactive
be detected by identifying the increase in glucose compounds and gamma wave radiation, which
movement. are potentially mutagenic.
PET scans can be effective at diagnosing In images produced by a PET scan, it is
and identifying the location of tumors in the often difficult to identify boundaries between
nervous system. It also provides an overall tissue, even between dramatically different
picture of brain activity, which may be useful in internal organs. To make up for this deficit, PET
diagnosing disorders of cognitive deficits, like scans are frequently performed simultaneously
dementia associated with Alzheimer’s disease or with an anatomical analysis like a CT scan.
Pick’s disease. PET scans have also been used PET scans generally have very poor spatial
to image the activity of specific brain areas as a and temporal resolution. With PET scanning, you
person performs behavioral tasks, but this use of can really only see differences between areas if
PET scan has largely been replaced by functional the volume is in the range of 5-10 cm3. Anything
magnetic resonance imaging (fMRI; see section smaller than a cubic centimeter will be impossible
6.2.3). to detect with current PET scanners. As to the
A second application of PET scanning speed of the PET signal, it often takes tens of
is to visualize levels of receptors in vivo. This seconds or minutes before a change in signal
experimental approach relies on the nature of can be observed and detected.
the interaction between specific radioactively-
labeled compounds and receptors (such as [11C] 6.2.3 Functional magnetic resonance
raclopride and dopamine receptors, or [18F] imaging (fMRI)
ASEM and acetylcholine receptors). Once the
radiolabeled compound binds to the receptor, Example questions answered:
the PET scan is able to detect the location of the “Do neurons in the right hemisphere cingulate
radioactive signal and the strength of that signal. gyrus increase in activity when a person sees
The downside of the PET scan as a their loved ones?”
diagnostic tool is similar to a limitation of the “Which areas of the brain change in activity when
a person is planning a motor action?”
B0
1 2 3 4
Figure 6.16 (1) Protons spin around an axis, aligning randomly at rest. (2) In the presence of a magnetic
field B0, their spin aligns with or directly opposite of the magnetic field. (3) Exposure to radiowaves
knocks the protons out of their alignment into a high energy state. (4) As the protons return back to their
alignment with the magnetic field, they release energy.
6-15
The functional magnetic resonance is not (paramagnetic). Because of this difference,
imaging (fMRI) technique is probably the most we are able to use sensitivity to a magnetic field
well-known method of studying brain activity. as a measure of changes in oxygenation levels.
Because fMRI can be performed while a person Like the PET scan, the fMRI hinges on the idea
is engaged in a task, many research studies that more active areas of the brain have different
use fMRI as a means to correlate behavior with metabolic demands than less active areas of the
activity patterns in specific parts of the brain. brain. When there is more activity in one area of
An fMRI machine basically consists of the brain, the neurons in that area need more
two main components. As with the CT scan or oxygen, and the adjacent blood vessels react by
PET scan described above, the fMRI machine dilating. This change in blood flow is detected by
is a circular tunnel through which a person on a the fMRI, and is called the blood oxygenation
table moves. As the person moves through the level-dependent signal, or BOLD signal.
scanner, an extremely powerful magnet revolves Temporal resolution of the fMRI is limited by the
around their head. The power of a typical magnet speed of blood vessel dilation, which occurs on
used in a hospital fMRI may be as powerful as the order of seconds to tens of seconds.
10,000 gauss (1 Tesla), strong enough to lift a The main reason fMRI is useful in so
car. The more powerful fMRI machines can be many research applications is that you are able
as powerful as 100,000 gauss (10 Tesla). The to visualize brain activity real-time during the
stronger the magnets, the better the spatial performance of complex behavioral tasks. You
resolution that the machine can produce (our can present specific visual stimuli to a person
current best spatial resolution is on the order of in an fMRI scan and evaluate which parts of the
millimeters). The second component is a device brain changes in activity. For example, seeing
that emits radio waves. Just like the magnet, the pictures of faces causes increased blood flow into
radio emission device revolves around the head. the fusiform face area. You can ask a person to
Both the magnetic field and the radio perform a gambling task and evaluate the areas
waves are crucial for the fMRI to work. They both
interact with protons, the charged subatomic
particles that have a small polarized direction
because they spin around an axis. Initially, when
these protons enter into a strong magnetic field,
each proton charge aligns either with or directly
against the direction of the field. Then, when hit
by a radio wave, the protons lose their alignment,
going into a high energy state. The protons then
fall back to a low energy state as they return to
alignment with the magnetic field. This process is
what is being detected by the fMRI.
As it turns out, the protons in oxygenated Figure 6.17 The fMRI scan detects the location
hemoglobin are sensitive to the magnetic field of blood flow changes as a person pays attention
(diamagnetic) while deoxygenated hemoglobin to different visual stimuli (top vs. bottom).
6-16
of the prefrontal lobe that are responsive to risk generation tattoos have trace amounts of metal
taking. that cause burns when exposed to the magnets
Although the technique has a great of the fMRI machine.
capacity for analyzing brain function, the nature The data collected by fMRI can be very
of the machine itself presents limitations. The difficult to analyze and are frequently subject
scanning tunnel is very small and claustrophobic, to false positives. The change in BOLD signal
making it difficult to safely study anxiety or panic measured in an fMRI is very small: one study
disorder without endangering the patient. The estimates that perfusion increases by only
machine can also be very loud, which is not trivial 0.4% even under the greatest activation. Using
if you are interested in studying younger patients. standard fMRI analysis methods, an infamous
The use of a tremendously powerful magnetic study demonstrated that even a dead salmon in
field presents a different set of limitations. At the an fMRI exhibits brain activity that is similar to
risk of severe injury or death, the patient entering those reported in other fMRI studies.
the scanner cannot have any magnetosensitive FMRI also assumes that increased blood
implants, such as metallic aneurism clips, flow is directly correlated with the amount of
intrauterine devices, or shrapnel. Even older neural activity, which may not always be the case.
6-17
6.3 Imaging the cells of the nervous system
The methods thus far discussed are limited developed in the 1930s, use an electron emission
in how closely we can see the components of the device in conjunction with high speed detectors
nervous system. For example, it could be useful to visualize structures that are on the order of
to try and see the specific cellular features of a nanometers, giving us a zoom of up to a million
healthy neuron and compare that with the features times!
of a neuron that has been damaged by multiple A different form of microscopy relies on
sclerosis. To be able to visualize the morphology the fluorescent properties of molecules such as
of structures smaller than hundreds of microns, green fluorescent protein (GFP). Fluorescence
you’ll need a different set of techniques. microscopes use light sources such as filtered
light or lasers which emit light at specific
6.3.1 Microscopy

Ocular Emission
“What is the diameter of the soma of a granule lens filter
cell?”
“How are the retinal neurons at the fovea different
from the neurons in the periphery?”
Dichroic
mirror
Among the techniques described in this
Light
chapter, short of physical dissection or autopsy, source
microscopy may be the oldest. Microscopy began Excitation
Objective filter
with the Dutch scientist Antonie van Leeweunhoek lens
in the late 1700s. Originally, microscopy was more
of a novelty for entertainment rather than a piece
of equipment fit for a laboratory. Using a series Sample
of precisely-crafted lenses and a bright source of
light, Leeweunhoek was able to see tiny animals
living in water.
Microscopy gives us the ability to see things
at a level of resolution that would otherwise not be
possible. Compared to today’s microscopes, the
earliest scopes provided poor magnification, able
to bring us only about 40 times closer than the
unaided eye (these days, a standard laboratory
microscope provides a level of magnification Figure 6.18 The fluorescence microscope
up to 400 or 1,000 times closer). Other types of (diagram, top) can be used to excite GFP (green)
microscopes, such as the electron microscopes expressed in hippocampal neurons (bottom).
6-18
wavelengths. Photons at specific wavelengths
activate the proteins, which in turn emit light at a
different wavelength. The emission of this second
color of light can then be detected.
Microscopy is a standard part of a
neuroscience research kit. Most of the techniques
below will rely on microscopy to visualize some
component of the nervous system.
6.3.2 Staining

“Where is the white matter located in the brain
stem?”
“What is the morphology of dendritic arbor of a
cerebellar Purkinje cell?”
Staining is an imaging method that is often

used in conjunction with microscopy. Thin slices
of brain tissue are exposed to various chemical Figure 6.19 A slice of cerebellum, with the myelin
processes. The chemicals that are used for stained with Luxol Fast Blue and the neurons
staining have different affinities for parts of cells. stained with cresyl violet (top; 100x magnified). A
For example, there are stains that specifically pyramidal cell treated with a Golgi stain (bottom).
stain myelin (Luxol Fast Blue), some that only
stain neurons (cresyl violet), and some that stain For staining to work, the tissue needs to be
only the genetic material found in cell nuclei subjected to a series of chemical processes. First,
(DAPI). the tissue needs to be fixed. Fixation is a chemical
One of the most influential biological process that is accomplished by exposing the
stains was developed in the late 1800s by the tissue to a chemical like paraformaldehyde
Italian anatomist Camillo Golgi. The Golgi stain (PFA). The most effective way to expose every
is a silver-based stain that filled every single part part of the body to fixative is to “hijack” the
of the neuron, from the dendrites to the axons, endogenous circulatory system by flushing
turning the cells black. The stain is only taken up fixative through the arteries, a process called
by less than 1% of neurons, and because of the perfusion. Chemically, fixatives cause adjacent
low rate of staining, individual neurons could be proteins to become covalently bonded (cross-
traced in their entirety and drawn. This stain led linked), a process which causes the proteins to
to a contentious battle between Golgi and a rival become unchangeable - they become “fixed” in
neuroanatomist Santiago Ramon y Cajal over the time. These fixatives are very harsh chemicals,
nature of the connections between neurons. and usually kill microorganisms and inactivate
6-19
the endogenous enzymes that normally degrade Certain staining methods can also be
biological tissue. (As a side note, fixatives are used to determine projections of neurons. These
particularly nasty carcinogens that can permeate techniques are collectively called tract tracing
easily through latex gloves.) methods. An anterograde trace stains cells from
the soma to the axon terminal, while a retrograde
trace is taken up by the axon terminals and
stains the soma. These strategies are helpful
PFA for visualizing the nature of connectivity in the
nervous system.
Staining cannot be done on living tissue; it
can only work on fixed tissue.
Injection
probe
Figure 6.20 A chemical fixative such as PFA
creates covalent bonds between lysine (blue)
amino acid residues of proteins. Retrograde Anterograde
After fixation, devices such as a
microtome or cryostat are used to slice the brain
into sections as thin as 10 microns. Stains do not
always reliably pass all the way through thick
sections of tissue such as an intact brain. With
thin slices, chemical stains are able to permeate Figure 6.22 In tract tracing, injection of different
through the depth of the tissue. staining dyes can help us identify the connectivity
of neurons. If an injection site contains somata,
the dye is transported in an anterograde direction
towards the area where the axon terminals are
located (green). If the injection site contains axon
terminals, the dye is taken up and transported
in a retrograde direction towards the cell bodies
(red).
6.3.3 Immunohistochemistry staining
Figure 6.21 A microtome (left) or a cryostat Example questions answered:

(right) are devices for taking brain sections. The “Where is the protein actin located in a neuron?”
microtome fits on a tabletop, and cuts accurately “Is the protein PSD-95 expressed in the same
down to 100 uM thin. The cryostat is larger, and areas as the NMDA receptor protein?”
can cut 10 uM thin slices.
Immunohistochemistry (IHC) is a
modification of the staining methods that gives
6-20
increased specificity over the other chemical stain As with other staining methods, IHC
methods presented above. IHC is used because begins with thinly prepared sections of fixed
it is good for identifying the location of specific tissue. Instead of exposing the tissue to various
proteins at a subcellular level. In other words, you chemical stains, IHC utilizes the molecular
can use IHC to figure out where specific neurons properties of antibodies, proteins that function in
are located inside or on the cell. the immune response. Each antibody has a part
of their Y-shaped structure that is able to bind to
other targets (which are called antigens) with
extremely high specificity. This other target could
be a specific protein, such as serotonin receptors
or amyloid precursor protein, or an enzyme such
as choline acetyltransferase. Antibodies are
created with a particular target in mind, so when
the antibody is bathed over the brain tissue, the
antibody will adhere only to that target.
The IHC protocol often uses two different
antibodies. The first antibody, called the primary
antibody, is selected because of its ability to bind
to the antigen that you are interested in studying.
For example, if you wanted to search for the
location of a protein called NeuN, the primary
antibody would be anti-NeuN. Afterwards, the
tissue will be exposed to the secondary antibody.
GFP
Primary Secondary
antibody antibody
Antigen
(protein of
Figure 6.23 At low magnification (top), interest)
immunohistochemistry in conjunction with
fluorescence microscopy can help us identify the Figure 6.24 The primary antibody (purple) is
morphology and location of different populations chosen because it binds to a specific protein
of cells. At high magnification (bottom), we can of interest (magenta). In a second step, the
identify the location of different proteins within a secondary antibody (light blue), conjugated with
cell, such as tubulin (green), which makes up the a fluorophore (in this case GFP), binds to the
microtubules. primary antibody.
6-21
This second antibody is chosen because its target often they bind to the wrong targets. When
is something that is found on the primary antibody. they do, it creates a false positive, causing a
As an additional feature, the secondary antibody fluorescent signal to appear when there is actually
is conjugated with a light sensitive fluorophore, no protein present. Nonspecific binding also
or light-producing molecule. Activation of this causes an increase in background noise, making
fluorophore on the secondary antibody under it more difficult to identify a genuine fluorescent
fluorescence microscopy is then used to identify signal, indicating presence of the protein of
the location of the primary antibody. interest. Various steps can be taken during the
It is also possible to use antibodies immunochemistry procedure that minimize the
and fluorescence microscopy to visualize the likelihood of nonspecific binding, such as thorough
elements of cells in a culture dish (in vitro). The rinsing and exposure to blocking agents.
theory behind this technique is the same as in For an immunochemistry protocol to
IHC, but the name is different. Instead, this work, an antibody must exist for the specific
approach is called immunocytochemistry (cyto target of interest. However, an antibody has not
= cell, while histo = tissue). This immunolabeling been developed against every single protein or
strategy can also be applied to a whole brain after enzyme. Another issue is that some proteins are
it has been made transparent through CLARITY structurally very similar to other proteins, and an
(section 6.1.3). antibody has not yet been developed that can
One of the main difficulties with differentiate the two. For example, the structure
immunochemistry is that the antibodies often of the dopamine receptor type 2 is so similar to
exhibit nonspecific binding. Although antibodies type 3, that there are no antibodies that can target
are used because of their ability to recognize and one without the other.
differentiate between similar-looking antigens,
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6.4 Changing nervous system activity
Visualizing the gross anatomy or cellular Neural manipulation became possible in
structures of the nervous system allows us to ask humans following the work of the brain surgeon
very meaningful scientific questions. However, Wilder Penfield. In the 1950s, Penfield worked
sometimes you are interested in controlling some to develop a treatment for epilepsy. In this
part of the nervous system, either by increasing procedure, the patient is given a local anesthetic
or decreasing activity. Using the following neural while the skin above their skull was resected,
manipulation strategies, it becomes possible allowing access to the brain. The surface of the
to establish causation between some aspect brain has no pain receptors, so brain surgery can
of the nervous system (neuron, structure, be done while the patient is completely awake.
neurotransmitter, gene, etc.) and function. With the patient’s brain exposed, Penfield used
Early neural manipulation strategies a brief electrical pulse delivered by an electrode
trace back to the late 1700s with the accidental placed at the surface of the brain. The stimulation
discoveries of the Italian biologist Luigi Galvani. activates descending motor systems, which
With a dissected frog leg on his lab bench, Galvani caused muscle contractions in very specific
discovered that he could cause the muscles to muscle groups of the patient. For example,
twitch by electrically activating the nerves that stimulating the dorsal most part of the motor
innervated the muscles of the leg. He called this cortex caused a twitch of the upper leg and hip
observation “bioelectricity,” which is the idea muscles. By moving incrementally across the
that endogenous electrical activity is important motor cortex, he was able to draw a graphical
for muscle control, and by extension, the activity representation of which areas of the motor cortex
of the whole organism. controls which muscles.
The techniques presented here are all
methods by which we can induce some type of
change in nervous system activity.
6.4.1 Electrophysiology (Ephys)

“How frequently do neurons in the striatum fire
action potentials?”
“Does increasing cortical activity change the
excitability of spinal cord neurons?”
Electrophysiology relies on using

Figure 6.25 Luigi Galvani observed that
specialized equipment, informally called a
electrically activating a nerve caused muscular
rig, to measure and manipulate the electrical
activity in the frog leg. The phrase “galvanized to
properties of the nervous system. Originally,
action” is a reference to Galvani’s discovery.
6-23
electrophysiology was used to detect the Electrophysiology on a cellular level usually
difference in electrical potential between the requires the concurrent use of a microscope to
inside of the neuron and the outside. The earliest get resolution down at the level of the neuron,
electrophysiology techniques examined the giant which may be on the order of tens of microns in
axon of the Loligo squid. The axon itself is so large diameter. At this level of magnification, tiny glass
with a diameter around 1 mm, the inside of these micropipettes filled with an electrolyte solution
neurons are very easy to access by running a can then be inserted into neurons, and electrical
conductive probe into the cell. Two researchers, currents can then be detected and recorded.
Alan Hodgkin and Andrew Huxley, earned a These currents can be the currents associated
Nobel prize in 1963 for the work that came out of with the movement of charged ions, such as
these electrophysiological techniques. sodium during an action potential.
Electrophysiology can also be used to
manipulate the activity of neurons. Instead of
simply detecting currents, electrophysiology
gives you direct physical control over the
electrical properties of the neuron, which gives
us the ability to manipulate different components
of the nervous system.
Pipette
Neuron
Figure 6.27 Rupturing the cell membrane with a

microscopic glass pipette allows the experimenter
to monitor and control the electrical conditions of
the neuron.
Electrophysiology can be a very versatile

technique. Because there are many strategies
that count as electrophysiology, you can ask
questions at many levels, from behavior and
neuronal circuitry to individual neurons and ion
Figure 6.26 An electrophysiology rig is the setup channels. With electrophysiology, you can record
used for recording and controlling the electrical the patterns of neuronal activity as a rat performs
activity of neurons (top). The isolated squid giant on a behavioral task, and stimulate neurons to
axon (bottom) was one of the earliest preparations see if you can modify the behavior. On the other
that informed us about the electrical properties of extreme, you can examine the activity of individual
neurons. ion channels, to determine the conditions when
6-24
they open and close. lobe causes the perception of flashes of light.
One weakness lies in the highly TMS is believed to have moderate benefits
experimental nature of electrophysiology. There for several different psychiatric conditions,
are many different preparations that can be used potentially making it a meaningful therapeutic
in studying the electrical activity of the nervous intervention. Activation of motor cortex may help
system: intact anesthetized, thin slice of living alleviate chronic pain conditions, Parkinsonian
brain, neuronal culture, or even frog oocytes that symptoms, and improve contralateral motor
express neuronal receptors. But, each step you function following stroke injury. Activation
move away from the awake and behaving animal, of prefrontal cortex can decrease anxiety,
the more difficult it becomes to draw inferences antidepressive symptoms, cigarette craving or
based on our results. What we gain in control consumption, and schizophrenia. Stimulation of
over the experimental preparation, we lose in
ability to generalize about data.
6.4.2 Transcranial magnetic stimulation

(TMS)

“Which part of the motor cortex sends signals to
the contralateral foot?”
“Can activation of parts of the prefrontal cortex
decrease the symptoms of depression?”
In physics, there is a close relationship

between electricity and magnetism. The
movement of magnets can generate electric
currents, and conversely, electricity can generate
magnetic fields, a process called induction. A
brain stimulation technique called transcranial
magnetic stimulation (TMS) relies on induction to
generate electrical currents through the skull. The
TMS machine itself is a handheld coil of wires in a
loop. Passing electrical current through that loop
produces a magnetic field. The magnetic field
generated then induces an electrical current at
some distance away from the coil. By placing the
coil at the surface of the scalp, we can electrically Figure 6.28 Running current through a magenetic
activate small areas of brain tissue. For instance, coil generates an electric field via induction (top),
using TMS above the motor cortex causes muscle which can activate or inactivate neural circuits in
contractions, and using TMS above the occipital TMS (bottom).
6-25
Introduction to Computational stimulus and the neuronal responses and the
Neuroscience relationship with electrical activity.
Computational neuroscience is a 2. Mechanistic models are used to
branch of neuroscience that focuses on determine how nervous systems relates
explaining neural mechanisms through with known anatomy and physiology. These
computational methods. This multi-disciplinary models simulate the behavior of a single
field draws from other fields such as electrical neuron or network of neurons.
engineering, physics, and computer science 3. Interpretive models lead to an
to better understand how the nervous system understanding of why the nervous system
processes information. Computational operates in a particular way. These models
neuroscience strives to answer a wide range of are used to examine neural cognition and the
questions in neuroscience research, including underlying nervous system functionality.
computation in single neurons, computation There is debate with how
in a neural network, neuron development, computational models can be used to
sensory processing, motor control, memory best reflect the nervous system. A model
and plasticity, as well as broader questions that focuses largely on defining biological
about vision, consciousness, and cognition. processes into mathematical terms may stray
Sometimes, using computational approaches from its intended purpose and not accurately
can be described as being an in silico reflect neural behavior. In other cases, a
preparation. mathematical model may oversimplify neural
Computational neuroscience provides behavior and may lead to false conclusions.
tools and methods for developing models, Thus, there is a focus on biologically plausible
which are used for answering different neural networks to best model the nervous
categories of questions. system.
1. Descriptive models characterize
what nervous systems do. These models
qualitatively describe data through neural
encoding as well as extract information
through neural decoding, the reconstruction
of information that has already been encoded
and represented in the brain by a network of
neurons. Reconstruction is the researcher’s
ability to predict sensory stimuli purely from
the action potentials from neurons. The
objective of neural decoding is to characterize Figure 6.29 Advances in computational
the electrical activity of neurons in relation neuroscience have led to the development
to responses in the brain. Neural encoding of robotic protheses that read neural signals,
characterizes the relationship between the and predict the corresponding motor output.
6-26
other brain regions can be antiepileptic, and may allowed researchers to create animal models of a
also minimize auditory hallucinations or tinnitus variety of human conditions. For example, we can
(ringing in the ears.) use gene excision to remove a small section of
The technique itself is completely the genetic code, such as the part that codes for
noninvasive. TMS can be delivered simply with a certain protein. This strategy is called knock-
placement of the electric coil on the surface of the out, and is helpful for identifying the function of
head. a genetic sequence. Alternatively, we can use
TMS may have some unexpected gene insertion to put in exogenous genes into an
consequences, such as temporary headaches, animal. For example, we can generate mice that
localized pain, changes in hearing, and bizarre express the human version of a gene. We call
changes in somatosensation. The most severe these humanized mice. This type of modification
side effect so far recorded is seizures, which is called a knock-in. There is an entire spectrum
can be very dangerous. Use of TMS is still highly of genetic modifications that can be performed,
experimental. including knock-downs (moderate decrease
As with fMRI, the magnetic fields in function), upregulations (some increase in
generated by a TMS device can cause dangerous function), or conditional knock-outs (an organism
interactions with any magnetosensitive implants, that is normal until exposed to certain chemicals).
such as deep brain stimulation devices, cochlear
implants, or aneurysm clips.
6.4.3 Genetic modification

“Do rats behave differently if they do not
synthesize the hormone leptin?”
“How do mutated voltage-gated sodium channels
change their neuronal action potential firing?”
Figure 6.30 A mouse with a hair-related gene

Since the rise of molecular genetics
knocked out (left) compared to a wild type mouse
techniques in the 1970s, researchers have
(right).
discovered some of the underlying genetic
commonalities between healthy people and those A recent advance in genetic modification
with neurological or psychiatric conditions. The technology published in 2012 called the CRISPR-
genomes of many animals have been completely Cas9 system allows for targeted editing of
mapped out including the nematode C. elegans the genome. The main advantage provided
(1998), drosophila (2000), mouse (2002), human by CRISPR-Cas9 is the simplicity, efficiency,
(2003), rat (2004), and the macaque monkey and precision of the method. While still highly
(2007). experimental, there are potential therapeutic
Knowledge of their genomes, and the applications for CRISPR-Cas9 in treating a
capability to manipulate their genomes, has variety of genetic diseases.
6-27
Cas9 complex
that the therapy will also be effective in humans.
Genetic modifications may also produce
unexpected side effects as a result of changes
to the genetic code. It is difficult to predict how a
Cleavage
specific gene manipulation will interact with other
DNA repair aspects of the animal’s physiology.
Homology 6.4.4 Optogenetics / Chemogenetics
Donor DNA Example questions answered:
“How does activating cortical glutamatergic drive

affect firing rate of neurons in the striatum?”
“Does inactivation of GABA-ergic circuits in the
Deletion / amygdala change anxiety behaviors?”
insertion New DNA
One of the problems with early neural
Non-homologous Homology directed repair
end joining stimulation strategies was a lack of specificity.
For example, many brain regions are home to
Figure 6.31 The CRISPR-Cas9 system is a
a hodgepodge of cell populations that produce
powerful method of gene editing.
and release different neurotransmitters. In
With the combined help of dedicated activating these areas, it was impossible to know
laboratories across the world, a wide variety if the effect of stimulation was due to activity of
of genetically-modified mice are commercially a specific population of neurons. Additionally, we
available for research purposes. Many scientific were unsure if the results of electrical stimulation
advances have come from these research were due to the activity of that specific brain area
models. It’s also possible to develop an animal where the stimulator was placed, or if it was due
with multiple genetics crosses, which allow for to the activation of axonal fibers that simply pass
several complex questions to be answered. through that area. This was described as the
A shortcoming of the information gained fibers of passage problem.
from these genetic modification techniques is the The following two strategies, optogenetics
difficulty in generalizing the findings beyond the and chemogenetics, were recent advances
specific genetic strain. For example, consider a in neuroscience techniques that increase the
knock-in approach to model a brain disorder in specificity of brain stimulation. As of now, both
mice. If a therapy is developed that helps these of these techniques are exclusively used in
animals, it is certainly a starting place that may nonhumans for research purposes.
lead to a human therapy. But, there is no certainty
6-28
Optogenetics the channel closes in less than a millisecond. The
speed with which ChR2-expressing neurons can
A revolutionary strategy developed in respond gives optogenetic strategies a temporal
2006 by researchers from Stanford University, resolution on the order of milliseconds.
optogenetics use light sensitive-ion channel ChR2 is possibly the most popular
proteins called channelrhodopsin, or ChR2. The optogenetic molecule, but not the only one. Since
light-sensitive component of ChR2 is a protein its adoption into neuroscience, there have been
that is derived from the rhodopsin molecule, the several other proteins with similar light-sensitive
same proteins that allow photoreceptors in the characteristics. Halorhodopsin is a light-sensitive
visual system to detect light. The ion channel pump that uses energy from yellow-green
component is a cation-permeable transmembrane wavelengths to actively push chloride into the
pore that can allow Na+ ions to move across cell, which inhibits neurons. Archaerhodopsin is
the cell membrane. When a photon of blue light a light-sensitive proton pump that extrudes H+
hits the ChR2 molecule, the protein physically ions, which inhibits neurons.
changes shape, causing the cation channel to ChR2 also has very high specificity,
open, enabling inward flow of positively charged since optogenetics is used in conjunction with
sodium ions. Therefore, ChR2 gives us the ability knock-in genetic modification technology or viral
to excite neurons with flashes of light. gene delivery to insert ChR2 into unique cell
470 nm light populations. This strategy allows researchers to
isolate the effect of activation of a specific cell
population within an area of the brain that has
many different cell types.
Chemogenetics
ChR2 Chemogenetics is an alternative strategy

to selectively activate specific cell populations.
Na+
Instead of using light to activate special receptors,
these techniques use various chemical agonists.
Figure 6.32 ChR2 is a transmembrane protein Chemogenetic receptors are usually G-protein
that is opened by blue light, which can cause coupled receptors that are activated only by
action potential firing. exogenous drugs, but not by any endogenous
neurotransmitters. The most well-characterized
The ability for ChR2 to change structure in chemogenetic receptor is called DREADD, which
response to light is very fast, and the subsequent stands for designer receptor exclusively activated
movement of changed ions down their by designer drugs. When the receptor is exposed
electrochemical gradient is even faster. A brief 0.5 to the designer drug, it can trigger the activation
millisecond flash of blue light is enough to trigger of the intracellular signaling pathway that can
sufficient inward Na+ current to induce a single either excite or inhibit the neuron, depending on
action potential. Once the blue light is turned off, the nature of the DREADD. So, when a DREADD
6-29
protein is inserted into a neuron, there are no Because chemogenetics requires the
changes in neuronal activity at rest. But once the drug to enter the system and subsequent GPCR
receptor is exposed to the endogenous drug, the activation before a change in behavior can be
DREADD is activated, which changes the activity observed, DREADD offers significantly less
of the neuron. temporal resolution than optogenetics (in an ex
vivo preparation - seconds to tens of seconds; in
a behaving animal - minutes).
Optogenetics / chemogenetics can be
used simultaneously with other techniques.
Combining optogenetics with electrophysiology
techniques has taught neuroscience about the
nature of the connectivity between brain areas.
Behavioral testing with simultaneous optogenetic
or chemogenetic stimulation has given us insight
into the roles that are played by specific neural
Figure 6.33 A chemogenetic system such as
circuits or neurotransmitters. These techniques
DREADD allows for control over intracellular
are quickly advancing our understanding of the
signaling pathways upon exposure to an
nervous system, and will continue to do so in the
exogenous ligand.
future.
DePaul University.
6-30
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6.12: Optimization of CLARITY for Clearing Whole-Brain and Other Intact Organs Jonathan R. Epp, Yosuke Niibori, Hwa-
Lin (Liz) Hsiang, Valentina Mercaldo, Karl Deisseroth, Sheena A. Josselyn, Paul W. Frankland eNeuro 8 May 2015, 2 (3)
ENEURO.0022-15.2015; DOI: 10.1523/ENEURO.0022-15.2015
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6-31
7-1
Allison Morales, OD (Illinois College of Optometry)
At over 400 miles of explored passages, the visual system to gain information about our
the Mammoth Cave system in Kentucky is the surroundings. Consider how tentatively you walk
longest known cave system on Earth. During the from the light switch to your bed right after turning
cave tour, the guides momentarily extinguish all off the lights!
the lights. The void that follows is overwhelmingly The visual system is complex and consists
eerie. Opening and closing your eyes makes no of several interacting anatomical structures. Here,
difference. You may have difficulty figuring out we will describe the process of how photons
which way is up and down, and might even lose of light from our surroundings become signals
your balance when you tilt your head. that the brain turns into representations of our
Humans are remarkably dependent on surroundings.
Sensation vs. perception of you while all the other stuff fades into the
The following 3 chapters are focused background.
on sensation and perception. By definition, Perception is also shaped by past
the words “sensation” and “perception” are memories. Consider the following scenario.
very similar. However, in psychology and You are at home, studying by yourself quietly,
neuroscience, the two have slightly different when you hear footsteps and the jingling of
meanings. Both terms are related to processes keys. This process is sensation. Based on the
of getting information from the environment. fact that you have a roommate, and you know
“Sensation” is the detection of stimuli, they have a nightly routine of studying late at
whereas “perception” is the interpretation of the library before returning home, you interpret
those stimuli. The quantity of stimuli that you those sounds as your roommate coming home.
sense far outnumbers what can be realistically This process is perception.
perceived. For example, imagine
you are at a loud party, having a
conversation with someone. You
sense so many things here: all the
friends and strangers you see, the
smells of sweat or food, and the Sensation Perception
sounds of music and various voices.
Figure 7.1 Sensation refers to the ability to detect stimuli,
But while speaking to your friend, all
while perception is concerned with interpretation of those
you perceive is the person in front
stimuli.
7-2
Chapter 7 outline
7.1 The Eye

7.2 The Retina
7.3 The Optic Nerve
7.4 Visual Perception in the Brain
7.1 The Eye
Visual sensation starts at the level of the frequencies. The frequency at which a photon
eye. The eye is an organ that has evolved to oscillates is directly related to the color that we
capture photons, the elementary particle of light. perceive. The human visual system is capable of
Photons are unusual because they behave as seeing light in a very narrow range of frequencies.
both particles and as waves, but neuroscientists On the short end, 400 nm wavelengths are
mostly focus on the wave-like properties. Because observed as violet, while on the long end, 700 nm
photons travel as waves, they oscillate at different wavelengths are red. Ultraviolet light oscillates at
400 nm 600 nm
γ γ
Radio
X-ray UV IR Microwave
waves
10-16 10-14 10-12 10-10 10-8 10-4 10-2 100 102 104 106
Wavelength (m)
Visible spectrum
380
450
495
570
590
620
750
Figure 7.2 Photons (γ) oscillate at different frequencies. If the oscillation repeats every 400 nanometers,
we perceive that color as violet (top left), but if it oscillates at 600 nm, we perceive those wavelengths as
orange (top right). Humans are only able to detect a narrow range of particles within the electromagnetic
spectrum, between 400 and 700 nanometers (bottom).
7-3
a wavelength shorter than 400 nm, while infrared the incoming rays of light so that they converge
light oscillates at a wavelength longer than 700 precisely at the retina, the posterior most part of
nm. Neither ultraviolet nor infrared light can be the eye. If the light rays fail to properly converge,
detected with our eyes. a person would be near-sighted or far-sighted,
For us to see light, three basic conditions and this would result in blurry vision. Glasses or
need to be met. First photons need to be present. contact lenses bend light before it reaches the
When there are no photons of light, as in the cornea to compensate the cornea’s shape.
depths of the Mammoth caves, we are unable to After passing through the cornea, light
detect anything. enters through a hole in the center of the eye called
Secondly, photons of light must reflect the pupil. The diameter of the pupil can change
off objects in the surrounding world. If photons depending on ambient light conditions. In the
cannot bounce off the object, the eye cannot dark, the pupil dilates (also called mydriasis), or
collect the photons. Black appears colorless gets bigger, which allows the eye to capture more
since it absorbs more photons, while pure white light. In bright conditions, the pupils constricts
reflects photons. The wavelengths that reflect off (also called miosis), or gets smaller, which
objects determine the color that we perceive. decreases the amount of light that enters the eye.
Third, photons need to reach the back Two muscles, the pupillary dilator muscle and
of the eyeball. Photons pass through several the pupillary sphincter muscle, are responsible
anatomical structures before the nervous system for change in pupil size. The pupillary dilator
processes and interprets them. muscle causes dilation and is downstream of the
The anterior, or front-most part of the eye, sympathetic branch of the autonomic nervous
is the cornea. The cornea refracts, or bends, system, while the pupillary sphincter causes
constriction and is activated by the
parasympathetic nervous system.
Retina The next structure that light
passes through is the lens. Like the
Cornea
cornea, the lens refracts light so that
the rays converge on the back of the
Optic eye. The lens of the eye is shaped
nerve like a camera lens or a magnifying
lens, convex on both sides (biconvex).
Pupil Unlike the cornea, the lens is capable
of adjusting its shape, a process called
Lens accommodation. A circular muscle
that surrounds the lens, called the
Ciliary Optic disk ciliary muscle, changes the shape
muscle
of the lens depending on the distance
Extraocular
muscles of the object of focus. Whenever you
focus your eyes on something close,
Figure 7.3 Anatomy of the eyeball. such as holding your hand a few inches
7-4
Viewing something Viewing something
far near
Lens
Far Lens
Figure 7.5 The lens is a biological tissue that

flattens when we are focusing on something far
Figure 7.4 If the light refracts incorrectly, the
away, and gets thicker when we focus up close.
image does not focus on the retina and our field
This process is called accommodation.
of view will be blurry.
away from our face, the lens becomes thicker in There are six muscles that control eye
the middle. Conversely, when you focus on the movement. These muscles, plus the muscle that
distant horizon, the lens flattens. controls upper eyelid movement, are called the
Another interesting consequence of the extraocular muscles. These seven muscles
shape of the lens is the way it bends light. Think receive innervation from three cranial nerves,
back to when you’ve held a magnifying lens in specifically cranial nerves 3, 4, and 6.
front of you as you look through it: The world you
see through the lens is both upside down and
reversed. This is exactly what the lens in
Levator palpabrae
our eyes does as it refracts light. As we superioris
look straight ahead, light from the upper Superior
oblique
part of our vision, like the ceiling, gets
projected to the bottom of the eyeball, Superior
while light from the floor passes through rectus
the lens and refracts to the upper part of
the eyeball. Additionally, light from the left
part of our environment is refracted onto
the right part of the eye, and vice versa.
We use the term visual field to Lateral
describe the portion of our surroundings rectus
Inferior
that can be seen without moving your eyes. rectus
If you look straight ahead, information on Medial Inferior
the left half of our vision are in our left rectus oblique
visual field, which is projected onto the
right half of both eyes. Conversely, objects Figure 7.6 The extraocular muscles are a series of
in the right half of our vision are in our right seven muslces, six of which control eyeball movement
visual field, which is projected as images and one (leavtor palpabrae superioris)which controls
onto the left half of both eyes. the eyelid.
7-5
7.2 The Retina
The back of the eyeball is the retina being shuttled into the brain via the optic nerve.
(ret-n-UH). The medial half of the retina is also The other two layers of cells modify that route
referred to as the nasal hemiretina since it is of communication. In the next paragraphs, we’ll
closer to the nose, while the lateral half of the take an in-depth look at the role of each of the
retina is called the temporal hemiretina since it five layers of neurons in the retina.
is closer to the temporal bone of the skull. The In the order of the pathway of
terms “upper hemiretina” and “lower hemiretina” communication, the five neurons of the retina are:
are commonly used as well.
In the center of the retina is a small pit 7.2.1 Photoreceptor cells
called the fovea. Light from only about 2 degrees Photoreceptors are the first cells in the
from the center of the visual field gets focused neuronal visual perception pathway. They are
onto the fovea. Compared to the rest of the retina, the cells that detect photons of light and convert
the fovea is where we have the highest acuity, or them into neurotransmitter release, a process
the clearest vision. As you are reading this text, called phototransduction.
light information from only 4 or 5 letters lands on Morphologically, photoreceptor cells
the fovea. have two parts, an outer segment and inner
segment. The outer segment contains stacks of
membranous disks bounded within the neuronal
membrane. These membranous disks contain
molecules called photopigments, which are the
light-sensing components of the photoreceptors.
Hundreds of billions of these photopigments can
be found in a single photoreceptor cell.
The inner segment contains the nucleus
and other organelles. Extending from the inner
segment is the axon terminal. Photoreceptors are
Figure 7.7 The fovea appears as a “pit” with
classified into two categories, named because of
the neuronal components swept away from the
their appearance and shape: rods and cones.
center of our vision.
The retina is the beginning of the nervous Rod photoreceptor cells

system’s involvement with the visual system. It Visual information from our peripheral
consists of five layers of neurons (described vision is generally detected by our rod cells,
below). The pathway of information moves from which are most densely concentrated outside the
the back of the eye towards the front, before fovea.
exiting the back of the eye in an area called the Rod cells are organized to have high
optic disk. Visual information is passed directly synaptic convergence, where several rod cells
through three of the five neuronal layers before (up to 30) feed into a single downstream route of
7-6
Out to optic in low-light conditions, which is
Retinal
ganglion nerve why our surroundings appear to
cells have a blue-ish tint at night. This
phenomenon is known as the
Amacrine
cells Purkinje shift, named after the
Direction of Czech anatomist Jan Purkinje who
incoming light
observed that his favorite brightly-
colored flowers appeared dull and
Bipolar
cells more blue as the sun was setting.
γ Cone photoreceptor cells

Horizontal Cone photoreceptor cells
cells
allow for high-acuity vision. They
are most densely packed at the
fovea, corresponding to the very
Photoreceptors
center of your visual field. Despite
being the cell population that
Cones Rods
we use for our best vision, cone
Figure 7.8 The five neuron layer of the retina. cells make up the minority of
communication (the bipolar cells, to be specific -

see 7.2.3). An advantage of a high-convergence
network is the ability to add many small signals
together to create a seemingly larger signal.
Day
Consider stargazing at night, for example. Each
rod is able to detect low levels of light, but signals
from multiple rod cells, when summed together,
allows you to recognize faint light sources as a
star. A disadvantage of this type of organization
is that it is difficult to identify exactly which
photoreceptor is activated by the incoming light,
which is why accuracy is poor when seeing stimuli
in our peripheral vision. This is one of the reasons Night
that we cannot actually read text in our peripheral
vision or see the distinct edges of a star.
Rod cells are most sensitive to light that
has a wavelength of 500 nm (blue-ish green).
Light at other wavelengths still causes changes Figure 7.9 Demonstration of the Purkinje shift. At
in the way rod cells respond, but to a lesser night, normal bright colors appear blue-ish due to
degree. Rod photoreceptors are maximally active increased activity of the rod photoreceptors.
7-7
420 498 534 564
Normalized absorbance
100 (M-cones) exhibit peak responding at 530
nm green light, and the long wavelength
cones (L-cones) are most responsive in
50 560 nm red light. Each of these cones
is activated by other wavelengths of light
S R M L too, but to a lesser degree. Every color
on the visible spectrum is represented
0
400 500 600 700 by some combination of activity of these
Wavelength (nm) three cone photoreceptors.
The idea that we have two different
cellular populations and circuits that are
Figure 7.10 Different photoreceptor cells respond to used in visual perception is called the
different frequencies of light. duplicity theory of vision, and is our
current understanding of how the visual
photoreceptors in the human retina, outnumbered system perceives light. It suggests that
by about 20-times more rod cells. both the rods and cones are used simultaneously
Unlike rod cells, cone cells have very low and complement each other. One component,
synaptic convergence. In fact, at the point of called the photopic vision system, uses cone
highest visual acuity, a single cone photoreceptor photoreceptors of the retina, and is responsible
communicates with a single pathway to the brain. for high-acuity sight and color vision in daytime.
The signaling from low-convergence networks Its counterpart, called scotopic vision, uses rod
is not additive, so they are less effective at low photoreceptors and is best for seeing in low-light
light conditions. However, because of this low- conditions, such as at night.
convergence organization, cone
cells are highly effective at precisely 180000
Temporal Nasal
160000 Cones
identifying the location of incoming
Number of cells per mm2
Blind spot
light. 140000
Cone photoreceptors are 120000 Rods
100000
responsible for processing our
80000
sensation of color (the easiest way
60000
to remember this is cones = color).
40000
The typical human has three different
20000
types of cone photoreceptors cells,
0
with each of these three types tuned 60 40 20 0 20 40 60 80
to specific wavelengths of light. The Fovea Angle
short wavelength cones (S-cones) (degrees)
respond most robustly to 420 nm violet Figure 7.11 The cone photoreceptors are dense in the fovea,
light. The middle wavelength cones while the rod photoreceptors are mostly in the periphery.
7-8
Clinical connection: Color vision deficiency of the three types of cone cells fails to respond
Color vision deficiency is a very common to the correct wavelengths of light, the person
condition resulting from a dysfunction in cone will lose the ability to differentiate between
photoreceptor cells. As you know, each person certain colors on the visible light spectrum. For
has three types of cone cells. However, if one example, lacking functional L-cones causes
a person to have difficulty
Prevalence distinguishing purple from
92% Normal color vision blue.
Deuteranomaly Color vision
2.7% (M cell deficiency) deficiency can either be
Protanomaly acquired (as a symptom of
0.66% (L cell deficiency)
disease or as a side effect
Tritanomaly
0.01% (S cell deficiency) of exposure to certain
chemicals) or inherited.
<0.0001% Achromatopsia
Most cases are inherited,
and the genes associated
with color vision deficiency
are often recessive
and located on the
X-chromosome. Because
these genes are sex-linked,
color vision deficiency is 15
Figure 7.12 Deficits of the the different photoreceptors lead to times more likely to occur in
seeing the visible spectrum in atypical ways (top). Color vision men than in women with a
deficiency can be assessed with Ishihara plates, a series of images. prevalence of about 8% of
An inability to see the 74 (bottom left), the 42 (bottom middle), or a males and less than 1% in
6 (bottom right) may indicate some form of color vision deficiency. females.
On the molecular and cellular scale, glutamate release, and hyperpolarization causes
the neuronal encoding of light information is a decrease in glutamate release.
counterintuitive. We normally think of neurons as In the dark, photoreceptor cells have
being excited when they are activated, releasing leak sodium channels that allow for extracellular
more neurotransmitter upon experiencing a sodium to enter those neurons, which is
stimulus. Photoreceptors, on the contrary, called the dark current. This current causes
decrease in excitability when they are exposed cellular depolarization. When a photon of light
to light. Additionally, they do not fire action strikes the photoreceptor, the cell responds by
potentials. Instead, their membrane potential decreasing its intracellular stores of a signaling
fluctuates, which determines the amount of molecule called cGMP, which in turn decreases
glutamate release: depolarization causes more the dark current. Light causes the neuron to
7-9
cis isomer Sidebar: Lateral inhibition
Bring your vision over to one of the white
“intersections” in the Hermann grid below. In your
peripheral vision, do you see faint fuzzy outlines of
gray circles at the other white intersections?
This phenomenon happens because of the
circuitry of the horizontal cells. In being activated, they
Light Enzyme
block adjacent signaling pathways from also sending
information forward. Because horizontal cells inhibit
adjacent neurons at the same “level,” we describe this
phenomenon as lateral inhibition. It is hypothesized
that lateral inhibition evolved to allow for better edge
trans isomer
detection, the ability to easily differentiate the outlines
of objects.
Figure 7.13 11-cis retinal can absorb a Now bring your focus to one of those fuzzy gray
photon, causing retinal to enter the high blobs. You will notice that the grayness disappears
energy state, 11-trans retinal. immediately when we look directly at it, but a new
gray blob appears where you were just looking at.
become hyperpolarized, which inhibits This happens because the size of the receptive field
neurotransmitter release. for each photoreceptor-to-bipolar synapse differs at
These neurons sense light the fovea from the periphery. Foveal photoreceptors
because of the presence of the have very little convergence onto their bipolar cells, so
photopigments found in the outer section they have very high precision, and are therefore less
of the photoreceptors. The photopigment susceptible to the illusion as seen above.
molecule has two components. Retinal
is a chemical synthesized from Vitamin
A. In the dark, retinal exists as 11-cis-
retinal, which has a low energy molecular
configuration. Light can be highly
energetic. When a photon hits retinal,
it causes the chemical to change to all-
trans-retinal, which is the high energy
state configuration. While in the all-trans-
retinal configuration, cGMP levels are
decreased, therefore blocking the dark
current, which causes hyperpolarization.
The other component is a protein Figure 7.14 Gray blobs appear at the intersections of
called an opsin. Opsins exist in different this Hermann grid because of lateral inhibition driven
forms, and they cause retinal to respond by horizontal cell activity.
7-10
differently depending on the wavelength of light: dendrites receive neurotransmitter signals from
some opsins cause the photoreceptors to be photoreceptors, and they send axonal projections
maximally activated at 420 nm, others at 530 nm, to the next two layers of neurons in the retina
and so on. (amacrine cells and retinal ganglion cells).
In mammals, bipolar neurons receive
7.2.2 Horizontal cells inputs exclusively from either rod or cone
Horizontal cells are interneurons that do photoreceptors. In other words, there are no
not directly participate in the pathway of signaling bipolar neurons that receive both rod and cone
in visual perception. Rather, they communicate photoreceptor input.
laterally, receiving synaptic inputs from As we’ve already discussed, photoreceptor
photoreceptors, and forming synaptic connections cells release glutamate. At most synapses in the
with the axons of nearby photoreceptors. Like nervous system, glutamate is excitatory. However,
most interneurons in the nervous system, at synapses between photoreceptors and bipolar
horizontal cells are inhibitory. cells, glutamate activates metabotropic mGluR6
Photoreceptors release glutamate onto receptors, which are inhibitory. In the light, there
the horizontal cells, which causes the horizontal is a decrease in glutamate release from the
cells to depolarize. More glutamate is released photoreceptors, and this leads to an increase in
when the photoreceptors are in the dark. In bipolar cell activity.
the light, the amount of glutamate released
is decreased, which causes horizontal cells 7.2.4 Amacrine cells
to hyperpolarize. This hyperpolarization then Amacrine cells, like the horizontal cells,
decreases neurotransmitter release onto nearby are interneurons that modify the communication
photoreceptor axons. Less inhibition onto pathway rather than directly being involved with
these photoreceptors causes depolarization, light sensation. Amacrine cells receive inputs from
which decreases signaling from these adjacent bipolar cells, and in turn, modulate the activity
photoreceptors. of nearby neurons. Like most interneurons,
This complex pattern of neurotransmission amacrine cells synthesize and release the
can be summarized more simply: activation of a inhibitory neurotransmitter GABA.
single photoreceptor causes inhibition of adjacent Amacrine cells exist in several different
photoreceptors. The activity of horizontal cells shapes and sizes. They help us detect directional
helps us isolate the origin of a light signal by motion, aiding us in knowing when to transition
minimizing the noise around it. between our scotopic or photopic vision systems.
Some amacrine cells also perform circadian
7.2.3 Bipolar cells regulatory functions.
Bipolar cells are the second type of
neuron that is directly responsible for visual 7.2.5 Retinal ganglion cells
perception, receiving visual input signals from Retinal ganglion cells are the third and
photoreceptor cells. They are named because of last cell type that directly conveys visual sensory
their morphology: from the cell body, they extend information, receiving inputs from the bipolar
projections in two opposite directions. Their cells. The axons of the retinal ganglion cells
7-11
bundle together and form the optic nerve, which receive light information through communication
then exits the eyeball through the optic disk. downstream of the photoreceptors and bipolar
These axons are unmyelinated before leaving cells, a small population of retinal ganglion
the optic disk – if they were myelinated, the lipids cells (1-2%) are photosensitive. These cells
that make up the myelin sheath would diffract contain a molecule called melanopsin, a light-
light and cause imperfections in vision. sensitive opsin molecule just like the photopsin
Unlike the two cells before them (the or rhodopsin found in photoreceptors. These
photoreceptors and bipolar cells), retinal ganglion cells contribute significantly to our body’s ability
cells communicate using action potentials. to adjust the circadian rhythms based on external
Although most retinal ganglion cells light cues (see chapter 12 for more information.)
Sidebar: The blind spot

Take a look at the image below. Close your right eye and bring your face close to the page,
focusing on the plus sign. Slowly move your head away from the page. At a distance of about one
and a half feet away, the dot will disappear!
The dot disappears under these specific conditions because visual information from the dot
falls directly onto the blind spot. The blind spot is about 15 degrees temporal from the fovea. We
don’t notice the blind spot in everyday life because usually both eyes are working simultaneously,
so when something enters the blind spot of the right eye, it appears in the visual field of the left
eye. The blind spot only comes into effect when using monocular vision, or when we only see with
one eye. The blind spot is elliptical, and you can demonstrate this using the drawing above: Bring
the dot into your blind spot as before, but this time, rotate the page, pivoting around the plus sign.
The dot reappears as it moves above or below the blind spot.
Now, repeat with the figure below. Hold the page at the same distance where you noticed
the blind spot. How would you describe what happens to the break in the line? While we are unable
to physically detect any light that falls onto the blind spot, our brains fill in the gap in sensation by
“filling in” the blind spot with the adjacent visual stimuli.
Figure 7.15 The blind spot can be observed in monocular vision with stimuli like these.
7-12
The retina is not completely uniform across
the entire back of the eye. There are a few spots
of particular interest along the retina where the
cellular morphology is different: the fovea and
the optic disk.
There are two cellular differences that
explain why the fovea is the site of our best visual
acuity. For one, the neurons found at the fovea
are “swept” away from the center, which explains
why the fovea looks like a pit. Cell membranes
are made up mostly of lipids, which distort the
passage of light. Because there are fewer cell
bodies present here, the photons of light that
reach the fovea are not refracted by the presence
of other neurons.
Secondly, the distribution of photoreceptors
at the fovea heavily leans toward cone type
photoreceptors. Because the cone cells at the
fovea exhibit no convergence, they are most
accurately able to pinpoint the exact location of
incoming light. On the other hand, most of the
photoreceptors in the periphery are rod cells. With
their high-convergence circuitry, the periphery of
the retina is suited for detecting small amounts
of light, though location and detail information is
reduced.
Another anatomically interesting area of
the retina is an elliptical spot (1.9mm vertical by
1.75 mm horizontal) called the optic disk. This is
where the optic nerve exits the eye. At this part of
the retina, there is an absence of photoreceptor
cells. Because of this, we are unable to perceive
light that falls onto the optic disk. This spot in our
vision is called the blind spot.
7-13
7.3 The Optic Nerve
The optic nerve, or cranial nerve II, so the left nasal hemiretina crosses at the optic
exits the posterior end of the eyeball, and travels chiasm to project into the right hemisphere of the
posteriorly along the ventral surface of the brain. brain. On the other hand, visual information from
Like all other cranial nerves, the optic nerve is the temporal hemiretina projects ipsilaterally (left
paired, meaning there is one on each half of the temporal hemiretina projects into left hemisphere,
body - one for each eye. Both optic nerves merge and right temporal hemiretina projects into right
at a spot called the optic chiasm, then diverge hemisphere ).
yet again as they travel posteriorly towards the The easy way to keep track of this unusual
thalamus. system is to remember that all information from
the left visual field enters the right hemisphere
of the brain, while visual information from the
right visual field enters the left hemisphere of the
brain. Because of the light-refracting properties
of the lens, objects in the left visual field get
represented onto the right half of each eyeball.
Left visual Right visual

field field
Optic nerve
Optic
Figure 7.16 Cranial nerve II, or the optic nerve chiasm
(highlighted in red), exits each of the eyeballs
Thalamus
and meet at the optic chiasm before diverging.
The axonal connections in the optic

nerve are not quite as simple as its anatomical Primary
visual cortex
appearance. From each optic nerve, some of the
nerve fibers cross the midline, headed towards
the contralateral hemisphere. Other nerve fibers Figure 7.17 Visual information from the left visual
meet at the optic chiasm, but then project into field (blue) is carried into the right hemisphere of
the ipsilateral hemisphere. Visual information the brain, and visual information from the right
from the nasal hemiretina projects contralaterally, visual field (red) is carried into the left hemisphere.
7-14
The right half of the left eye is the nasal side,
so this information crosses contralaterally. Clinical correlation: Glaucoma
The right half of the right eye is the temporal The optic nerve is particularly sensitive
side, so this stays ipsilateral. This information to injury. A condition called glaucoma can
then passes towards the thalamus for the cause optic nerve destruction, leading to
beginning of central processing. blindness. Glaucoma affects up to 3 million
Not all of the axons convey direct Americans, but can be easily detected during
visual information into the thalamus for visual an annual eye exam. Glaucoma can result
perception. One pathway of the optic nerve from several different causes including
sends information into a midbrain structure high intraocular pressure, physical trauma,
called the pretectal area. The information medications, or a natural genetic weakness
sent into the pretectum is related to some of the nerve. High intraocular pressure is
of the more “primitive” visual functions. For the greatest risk factor for glaucoma, since
example, the ability for the eyes to follow hypertension compresses the axons, which
something unconsciously as it moves across can also decrease the blood flow to the optic
your field of view is called smooth pursuit, nerve. Almost all the first-line therapies
and this reflex is partly carried out by the to treat glaucoma decrease intraocular
optic nerve pathway into the pretectal area. pressure.
Another signaling pathway
that branches from the optic nerve is the
retinohypothalamic tract (RHT). It does
not carry any conscious visual information.
The RHT conducts light information from the
intrinsically-photosensitive retinal ganglion cells.
Instead of sending axonal projections towards
the thalamus, this information pathway forms
a synapse into a region of the hypothalamus
called the suprachiasmatic nucleus, or SCN.
This structure functions to help the body adapt
its sleep-wake cycle in the face of changing day-
night patterns (Chapter 12).
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7.4 Visual perception in the brain
The first synapse of the optic nerve is
formed in the thalamus at a subregion called the
lateral geniculate nucleus, or LGN (originating
from the Latin genu-, meaning “knee”). The LGN
is divided into six layers, named 1 through 6,
going from ventral to dorsal. Histologically, the
LGN is made up of three different populations of
neurons. The magnocellular cells (magn- means
large, as in “magnify” or “magnanimous”), or M
cells, are large-diameter neurons (~20 µM) that
are found in layers 1 and 2. The parvocellular
cells (parv- means small), or P cells, are small-
diameter (~10 µm) neurons found in layers 3
through 6. Ventral to each layer is a row of very
small neurons, called koniocellular cells (konio-
Figure 7.18 Synaptic circuitry showing the inputs
means dust), or K cells.
into the layers of the lateral geniculate nucleus of
We know that the visual information from
the thalamus.
the temporal retina synapses ipsilaterally, while
information from the nasal retina synapses
less about sensation and mostly about perception.
contralaterally. The specific synaptic inputs into
For example, many of the post-optic radiation
the LGN follow a specific organization depending
signaling pathways are concerned with questions
on the origin of the retinal ganglion neurons.
like attention, object orientation, and recognition.
Temporal retinal ganglion neurons synapse only
Many visual perception functions are performed
onto layers 2, 3, and 5 of the ipsilateral LGN, while
by multiple brain regions, and no single area
nasal retinal ganglion neurons form synapses
is responsible for any one compartmentalized
exclusively onto contralateral layers 1, 4, and 6.
function. In other words, there is still much work
The outputs of the LGN are a series of
to be done on understanding the precise function
axonal bundles called the optic radiations.
of the areas of the visual cortex.
These optic radiations are divided into two main
The outputs of the LGN are axons which
bundles, the upper and lower divisions. The
form synapses in the primary visual cortex,
upper divisions carry information from the lower
which is also called V1. Alternatively, V1 is also
visual field, whereas the lower divisions carry
called the striate cortex because it has a large
information from the upper visual field.
white stripe that can be seen in surgical dissection.
From the LGN of the thalamus, the optic
This white stripe is the bundle of incoming optic
radiations project to the occipital lobe at the
tract axons, which are heavily myelinated.
caudal (posterior) end of the brain. Once visual
Each neuron in V1 receives visual
information travels into the cortex, the process is
information from a specific patch of retinal cells.
7-16
Clinical connection: Anatomy of vision loss
Health care professionals can diagnose Left visual Right visual
field field
the location of an injury based on the deficits
in a patient’s visual field. To record the sites
of vision loss, they may use a pair of circles Left eye Right eye
vision vision
which show which areas of the visual field are
lost. For example, if a person is missing their
right eye, all information from the right eye will
be missing and the right circle will be colored
in black.
If the visual information-conveying
pathway is damaged, a person may suddenly
lose half of their visual field resulting in a
condition called hemianopsia (hemi- meaning
half, a- meaning none, and -opsia referring to
vision). There are a few forms of hemianopsia
that correlate to specific injuries of the optic
nerve. For example, injury to one branch of Figure 7.19 Injury to different parts of the optic
the nerve after the optic chiasm results in tract (numbers) leads to specific deficits in
homonymous hemianopsia, the loss of either vision (right).
the left or right visual field of both eyes.
Injuries may damage some optic of a person’s visual field. If the upper division
radiations while sparing the others. This of the right optic radiation is injured, the person
results in a condition called quadrantanopsia, will lose the upper left visual field of both of
resulting in a loss of a fourth, or one quadrant, their eyes: left superior quadrantanopsia.
This organizational pattern, where a section of visual perception. For example, V3 and V5 help
retinal inputs map onto neurons of a specific us comprehend motion, V4 contributes to color
section of V1, is called retinotopic organization. perception, and V6 helps with understanding our
For example, the dorsal part of V1 receives position in our surroundings.
information from the bottom half of the visual
field. Visual information from the fovea, despite Dual stream hypothesis
being only 1% of the total visual field, takes up After V2, visual information passes through
about half of all neurons in V1. two streams of communication: the dorsal stream
After processing in V1, visual information and the ventral stream.
is passed along to the secondary visual cortex, The dorsal stream is described as the
or V2. V2 represents the beginning of the visual “where” pathway because these structures help
association cortices. Following V2 are other visual us identify where objects are located in the space
cortical areas that contribute to various aspects of around us. The dorsal stream includes area V5,
7-17
stimuli and scenery or buildings, respectively.
When the visual system senses these complex
Fovea stimuli, those signals get processed through these
ventral stream pathways. These incoming stimuli
are compared with the memories stored in the
ventral stream, and this comparison contributes
to our capacity for perception and identification.
The two streams are not independent
of each other. Rather, successful organisms
require the melding of both components of
visual perception. For example, imagine you are
Left brain Right brain
a prehistoric organism living in a food-scarce
environment. Approaching a small berry tree, you
would use ventral stream structures to correlate
the berries with memories: Did these berries taste
good and give me the calories I need to survive?
Or did these berries make me violently ill, and
are therefore probably poisonous? If they are the
delicious berries that I want, I will use the dorsal
Figure 7.20 Retinotopic organization of the visual stream structures to take note of their precise
field. Note that adjacent areas of the visual field location so I can reach out for them and pick the
are represented in adjacent areas of the cortex, berries . In this example, proper interaction of the
and that the visual information in the fovea is dual streams contributes to goal-driven actions.
represented very heavily in the cortex. Dorsal stream
which contributes to perception of motion. These

structures also guide us when we move through
our environments, contributing to our sense of
spatial awareness. For example, a task such as
reaching out to grab an object in front of you uses
a combination of these features, so this task is
guided largely by dorsal stream structures.
The ventral stream is the “what” pathway,
Ventral stream
and helps in the identification of objects that we
see. Ventral stream structures are important for Figure 7.21 The dual stream hypothesis proposes
visual memory. The fusiform face area (FFA) that visual information is processed by two related
and the parahippocampal place area (PPA) are neural pathways after leaving V2, a dorsal stream
especially important for the storage of facial (green) and a ventral stream (purple).
7-18
Clinical connection: Dysfunction of the stops moving. People with akinetopsia have
dual-stream severe difficulty crossing the street or pouring
Deficits in the circuitry of visual a cup of tea. Usually, akinetopsia results from
processing up until this point in the chapter brain injury like trauma or a stroke.
result in largely predictable outcomes. Prosopagnosia, or face blindness, is
However, once that information enters the another unusual visual condition that results
cortex of brain, the circuitry involved becomes in people who have tremendous difficulty with
much more complex, and unusual visual identifying faces. People with prosopagnosia
perception disorders may result from atypical recognize that they are looking at a face.
neural communication in the brain. They see the eyes, nose, and mouth, but they
Akinetopsia, or motion blindness, often cannot identify who that face belongs
is a very rare visual condition resulting in the to. Some cases are so severe, that they
inability to perceive objects in motion. Instead cannot even recognize themselves in a mirror.
of seeing movement, these people see the Prosopagnosia is far more common than
world as a series of “freeze frames” that refresh akinetopsia; an estimated 1% of people have
occasionally, or only whenever the object some degree of face blindness.
Saccadic eye movements

Take a look at the objects around you
right now. You don’t notice it, but as you shifted
your focus from one object to the next, your eyes
made tiny, rapid, jerking motions over the different
objects instead of moving smoothly across your
field of vision. These rapid movements, driven by
the actions of the extraocular muscles, are called
saccades (pronounced “suh-KAHD”). Saccades
are among the fastest muscle movements in the
body.
These saccades help you accurately Figure 7.22 Eye tracking (right) allows us to
capture visual information from your surroundings. observe the saccades that may happen when we
The fovea, which has the highest acuity vision, scan over this facial stimulus (eye).
only collects information from a tiny portion of
your visual field. By performing these saccades,
you can scan over several objects with the
highest acuity, thus allowing your brain to build a
representation of the visual field.
DePaul University.
7-19
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7-20
8-1
Editor: Alexander Rajan, PhD
Our nervous system is equipped with a properties in response to the stimulus (such as a
variety of specialized biological “tools” that can retinal photoreceptor cell responding to photons).
detect much more than just photons of light. We Then, that information initiates a series of signals
can detect the shape of air waves, and interpreting into the CNS, reaching structures such as the
those signals give us sound information and the thalamus (in most cases; olfaction being an
perception of music. We can detect stimuli with exception), primary sensory cortical areas, and
our skin, such as temperature, pressure, and finally, higher order perception. Although there
textures. We can also detect physical information are several sensory components throughout
about our own bodies, as in the way our head is our body that detect these signals, there are no
tilted or the position of our limbs. In this chapter, sensory receptors in our central nervous system.
we describe these other forms of physical stimuli, As we discuss sensory and perception
and how that information is conveyed to and further, it’s good to keep in mind that not all
represented in the brain. sensations are perceived. For example, your
All sensory systems, including vision body can detect changes in blood pressure, and
(Chapter 7) and the systems described below, your brain responds to these changes activating
follow the same general path of communication compensatory neural circuits. However, this
into our nervous systems and awareness. First, response does not reach consciousness and are
the incoming signal must reach a cell (generally not perceived.
called a transducer) that can change its electrical
Chapter 8 outline


Unlike photons of light, sound waves are or through solids. Without a medium, sound fails
compressions and rarefactions of a medium. For to propagate: As the tagline from the thriller Alien
us land animals, that medium is usually air, but reads, “In space, no one can hear you scream.”
sound waves can propagate very well in water
8-2
8.1.1 Sound waves
Before we get to the anatomical structures Amplitude, or “How much do the waves displace
involved in sound perception, it is important to first the medium from baseline?”
understand the physical nature of sound waves. The larger the amplitude of the wave, or
All sounds, from the clattering of a dropped metal the greater distance between the peak and the
pan to the melodies of a Mozart violin concerto, trough of the signal, the louder the sound is.
are contained in their corresponding sound Loudness is measured in decibels (dB). To give
waves. There are three components of sound you an idea of approximate sound intensities, the
waves. background noise of a quiet library is about 40
dB, and a typical conversation is close to 60 dB.
Frequency, or “How often do the sound waves A rock concert or lawnmower is between 100 and
compress?” 110 dB, which is right around the pain threshold.
The more often they repeat, the higher Prolonged exposure to these high amplitude
the pitch. The highest notes humans are able to sound waves can lead to permanent damage to
hear is around 20,000 Hz, a painfully-shrill sound the auditory system resulting in hearing loss or
for those who can hear it. People often tend to tinnitus (a ringing in the ear, even in the absence
lose their high frequency hearing as they age. On of a sound stimulus).
the opposite end of the spectrum, low frequency
sounds are the deep rumbles of bass, and the
human ear can hear sounds down in the 20 Hz
Increasing amplitude
Increasing volume
range. Doubling the frequency changes the tone
by an octave: concert A is 440 Hz, and the A an
octave higher is 880 Hz.
Increasing frequency
Increasing pitch
Figure 8.2 Volume is a result of increased

amplitude of displacement.
Timbre, or “How complex is the wave form?”

Timbre (TAM-bur) refers to the “color” or
the “character” of the sound. Both a piano and a
Time guitar could play the exact same note, yet these
two instruments would produce very different
Figure 8.1 Pitch is a result of increased frequency sounds. This happens because the sound waves
of displacement. created by each instrument differ in complexity.
Both notes contain the same fundamental
8-3
Amplitude Viola playing D4 Violin playing D4 Bassoon playing D4
100 1,000 10,000 100 1,000 10,000 100 1,000 10,000

Hz Hz Hz Hz Hz Hz Hz Hz Hz
Figure 8.3 Timbre refers to the complexity of the waveform. Instruments sound different because the
they produce peaks at different frequencies related to the fundamental frequency.
frequency which gives us the pitch of that note. is coming from. In some nonhumans, the pinna
But each wave differs in the number of other high serves these functions and more: some animals
frequency components called overtones that are able to disperse excess heat through their
are contained within that note. These overtones ears (elephants), and some even use them to
oscillate at a frequency that are multiples of display emotion (dogs, horses).
the fundamental frequency (twice as often, for At the end of the auditory canal is the
example). A sound wave without any overtone tympanic membrane, or ear drum. This
frequencies is called a pure tone, or a sine wave membrane is a very delicate piece of tissue at only
tone. 0.1 mm thin, and is subject to damage by physical
Pinna
(Auricle)
8.1.2 Physical structures of
the auditory system
Our auditory system is a Semicircular
canals
series of physical structures and
nervous system components that
Ossicles
are responsible for conveying sound
waves into meaning and context.
The external component of
the auditory system begins with the
pinna or auricle, or more simply, the Auditory canal
ear. Its shape functions as a funnel, Cochlea
capturing and channeling sound
waves into the auditory canal. The
Tympanic Oval
pinna and the auditory canal are
membrane window
parts of the outer ear. Also, because (Eardrum)
the pinna is asymmetrical, its shape
helps us determine where a sound Figure 8.4 Anatomy of the auditory system.
8-4
injury such as head trauma, nearby explosions, or The movement of the ossicles are partially
even changes in air pressure during scuba diving. regulated by two different muscles, the tensor
When incoming sound waves reach the tympanic tympani muscle which connects with the malleus,
membrane, it vibrates at a matching frequency, and the stapedius muscle which connects to the
amplitude, and timbre. The tympanic membrane stapes. When these muscles contract, the ossicles
also represents the boundary between the outer move less, which decreases the intensity of loud
ear and the middle ear. sounds. This response, called the acoustic
Physically attached to the tympanic reflex, dampens incoming sound by about 15
membrane are the ossicles, a series of three bones dB. (This is why we talk much louder than normal
that convey that vibrational sound information. when we first leave a concert: we have lessened
These bones in order, called the malleus, incus, auditory feedback from our ears, so we tend to
and stapes, conduct vibrations of the tympanic talk louder to compensate.) Crickets use a similar
membrane through the air-filled middle ear. The reflex so that they don’t deafen themselves while
tympanic membrane and the ossicles function chirping!
to amplify incoming sounds, generally by a The stapes, the third of the ossicles, is
tenfold difference. This amplification is important physically connected to the oval window, a thin
because the inner ear is filled with liquid rather membrane that is at the entrance to the main
than air, and sound waves do not travel very well auditory structure of the inner ear, a hollow bone
when moving from air into a denser medium - called the vestibular labyrinth. The auditory
think about how muffled sounds are when you part of this structure is the spiral-shaped cochlea
submerge your head underwater. (cochlea is named for the Ancient Greek word
“snail shell”.) Think of the cochlea as a rolled-up
cone that makes about 2 and 3/4 turns. If this cone
was theoretically unrolled, the widest diameter
Malleus Incus
portion (called the base) would be closest to the
Connects oval window, while the narrowest portion (called
to tensor
tympani the apex) would be at the center of the spiral.
This change in shape from the base to the
Connects to apex is important: objects with different stiffness
Connects to stapedius
tympanic vibrate at different frequencies. The base of the
membrane cochlea is stiffer than the apex, and so it vibrates
Stapes are higher frequencies than the apex. This makes
Connects to different points along the spiral of the cochlea
oval window
responsive to different frequencies.
Inside the cochlea is a specialized epithelial
Figure 8.5 Anatomy of the ossicles, found in
membrane called the Organ of Corti. The Organ
the middle ear. Bones are labeled in black,
of Corti is the first nervous system structure that
connections to membrane labeled in blue, and
is responsible for processing physical vibrations
connections to muscle labeled in red.
and converting them into signals that the nervous
system can interpret.
8-5
Figure 8.6 Anatomy of the Organ of Corti and hair cells under progressively higher magnifications in an
electron microscope. The Organ of Corti is a spiral structure (left). The three rows of the outer hair cells
and the single row of inner hair cells can be seen by zooming in (middle). At highest magnification, the
stereocilia can be seen (right).
8.1.3 Neural components of the auditory endolymph. The endolymph is a high potassium,
system low sodium solution that is similar to CSF. It
The Organ of Corti contains the makes up the extracellular solution in the inner
components necessary for converting sound ear.
waves into action potentials. Adjacent to the Embedded along the interior surface of the
Organ of Corti in the cochlea is a liquid called Organ of Corti are the somata of hair cells, the
Figure 8.7 Physiology of hair cells. Physical deflection causes the opening of the mechanically-gated
ion channels, which allows movement of K+ into the hair cells, causing excitation.
Stereocilia
Mechanically-gated
ion channels
Hair cell
Synapse
Bipolar neuron Hair cell

of the spiral activity
ganglion At rest = baseline Strong deflection =
activity strong depolarization
8-6
primary sensory neurons that interpret physical picometer is one trillionths of a meter) is sufficient
movement. They are named “hair cells” because to cause changes in electrical signaling in a hair
of their cellular structure; each hair cell has cell!
somewhere between 30 and a few hundred hair- The length of the stereocilia differs between
shaped stereocilia that protrude away from the hair cells, and these differences allow them to
Organ of Corti, reaching into the endolymph. We respond to different frequencies of vibrations.
have two different populations of hair cells, the Shorter hair cells are more responsive to high
inner hair cells and outer hair cells. pitch sounds, and are located closer to the base
Movement of the inner hair cells is of the cochlea. On the other hand, longer hair
important for the detection of sounds. When a cells are more sensitive to lower pitched sounds,
vibration reaches the oval window, the endolymph and are located near the apex, in the center of
also vibrates, causing a physical movement of the the spiral. Accordingly, there are two “tuning”
membranes within the cochlea, which displaces mechanisms in the cochlea that make specific
the stereocilia. The physical movement causes inner hair cells sensitive to specific frequencies:
mechanically-gated ion channels to open, the position along the spiral, and the length of the
allowing K+ to enter the hair cells, resulting in stereocilia.
depolarization and neurotransmitter release. This The outer hair cells function as an
process of physical motion that leads to neural amplifier to increase the intensity of vibrations.
signaling is called mechanotransduction. Hair It is estimated that the outer hair cells increase
cells are very sensitive to stereocilia movement: sound by anywhere between 20 and 80 dB. We
a deflection on the order of 100s of picometers (a have three rows of outer hair cells.
Clinical connection: Hearing loss

Many people experience permanent
hearing loss, a decrease in volume by 25
dB or more. Hearing loss is divided into two
categories. Conductive hearing loss is
a result of changes to the auditory system
up to the oval window, such as a tumor in
the ear canal, a perforation of the tympanic
membrane, or changes in middle ear pressure
(such as how everything sounds muffled while
changing altitudes when an airplane takes off,
for example). Sensorineural hearing loss
results from changes at the level of the inner
ear or further up in the neural pathway, such
as hair cell damage, a brain tumor, bacterial Figure 8.8 Damaged hair cells under an
or viral infections, or exposure to various electron microscope.
toxins or drugs.
8-7
The most common cause Internal
implant
of hearing loss is excessive noise
exposure. Although the acoustic
Auditory
reflex is capable of dampening the
Sound nerve
intensity of the incoming vibrations, processor
prolonged exposure to high amplitude
sound waves can still cause damage.
Electrode
Motorcycles, the maximum volume
on headphones, or loud venues like
concerts and clubs can produce Figure 8.9 A cochlear implant directly stimulates the
sounds in the 95-110 dB range, which neural components of the auditory system.
can cause some permanent hearing
loss. Additionally, the acoustic reflex is not fast so it is common for people to lose sensitivity to
enough to minimize damage from sudden, loud high-frequency sounds. The loss of these hair
sounds in excess of 120 dB, such as a gunshot. cells can begin as early as a person’s 20s -
All of these sources of acoustic trauma are some places intentionally play high frequency
preventable by wearing appropriate hearing sounds to prevent teenagers from loitering.
protection, which can decrease the intensity of Partial hearing loss can be reversed with the
sounds by up to 30 dB. help of medical devices. A hearing aid is a
Old age is another common cause of processor that helps to filter out background
hearing loss, likely because older people have noise, decrease pitch, and amplify incoming
had more accumulated exposure to noise. sounds. A cochlear implant is a surgically-
An estimated 1 in 3 people older than 65 implanted device that receives incoming sound
have hearing deficits. We are born with about information and directly stimulates the auditory
15,000 hair cells, but throughout the course of nerve via electrodes, bypassing the external
our life, many get damaged irreparably. The components of the auditory system.
shorter hair cells are more sensitive to injury,
Hair cells form glutamatergic synapses onto the cochlear nuclear complex, which carries
bipolar neurons of the spiral ganglion. The axons out some auditory processing functions.
of these neurons make up the vestibulocochlear One of the primary functions of the superior
nerve (Cranial nerve VIII, historically called the olive is to help us figure out if a sound originates
auditory nerve. This nerve also carries vestibular from the left or the right side of our head. To do
information, which is also processed in the inner this, the superior olive performs two different
ear. See section 8.2.2 for more details.) Some calculations. First, sounds are louder the closer
neurons project into a pontine area called the you are to them. A difference in volume between
superior olive, an integrative center that receives what one ear and the other ear perceives, called
bilateral inputs from both ears. Other neurons the interaural level difference, is evaluated
project into an area of the rostral medulla called by neurons in the lateral superior olive. The
8-8
have ear openings at different heights on
their heads, increasing their ability to localize
the source of a sound on the vertical axis.
Auditory
cortex (A1) Auditory information is then passed
Brain into inferior colliculus (IC). Signaling
within the IC is important for interactions
Medial between multiple sensory inputs and a motor
geniculate response. These IC neurons are particularly
body Midbrain
responsive to biologically-relevant
sounds, such as unexpected noises,
Inferior
colliculus Midbrain which may signal an approaching
predator. Processing in the IC helps
the animal focus their attention
Nucleus of lateral
lemniscus Pons towards these stimuli.
The IC then conveys that
auditory information into the medial geniculate
Pons body, one of the nuclei of the thalamus. These
Superior olive thalamic neurons then send projections into the
primary auditory cortex, or A1 (historically
Medulla called Herschel’s gyrus.) A1 is the dorsal-
most part of the temporal lobe.
CN VIII Cochlear nuclear Many of the neural processing
complex components of sound, such as the Organ
of Corti, the spiral ganglion, and A1, are
Figure 8.10 The neural pathways involved in the tonotopically organized, meaning that
auditory system. adjacent physical areas are responsible
for conveying information from adjacent
second calculation is related to the speed of frequencies. For example, the hair cells that
sound. Sound travels roughly a kilometer in respond most to 440 Hz vibrations are right next
three seconds. Because of this delay, sounds to to cells that respond maximally to 441 Hz, but
reach one ear sooner than it reaches the other. far away from cells that respond most to 14,000
This interaural time difference is assessed by Hz. Likewise, in the cortex at A1, the cells that
neurons of the medial superior olive. The ability best process 440 Hz are adjacent to those that
for these neurons to properly localize sound is the best process 441 Hz, but far away from those
result of years of training. that maximally respond to 14,000 Hz.
Because both ears (in humans and most After signal processing in A1, that sound
non-humans) are at the same height, sounds information is then passed through the secondary
above and below can be difficult to localize. This and tertiary auditory cortices, which likely carry
is why sometimes people and animals tilt their out higher order auditory functions. One of the
heads to try to hear better. Some species of owls earliest studied cortical areas involved in auditory
8-9
processing is Wernicke’s area, which is critical
Clinical connection: Tinnitus
to the understanding of speech and language
Tinnitus is a condition characterized by
(See chapter 14 for more details).
the occasional perception of a ringing, whistling,
There is evidence to support a dual
buzzing, or clicking sound in the absence of a
stream organization to auditory perception,
genuine stimulus. Tinnitus is a symptom rather
just like in the visual system in cortex. The
than a disease. It often appears after some degree
dorsal auditory stream helps identify the
of hearing loss or injury; alternatively, it can come
location of sounds (analogous to the where
and go without any particular underlying cause.
pathway), speech production, and language
An estimated 15% of people experience some
related memory, while the ventral auditory
amount of tinnitus, but about 2% of people have
stream contributes to sound recognition
clinically significant tinnitus.
(similar to the what pathway) and sentence
It is still unknown what causes tinnitus,
comprehension.
however a common predictor of tinnitus is
hearing loss. This correlation has led researchers
to our current leading theory about tinnitus,
which suggests that the perception of phantom
sounds originates in the brain as a result of
faulty plasticity: the “understimulated” brain,
which doesn’t receive expected auditory inputs,
produces these abnormal signals.
Figure 8.11 Tonotopy is maintained across many of the auditory neural structures, from the cochlea to
the auditory cortex.
Corresponds to
apex of cochlea
Corresponds to
base of cochlea
Cochlea 1 2 4 8 16
A1 .5
A2
8-10
When we tilt our head to the side, or (the prefix oto- meaning “ear”, and the suffix
look up and down, that movement information -lith meaning “rock”) embedded in a 50 uM thick
is conveyed to our brain using the vestibular gelatinous membrane. Also embedded within
system. The vestibular system is a sort of three- this membrane are the stereocilia of a different
dimensional compass that can detect head population of hair cells. These otolith hair cells
movement, and that information helps us figure are biologically similar to the hair cells found in
out how our head is oriented and how to balance the cochlea: deflection of the stereocilia allows
ourselves in changing conditions. for K+ in the surrounding endolymph to enter the
The vestibular system is made up of two cells through mechanically-gated ion channels.
structures that are intimately tied in with the The main difference is the nature of the stimulus
anatomical features of the inner ear. that cause the sterocilia to bend. In the cochlea,
vibrations in the surrounding tissue cause hair cell
8.2.1 The Otolith Organs movement. In the saccule and utricle, however, it
Next to the cochlea and within the vestibular is a shifting of the physical weight of the otoconia
labyrinth are two membranous sacs, the saccule that result in hair cell movement.
and the utricle. Collectively, these structures The information encoded by the hair
are responsible for determining changes in cells is passed into the brain via a branch of the
inertia. The saccule is more sensitive to vertical vestibulocochlear nerve (CN VIII). These axons
movements, like when you are standing in a send projections to several brain areas, notably
moving elevator. The utricle is more responsive the cerebellum, which is a structure critically
to horizontal movements, such as when driving important for balance. CN VIII also projects into
around a corner too quickly. the reticular formation of the brain stem, the
Within the saccule and utricle are otoliths, spinal cord, and the thalamus.
are a series of small calcium carbonate crystals
8.2.2 The Semicircular Canals
The semicircular canals are the
Semicircular
canals structures that are responsible for detecting
Utricle head rotation. Anatomically, they are a series of
Saccule three arch-shaped membranous tubes within the
vestibular labyrinth, each one oriented at a right
Cochlea angle to each other. Because of this shape, the
semicircular canals sense and convey information
about any direction of head movement: roll, pitch,
Ampullae and yaw.
These semicircular canals are filled with
endolymph, the same potassium-rich solution
Figure 8.12 Anatomy of the vestibular system. that is in the cochlea that is important for auditory
8-11
sensation. At the end of each of the three canals cells have mechanically-gated ion channels
is a small swelling called the ampulla. Contained which work on a “push-pull” system: when the
in the ampulla is a gelatinous membrane called stereocilia are deflected in one direction, the hair
the cupula. Here, hair cells extend stereocilia, cells depolarize, while deflection in the opposite
as well as one cellular protrusion called a direction causes hyperpolarization.
kinocilium, into the cupula. When we tilt our
head, the endolymph in the semicircular canals Vestibular reflexes
flows in the ampulla, which physically displaces Many axons from the pontine vestibular
the cilia. As in the auditory system, these hair areas send projections into the cerebellum, and
these signals are important for reflexes related to
balance. For example, imagine you are standing
Clinical connection: Vertigo facing forward on a crowded bus when it stops
Vertigo is the sensation of spinning or abruptly. The sudden change in inertia causes
movement while standing still. Vertigo often your body to reflexively pushing your toes into
leads to dizziness, imbalance, ear pain, the ground, preventing your body from toppling
nausea, or vomiting. It can indirectly lead to forward. This behavior is driven by neural signaling
injuries, especially as a person stands up in the vestibular organs and their communication
or if they experience vertigo while driving. with the cerebellum.
A symptom rather than a disease itself, an A similar postural reflex that depends
estimated 7% of people experience vertigo in on vestibular inputs is the righting reflex. This
their lifetimes, affecting women about 3 times is a behavior that develops early in several
as often as men. animals from humans to Drosophila, and allows
There are a variety of conditions that the animal to correct their body position if they
could cause a person to experience vertigo. are in an abnormal orientation (imagine a baby
Benign paroxysmal positional vertigo can who can get back to crawling on all fours after
come and go spontaneously, and is generally they have fallen on their side). Generally, this
not a sign of an underlying health condition. reflex is learned during the first few weeks of life.
People with Meniere’s disease, a chronic Knowing up from down depends on the afferent
condition diagnosed in early adulthood, vestibular signals, however performance of the
often experience vertigo along with other motor task also requires integration of visual and
ear-related symptoms such as tinnitus or somatosensory inputs.
hearing loss. Bacterial or viral infections can A more subtle reflex is the vestibulo-
cause inflammation of the inner ear, resulting ocular reflex (VOR), which is observed as our
in abnormal vestibular signaling. Excessive eyes stay fixated on a target while our head
alcohol intoxication decreases the density moves. This allows our vision to stay focused,
of the endolymph and potentiates inhibitory even as the head is moving. For example, after
signaling, resulting in exaggerated motor rotating your head to the right, the eyes reflexively
responses following head movement. Severe move to the left, which allows for the visual field
head trauma that damages the inner ear may to be stabilized briefly. It can be observed as a
also cause vertigo. physician performs a diagnostic assessment
8-12
Semicircular
canals Right Left Inhibitory
CN VIII Excitatory
CN III
Vestibular
nucleus Lateral rectus
Medial
rectus
CN VI
Figure 8.13 Neural circuitry underlying the vestibulo-

ocular reflex (VOR) originates at the semicircular
canals that detect head movement and ends with
compensatory extraocular muscle activation.
called the rapid head impulse test, where they move

your head quickly side to side (as if you were shaking
your head “no”) while watching your gaze.
This response is driven through a series of
three synapses. The first synapse is formed between
the axonal projections from neurons of the vestibular
system, and neurons of the vestibular brainstem
nuclei. From here, these neurons send axonal
projections to the contralateral hemisphere (that is
to say, their axons decussate) and form synaptic
connections with two populations of neurons in the
contralateral pons. One set of motor neurons excite
the extraocular muscle opposite of the eye movement:
a right head turn will trigger excitation of the lateral
rectus of the left eyeball, which pulls the left eyeball in
the temporal direction (left). The other population are
interneurons that eventually excite the medial rectus
of the right eyeball, the extraocular muscle that pulls
the right eyeball in the nasal direction (left, again).
Simultaneously, there are inhibitory circuits that act at
the opposite muscles to inhibit the eye from moving
in the same direction as the head turn. Operating on
the span of about 10 ms, the VOR is one of the fastest
reflexes in the body.
8-13
The nerves that receive somatosensory lobe, immediately adjacent to the central sulcus.
inputs (soma- referring to the body, in the same In primates, S1 is subdivided into Brodmann
way the cell body is also called the soma) are the areas 3a, 3b, 1, and 2.
afferent branch of the somatic nervous system, There are many different types of sensory
a component of the peripheral nervous system. receptors in the skin, each of which detects a
They give us the ability to detect information very specific type of stimulus: for example, deep
about the body. These nerves can sense a wide movement of joints, vibrations as you run a
variety of physical stimuli, including pressure, finger over a fabric, or the cold touch of an icicle
stretch, vibration, heat, and pain. in winter. For some perceptions, many of these
The information about our body gets sensory receptors are combined, but often these
processed minimally in spinal cord circuits, sources of information are carried in separate but
ascends through the brain stem, passes through parallel paths, a theory called the labelled line
signal processing within the thalamus before principle. The type of information (eg, light touch
reaching circuits in the somatosensory cortices. on your finger) can be tracked from the sensory
The first cortical region to receive these signals receptor, through specific parts of the spinal cord,
is the primary somatosensory cortex, or S1, through nuclei of the thalamus, and into particular
which is the anterior-most gyrus of the parietal subregions of primary somatosensory cortex.
The neurons in the spinal cord, thalamus,
and S1 demonstrate somatotopic organization,
meaning that specific points on the body map
to specific neural populations. For example,
touching the skin on the hip will activate neurons
found in the dorsal-most aspect of S1, while
sensations on the tongue activate the neurons of
ventral and lateral S1. Thus, there are two key
bits of information kept together throughout the
somatosensory pathway: what kind of stimulus,
and where.
The mapping of this organization was
discovered during brain surgery. In epilepsy
surgery, parts of the operation are performed as
the person is awake. The famed neurosurgeon
Wilder Penfield electrically stimulated a small
section of S1, then asked the person what
Figure 8.14 Different parts of the body ultimately they feel. Patients would respond that they feel
send their signals through to different areas of the sensations in their hand when the medial S1 was
somatosensory cortex. activated, the little finger when a more ventral
8-14
area was activated, and so on. In repeating this Some of the outputs of S1 then project into
process while moving slowly across the span the secondary somatosensory cortex, or S2,
of S1, Penfield mapped out the organization of located posteriorly within the parietal lobe, where
S1. One key observation in doing this process higher order processing takes place.
was the volume of brain regions corresponding
to different body parts was not necessarily 8.3.1 Cutaneous receptors
proportional to the volume of skin: for example, Imagine reaching your hand into your
a large portion of the cortex was dedicated to pocket. In doing so, you may feel something
sensory information from the lips or the fingertips, circular with tiny ridges all along the perimeter,
while very little was dedicated to the shoulders roughly an inch in diameter. A series of highly
or trunk. This observation indicates that certain specialized sensory receptors just under the
areas of the body are more densely packed surface of our skin (the “cutis” in cutaneous refers
(lips, fingertips) with sensory neurons compared to the skin) allows us to sense this stimulus. That
to others (shoulders, trunk). A representation of information travels through ascending, afferent
a person drawn to the scale of how large each nerves into S1 and S2, and this is where we
area is represented in S1 is called the sensory perceive that we have a quarter in our pocket.
homunculus. It helps to divide the variety of cutaneous
receptors into three categories, roughly based on
the types of sensations they detect and convey.
Mechanoreceptors
Cutaneous (meaning found in the skin)
mechanoreceptors are responsible for sensing
mechanical changes to the skin, such as
pressure or stretch. On a molecular scale, these
mechanoreceptors detect changes at the skin
using mechanically-gated ion channels. These
transmembrane proteins are specialized for
detecting the physical distortion of the channel,
similar to the channels found in the stereocilia of
the hair cells or vestibular cells. When pressure
is applied to these proteins, the cation channel
opens and Na+ moves down its electrochemical
gradient into the neuron, causing depolarization.
The class of mechanoreceptors can
be divided into two categories based on their
Figure 8.15 The somatosensory homunculus electrical properties in response to stimuli: slowly-
shows which parts of the body are heavily adapting and rapidly-adapting. Slowly-adapting
represented in somatosensory cortex, like the mechanoreceptors change their action potential
hands or mouth. firing rate as long as the stimulus is present,
8-15
potential firing properties only at two timepoints:
the moment the coin lands in your hand, and the
moment that coin is removed. These neurons
signal a change in status, and are sometimes
Channel also called phasic receptors.
closed There are four different classes of
cutaneous mechanoreceptors, two of which
are slowly-adapting and two which are rapidly-
adapting. These different mechanoreceptors
Pressure have slightly different shapes, and are therefore
applied capable of detecting different types of stimuli.
Channel 1. Tactile epithelial cells (also called

open Merkel’s discs) are located in the superficial
skin layers, and are very densely populated
underneath our fingertips. They sense pressure
and help us perceive edges, points, and corners.
These are the most precise mechanoreceptors
Pressure
removed
Figure 8.17 Slowly-adapting mechanoreceptors
modify their action potential firing as long as
Channel a stimulus is present, while rapidly-adapting
closed
mechanoreceptors do so only at the moments
when a stimulus is changed.
Slowly-adapting mechanoreceptor
Figure 8.16 Mechanoreceptors respond to a Stimulus

physical distortion of the channels.
Action
while rapidly-adapting mechanoreceptors only
potential
change activity at the moment there is a change firing
in stimulus. For example, imagine the stimulus of
a coin that is sitting in the palm of your hand. The Rapidly-adapting mechanoreceptor
slowly-adapting sensory neurons may increase
their firing rate as long as the coin is in your Stimulus
palm. When the quarter is removed, they return
to their baseline firing rate. These are sometimes
also called tonic receptors. However, a rapidly- Action
adapting sensory neuron will change its action potential
firing
8-16
Free nerve Each cutaneous mechanoreceptor is
endings Tactile able to detect somatosensory information in
epithelial
an area of skin. The particular patch of skin that
cells
responds to particular cutaneous stimuli is a
Tactile receptive field, and the smaller the receptive
corpuscles
field, the better the brain can distinguish
between two different adjacent tactile stimuli.
Receptive fields differ in size throughout the
Bulbous body. For example, the receptive fields at the
corpuscles fingertips and the lips are very small (roughly
Lamellar 10 mm2), while the receptive fields on the
corpuscles back are much larger. Additionally, different
classes of mechanoreceptors have different
Figure 8.18 Cutaneous mechanoreceptors in the skin sizes of receptive fields: deeper structures,
have different physiological properties and respond like lamellar corpuscles, have larger receptive
to different types of stimuli. fields compared to receptors found closer to
the skin surface.
with resolution at the level of 0.5 mm, which allow
The approximate size of a receptive field
us to detect different distances in bumps while
can be assessed in people using a two-point
running your fingers across Braille. These tactile
discrimination task. Here, the experimenter will
epithelial cells are slowly-adapting receptors, and
place two adjacent stimuli simultaneously onto
they release serotonin at their synapses.
the skin of a blindfolded person at different places.
2. Lamellar corpuscles (also called
The patient is then asked if they feel one or two
Pacinian corpuscles) are mechanoreceptors
stimuli. In areas with large receptive fields, like
wrapped in several layers of connective tissue.
They mostly respond to high-frequency vibrations
Large Small
and deep pressure. They are rapidly-adapting
receptive field receptive field
receptors, and are the deepest of the cutaneous
receptors.
3. Tactile corpuscles (also called
Meissner’s corpuscles) are highly sensitive to
light touch, skin movement, and low-frequency
vibration. Like the tactile epithelial cells, tactile
corpuscles are also found in the superficial skin
layers, concentrated heavily at the fingertips. One signal Two signals
These receptors are rapidly-adapting receptors
Figure 8.19 In skin areas with a large receptive
4. Bulbous corpuscles (or Ruffini
field (left), two adjacent stimuli may feel like one.
endings) respond to stretching of the skin,
Skin areas with small receptive fields (right) are
such as the sensation of an object slipping out
better able to distinguish two similarly-spaced
of a closed hand, for example. These bulbous
points.
corpuscles are slowly-adapting receptors.
8-17
the top of the thigh for instance, a pair of points axonal projections through the two different
2.5 cm apart (1 inch) may feel like one single signaling pathways. The dorsal-column medial
point of contact. The distance between the two lemniscus (DCML) tract sends projections
points is increased incrementally until the patient through the ipsilateral white matter. These DCML
reports they first feel 2 points. signals carry crude touch, pressure, vibration, and
The somatosensory afferents from these two-point discrimination information. The other
receptors have their cell bodies located in the ascending pathway is the spinothalamic tract,
dorsal root ganglion (DRG), a clump of somata which projects upwards through the contralateral
that are close to the dorsal side of the spinal cord. white matter. Spinothalamic tract carries light
These touch receptors are the primary neurons, touch and pressure information, as well as heat
and are classified as pseudounipolar neurons and pain (described below).
based on their morphology. Pseudounipolar The DCML neurons form synapses onto
neurons don’t have true dendrites; instead neurons found in the medulla. At this point, these
each soma sends a single protrusion which neurons decussate (cross the midline), then
branches into two directions, one towards the ascend further into the ventral posterior lateral
skin surface where it terminates as one of the (VPL) nucleus of the thalamus. Spinothalamic
mechanoreceptors, and the other direction tract neurons project directly into the thalamus.
towards the spinal cord. Mechanosensory The thalamic neurons are the tertiary
information travels via Aβ axons, which are large neurons of the somatosensory system. They
diameter (~10 μM) axons that can send signals project into S1, in particular Brodmann areas 3b
on the order of 50 meters per second. and 1.
The next neurons in the ascending
signaling pathway are the secondary neurons of Thermoreceptors
the spinal cord, which have their cell bodies in Thermoreceptors are the cutaneous
the dorsal horn. These neurons send ascending receptors that sense temperature. There are two
classes of thermoreceptors. The low-threshold
Dorsal root thermoreceptors detect innocuous, non-harmful
ganglion temperatures in the range of 15 to 45 degrees C.
High-threshold thermoreceptors detect painful
and potentially damaging temperatures hotter
than 45 C or colder than 15 C.
Thermoreceptors are located in a class of
Spinal cord cutaneous receptors called free nerve endings.
Compared to the mechanoreceptors, free nerve
Sensory signals endings are found closest to the surface of the
from skin skin. Like mechanoreceptors, the free nerve
endings are the sensory end of the pseudounipolar
Figure 8.20 Somatosensory neurons are neurons which have their cell somata in the dorsal
pseudounipolar, and have their cell bodies in the root ganglion.
dorsal root ganglion.
8-18
Dorsal column- Spinothalamic tract
medial lemniscus
tract
Somatosensory
cortex
Tertiary
neuron
Thalamus
Secondary
neuron
Midbrain
Medial
lemniscus
Medulla
Lateral
spinothalamic
Spinal cord tract
Primary
Dorsal root Dorsal root
neuron
ganglion ganglion
Crude touch, pressure, vibration, two- Light touch, pressure, heat and pain
point discrimination information from skin information from skin
Figure 8.21 Summary of the two major ascending somatosensory pathways, the dorsal column-medial
lemniscus (left) and the spinothalamic tract (right).
Expressed on these free nerve endings dramatically than other proteins, making them
are a population of receptors called transient ideal for sensing temperature. TRP channels are
receptor potential receptors (TRP channels). All nonselective cation channels. Cold sensations
proteins are sensitive to changes in temperature, are detected by the action of the TRPM8 receptor,
but these TRP channels change shape more which is also activated by menthol, a chemical
8-19
isolated from peppermint that produces a cooling the spinal cord, and the ascending pathway runs
sensation. Warm sensations are sensed by the through the white matter of the lateral aspect of
TRPV1 receptor, which is also activated by the the spinothalamic tract.
chemicals capsaicin, the compound that makes
spicy peppers feel hot, and allyl isothiocyanate, Nociceptors
which is found in wasabi. Detection and avoidance of pain is a
Temperature information does not get highly-adaptive behavior that can improve
passed along the same neurons that carry the odds of survival chances of an animal.
mechanosensitivity signals. Cool and cold Pain detection is carried out by nociceptors.
temperature sensation is passed through thinly- Nociceptors can detect a variety of noxious
myelinated Aδ fibers, which are smaller in stimuli, ranging from crush to acid and high heat.
diameter (~5 μM) and transmit signals slower They are expressed on free nerve endings.
(~25 m/s) compared to the Abeta fibers. Warm Many pain-detecting neurons respond to more
and hot temperature sensation are passed than one type of noxious stimulus, and these are
through unmyelinated C fibers, which are even called polymodal nociceptors. Nociceptors also
smaller (~1 μm) with slower conduction velocity send their signals through Aδ and C fibers. Adelta
(~1 m/s). fibers detect sharp, highly-localized pain, while
The secondary neurons of the C fibers carry a more dull, throbbing pain that is
thermoreceptors are within the dorsal horn of difficult to pinpoint.
Clinical connection: Pain disorders

In healthy individuals, nociceptors that allodynia and hyperalgesia can be symptoms
detect pain send those signals into the spinal of neuropathic pain, a broad category of
cord. But in people experiencing allodynia, pain conditions resulting from damage to the
noninjurious tactile stimuli, such as strands nervous system.
of hair brushing across your forehead or the People experiencing pain even in the
feeling of a shirt resting on your shoulders, absence of pain-producing stimuli may be
cause the sensation of pain. Diabetes, physical diagnosed with chronic pain. Chronic pain
trauma, or postherpetic neuralgia may cause may be localized or widespread, affecting
allodynia. Drugs that modify the action potential large areas of the body at once. Up to 10% of
firing properties of the afferent somatosensory the global population may experience chronic
pathway, such as topical anesthetics (voltage- pain, and a variety of risk factors contribute,
gated sodium channel inhibitors) or calcium from advanced age, being male, low
channel antagonists, can help relieve the pain. socioeconomic status, unhealthy lifestyles,
A related disorder is hyperalgesia, an and a history of surgical intervention. Chronic
abnormally heightened perception of pain. pain can lead to significantly shorter lifespans,
Hyperalgesia can be the result of sensitization and may contribute to the opioid misuse
or as a withdrawal symptom of opioid use. Both epidemic.
8-20
A philosophically-opposite condition
is called congenital insensitivity to pain Hyperalgesia
(CIP). People with CIP are incapable of
Pain intensity
perceiving pain, no matter how severe. CIP
is a rare genetic condition that is observed Injury Healthy pain
response
from birth. People with CIP have significantly Allodynia
shorter lifespans since they do not sense
that their bodies may be injured, and may
Pain threshold
not learn to avoid exposure to damaging
stimuli. Some patients may walk for days
Stimulus intensity
on a compound fracture of the shin bone, or
never even notice that their back is broken.
Figure 8.22 Allodynia and hyperalgesia are pain
CIP is associated with mutations in the
disorders characterized by altered responses to
SCN9A gene, which codes for a component
somatosensory stimulation.
of the voltage-gated sodium channels that
are expressed in nociceptors.
There are several molecular components in detecting painfully cold or painfully hot
that make up the pain detection systems in the temperatures.
skin. Imagine you are reaching into your
Some mechanoreceptors are likely bookbag, and accidentally stick your fingertip
expressed on free nerve endings. Nociceptive with the sharp end of a pencil. Within half a
mechanoreceptors can sense crushing, shearing, second, the withdrawal reflex causes a series
or cutting of the skin. These may have a high of muscular changes which moves your hand
threshold of activity, which prevents them from away from the pointy end. This motor response
being activated under harmless circumstances. is driven by a circuit of neurons in the spinal
Acid-sensing ion channels are cation cord, and is mediated completely independently
channels that respond to low pH conditions in the from descending motor control from the brain.
dermis, which is usually seen in inflammation, The nociceptive input from the sensory neurons
which is often downstream of tissue injury. The enters the spinal cord through the dorsal horn
inflammation causes a release of various cellular where it forms a synapse onto an excitatory
signaling molecules (such as prostaglandins interneuron. This interneuron then signals to two
and cytokines) which cause sensitization, an other populations. The first is the motor neuron
enhancement of future incoming pain stimuli. that innervates the flexor, a generic term used
High-threshold thermoreceptors are to describe muscles that withdraw your hand
also involved in pain detection. On a molecular when contracted. The other connection is formed
level, the same TRP channels that sense cool with an inhibitory interneuron, which innervates
and hot (TRPM8 and TRPV1) are also implicated the motor neuron that controls the extensor, a
8-21
generic term used to describe the muscle that
functions opposite the flexor. In total, simultaneous Clinical Connection: Referred pain
activation of an extensor and inhibition of the One of the warning signs that a
extensor result in the rapid withdrawal of the person is having a heart attack is perception
hand. of pain in the shoulders or medial aspect
In addition to communicating with the of the left arm. This sensation is referred
neurons involved in the withdrawal reflex, pain: the feeling of pain at a site separate
the nociceptive signals also send ascending from where an injury is located. Referred
projections through the white matter of the lateral pain happens when the nervous system is
spinothalamic tract. unclear about how to process signals from
an internal organ, and the brain interprets
Flexor those afferent signals as bodily pain. Injury
at different internal organs cause different
patterns of somatic pain: liver injury may
present as pain in the shoulder blades, lung
cancer sometimes causes shoulder pain,
and kidney stones can cause pain in the
lower back, abdomen, and sides. Even the
headache-like pain you get from a “brain
Extensor freeze” from drinking cold liquids too quickly
is a form of referred pain.
It is unclear what causes referred
pain. The convergence projection theory
suggests that the afferent projections from
Figure 8.23 A painful stimulus produces a
the internal organs and the nociceptive
withdrawal reflex, which is driven by the action of
somatosensory neurons of the skin form
skeletal muscles.
8.3.2 Proprioception the dorsal column-medial lemniscus tract.

Raise your arms above your head. Even Proprioception is also processed in S1, more
without seeing your arms, your nervous system specifically Brodmann areas 3a and 2.
has mechanisms that inform you about the There are two main neural systems
location and position of your body parts, including that work together to give us our sense of
how much your joints are bent. This sense is proprioception.
called proprioception, and is critically important
for coordinated movement and motor reflexes Muscle spindles
that contribute to those tiny, rapid adjustments Wrapped around the intrafusal skeletal
that are made while maintaining balance. muscle fibers is a series of nervous structures
Proprioceptive information ascends called muscle spindles which detect the
through the spinal cord and into the brain via status of the muscle. Each muscle spindle is
8-22
Lung and
diaphragm
Thymus Spleen Thymus
Heart
Liver and
gallbladder Stomach Liver and
gallbladder
Pancreas
Small
intestine
Appendix
Ovary
Colon
Kidney
Bladder
Ureter
Figure 8.24 A map of referred pain sensations on the body and the corresponding visceral organ
that may be triggering the pain.
synapses onto the same population of

spinothalamic tract secondary neurons. Spinothalamic
When these secondary neurons project tract
towards the brain, there is no ability to
differentiate the origin of the signal coming
from the primary neuron. The central
sensitization theory suggests that the
neurons of the spinal cord change in
their excitability threshold with prolonged
exposure to injurious stimuli. So, when an
injured internal organ repeatedly sends
signals into the secondary neurons, a host
Figure 8.25 The convergence theory suggests
of neurotransmitters cause sensitization of
that the signals from the internal organs and pain
the nociceptive signaling, which are now
sensory inputs share the secondary neuron.
activated under non-noxious conditions.
8-23
between 6 and 10 mm long, and spirals around flexion to prevent excess stretching, which can
the thickest part of the muscle fiber. When a cause damage to the muscles.
skeletal muscle is flexed, it widens in diameter, The most-well known example of the
becoming shorter and thicker. As it does, the stretch reflex is the knee-jerk reflex (or the
muscle spindle wrapped around it also changes patellar tendon reflex), which may be tested in
in shape. The muscle spindles communicate this a standard medical physical. Here, the patient
information to the nervous system through the sits on the end of the exam table with their knee
action of nonselective-cation mechanoreceptors bent and their lower leg dangling freely over
that respond to physical distortion - muscle the edge. The examiner uses a pointed rubber
stretching increases firing rate, while muscle hammer to gently tap on the tendon that connects
flexion decreases firing rate. Muscle spindle the kneecap (patella) to the muscle in front of the
density is much greater among skeletal muscles shin bone. When tapped, it causes a stretch of the
that are used for very precise movements (like quadriceps, the muscle on the top of the thigh.
in the hand) compared to those used for coarse The muscle spindles detect this extension of the
movements (like in the thighs). muscle, they communicate this information with
an excitatory motor neuron of the spinal cord that
Muscle spindle
causes a flexion of the quadriceps, which causes
Flexed the foot to kick forward. The circuitry of this reflex
muscle
is described as a monosynaptic reflex arc. (There
fiber
is also a spinal cord inhibitory interneuron that
receives muscle spindle inputs that decreases
Excited muscle
the activity of the hamstring, the muscle on the
spindle
bottom of the thigh. In this reflex, the quadriceps
Stretched
muscle is the flexor while the hamstring is the extensor.)
fiber The neural circuitry responsible for the
knee-jerk reflex is located in the L2, L3, and L4
Figure 8.26 Muscle spindles wrap around the regions of the spinal cord. If the knee-jerk reflex is
center of the inner muscle fibers and detect weak or absent, there may be some degeneration
flexion. or death of the nerves that communicate with the
muscles, or possibly an injury to these specific
areas of the spinal cord.
There is also a motor function of these
muscle spindles. Through a circuit of neurons
Golgi tendon organs (GTOs)
in the spinal cord, they communicate with the
Made up of collagen fibers, GTOs are
gamma motoneurons that terminate at these
found at the insertion site between muscles
intrafusal muscle fibers. The combination of
and tendons. Signals from the GTO convey
the sensory and motor components allow the
information about the amount of the tension that
muscle spindles to function in the stretch reflex
each set of skeletal muscles is experiencing as
(also called the myotatic reflex), a spinal cord-
we move around. They also contribute to our
mediated response to muscle stretch that causes
detection of weight, as we lift something heavy
8-24
Muscle spindle
sensory neuron Spinal cord
Quadriceps Inhibitory
(flexor) interneuron
Hamstring
Stimulus (extensor) Excitatory
neurons
Sample neuronal firing

Stimulus
Muscle spindle
Motor neuron (quadriceps)
Inhibitory interneuron
Motor neuron (hamstring)
Time
Figure 8.27 The knee jerk reflex is downstream of a series of neural circuits that start with changes in
muscle spindle activity.
8-25
for example. Each GTO connects to about 20 Muscle fibers
muscle fibers and is about 0.5 mm long.
During muscle contraction, the tension
in the GTO increases. Contained within the Axons from
motoneurons
GTO are nonselective cation mechanoreceptors
that open during this physical deformation Sensory inputs
(similar to those found in other aspects of the into spinal cord
somatosensory system) causing changes in the
excitable properties of the GTO. The outputs of
the GTO communicate with interneurons found in
the spinal cord. These interneurons in turn inhibit
the motor neurons that innervate the muscle that
is “pulling” on the tendons.
The GTO communicates via Aα fibers.
These large diameter axons (15 μM) are heavily
myelinated, and can transmit action potentials
as fast as 100 meters per second, which are the
Tendon
fastest projections in the somatosensory system.
Figure 8.28 Anatomy of the Golgi tendon organ.
DePaul University.
8-26
Image credits
Cover: https://pixabay.com/photos/guitar-ropes-instrument-music-wood-56916/
8.1 https://upload.wikimedia.org/wikipedia/commons/1/18/Sound_wave_physics.gif Modified by Austin
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8.6 https://wellcomecollection.org/works/fsg372tb
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9-1
Ben Marcus, PhD (University of Chicago)
In the previous two chapters, we examined chemical senses are closely intertwined; odorants
some of the ways we detect and perceive affect how we perceive taste, and bad tasting
our physical environment, including through foods often smell bad. Try eating a fancy meal
phenomena such as light, sound, and tactile with a stuffed-up nose, and you’ll quickly notice
sensations. that you lose the subtle complexities (and most
In this chapter, we will complete our tour of the joy!) of those foods.
of the senses by exploring how we sense and Chemicals in our body, such as the amount
perceive chemical compounds. In particular, we of carbon dioxide in the blood or the presence of
will describe the neural processes underlying our toxins in our digestive tract, are detected with our
senses of smell, taste, and the chemical status of internal chemosensory systems. Many of these
our internal homeostatic state. sensory systems are intimately tied with our
Our olfactory system (smell) is autonomic nervous system (Chapter 2). Changes
activated by compounds called odorants, in chemical balance here results in unconscious
while our gustatory system (taste) is activated or involuntary physiological changes to restore
by compounds called flavorants. These two homeostasis.
Chapter 9 outline
9.1 Olfactory System

9.2 Gustatory System
9.1 Olfactory System

Olfaction is the ability to sense and eyesight: think about smelling a burning bonfire
perceive volatile chemicals that are suspended from miles away.
in the air. The typical human can distinguish up Smells affect our conscious behavior.
to 10,000 distinct odors, ranging from the sweet They can motivate us to approach freshly-baked
aroma of esters produced by apples and oranges, bread or avoid a rotting animal carcass. These
to the putrid smells of sulfurous compounds chemicals serve as survival cues: bread gives
produced by skunks and rotten eggs. Because us energy-rich carbohydrates while a decaying
odors can drift along in the air, some chemicals carcass can expose us to disease. Odorants
can be detected long before the source is within can even affect our behaviors unconsciously:
9-2
Figure 9.2 Ventral view of a human brain (left) and
a woodchuck (right), showing that proportionally
less brain tissue is dedicated to olfactory systems
(red) in humans compared to other mammals.
even subconsciously detect sickness through

body odor.
Figure 9.1 A threatened skunk produces
mercaptans, volatile chemicals that serve as a 9.1.1. Anatomy of the Olfactory System
warning signal against to deter predators. Your sensation of smell begins when
an odorant traverses your nostrils and passes
sleeping amidst the scent of a romantic partner through the nasal cavity, an empty, air-filled
increases the efficiency of our sleep, and space just behind the front of the skull. The
subliminal exposure to citrus smells can lead dorsal-most portion of the nasal cavity is covered
people to clean their space more completely after in a mucus-covered patch of tissue called the
eating a crumbly biscuit (an effect described in a olfactory epithelium.
study called “Smells Like Clean Spirit,” a nod to Embedded within the olfactory epithelium
90s punk band Nirvana). are the olfactory receptor neurons (ORNs,
Olfaction is one of the oldest functions we also called olfactory sensory neurons, or
possess as animals. While our sense of smell has OSNs), neurons which begin processing smell.
seemed to take a backseat to other senses relative ORNs are bipolar neurons, with long dendritic
to other animals (about 2% of the total mouse projections protruding into the epithelium. Here,
brain mediates smell, while only a scant 0.01% they peek out and contact the air, making them
of the volume of the human brain is dedicated to the only neurons that are directly exposed to the
this function), scientists now appreciate that our outside world. This, unfortunately, causes them
olfactory system is simply more specialized. For to encounter all sorts of dangers such as toxins,
example, humans use the smells of sweat to clue particulates, and microbes. They are one of the
us into the emotional state of others, and we can few known populations of neurons where adult
9-3
Olfactory bulb Olfactory Olfactory bulb
tract
Glomerulus
Cribriform plate
Cribriform plate
Olfactory nerves
Nasal cavity Olfactory

epithelium
Airflow
ORNs Olfactory
Mitral cells
ensheathing cells
Basal Supporting cells Fibroblasts
cells
Figure 9.4 The cellular anatomy of the olfactory

Figure 9.3 Cross section showing the major epithelium and olfactory bulb.
anatomical structures of the olfactory system.
been matched with their corresponding odorant.
neurogenesis occurs, each having a lifespan The initial research into the genetics underlying
in the range of 30 days to a year. The average these neurons earned Drs. Linda Buck and
human olfactory system has somewhere between Richard Axel a Nobel prize in 2004, but there is
6-20 million ORNs. still much work to be done.
Within the olfactory epithelium are a Olfactory receptors are transmembrane
population of supporting cells, which function G protein-coupled receptors that signal
much like glial cells. They help dispose of dead downstream effectors using the intracellular
and dying cells, metabolize pollutants, and may transduction molecule Gαolf. This protein complex
also help to physically maintain the epithelium. is 90% similar to the stimulatory G-protein Gs,
On the dendrites of ORNs are olfactory and likewise triggers activation of adenylate
receptors. It is estimated there are about 1,000 cyclase, elevating the intracellular concentration
different genes (about 3% of the total human of cyclic AMP (see section 5.3 for a refresher on
genome) that code for roughly 400 different this signaling pathway). Activation of Gαolf causes
olfactory receptors. Each ORN expresses only depolarization, causing the ORN to fire action
one type of olfactory receptor, and each receptor potentials.
is believed to respond to activation by a different ORNs encode the intensity of smells
chemical. For example, the receptors expressed through the frequency of action potential
on ORN293s are highly responsive to cadaverine, firing, which changes in accordance with the
the smell characteristic of death and decay. Even concentration of odorant molecules. Imagine
though scientists have identified the odorants that standing over a fresh-baked pizza and inhaling
activate some receptors, most of the olfactory deeply. Due to the high concentration of odorant
receptors are still “orphaned,” and have not yet molecules in the air, several receptors will be
9-4
activated, leading to frequent neuronal firing. olfactory bulb is a highly specialized clump of
Now, imagine you are down the block from a tissue called a glomerulus. The typical human
pizza restaurant, getting only a slight whiff of has a little under 2,000 glomeruli, and each
those same scents. Here, the concentration of glomerulus only receives inputs from ORNs that
odorants is low, meaning that the ORNs fire less express the same type of olfactory receptors.
frequently.
Olfactory tract
Mitral cell bodies
Glomeruli
ORNs
Figure 9.6 Communication between the ORNs

and downstream neurons occur at glomeruli.
Different colors indicate distinct populations of
ORNs, which express only one type of olfactory
receptor.
Within each glomerulus are the dendrites

Figure 9.5 The cribriform plate at the base of the of the secondary neurons, which exist in two
skull allows for the axons of the ORNs to pass types: The mitral cells and the tufted cells.
into the brain. These two cell populations project axons directly
into the olfactory cortex. This makes the olfactory
Following activation of the receptors, the system the only sensory system that does not
axons of the ORNs pass through the skull through pass signals through the thalamus before cortical
a tiny series of holes at the cribriform plate, a processing.
sieve-like section of the ethmoid bone. These There are also two types of inhibitory
primary neurons form synaptic connections onto neurons that regulate this pathway: granule cells
neurons in the olfactory bulb, the beginning of found within glomeruli, and periglomerular cells,
the olfactory nerve (CN I). Like the optic nerve, which send axonal projections into the glomeruli,
the olfactory nerve runs along the ventral surface both help refine the synaptic processing of scent
of the brain. information using lateral inhibition, a system
The site of synaptic connectivity between similar to that found in the retina of the visual
the ORNs and the secondary neurons in the system (Chapter 7).
9-5
Collectively, the olfactory cortex is made to be the reason why smell and memory are
up of several different regions. strongly linked. Think about a time when you
caught a slightest whiff of a scent, and that
1. Piriform cortex scent mentally transported you to a distant place
The piriform cortex is the main cortical from a long time ago (this experience was also
input site for axonal projections from the olfactory described by author Marcel Proust in his highly-
bulb. In some species of mammals that rely very regarded novel, In Search of Lost Time.) We
heavily on their sense of smell for survival, up to form associations between specific smells and
10% of total cortical volume is piriform cortex. emotionally salient memories. Some odorants,
The outputs of the piriform cortex project into like the volatile Maillard reaction products that are
other structures of the olfactory cortex, as well as made as a product of cooking, remind us of the
the mediodorsal thalamus, a relay center that “good ole days” watching a parent bake or grill.
contributes to learning and decision making. Many bakeries take advantage of these positive
memories and point their exhaust out into the
2. Cortical amygdala street to entice passersby.
The amygdala is a part of the brain Unfortunately, the memories associated
that helps mediate complex emotional states with smells can also have negative valence. For
(chapter 15). Generally, it is subdivided into a example, the smell of petroleum and oil fumes
few different subnuclei. One of them in particular, can trigger a sickness-like conditioned response
the cortical amygdala, receives strong inputs in Gulf War veterans.
from the olfactory nerve. The cortical amygdala
sends projections into the hippocampus, a brain 3. Entorhinal cortex (EC)
structure critically important for the formation of The entorhinal cortex is a small section
new memories. of the medial temporal lobe. As with the cortical
The strong neural connections between amygdala, the EC sends strong connections
the olfactory nerve and amygdala are believed
Figure 9.7 The close connections between the

olfactory nerve and amygdala + hippocampus Figure 9.8 The entorhinal cortex (red) is found
may account for why smells are strong triggers of along the ventral surface of the medial temporal
emotional memories. lobe.
9-6
into the hippocampus, indicating that olfactory Do humans respond to pheromones?
signals contribute to the strong associations Some species secrete chemicals
formed between smell and memory through EC, which influence the behavior of other
as well. members of the same species. These
Other than receiving and processing pheromones trigger complex responses
olfactory signals, the entorhinal cortex is also in others, such as motivating social insects
involved in spatial navigational tasks. like ants to follow meandering trails towards
faraway food sources or causing a group of
4. Orbitofrontal cortex (OFC) bees to swarm and attack a predator.
As the name implies, the orbitofrontal There is still debate over whether
cortex (OFC) is found just behind the orbit, or not humans produce and release
the bony socket of the skull where the eyes pheromones, and whether or not other
sit. OFC is found at the ventral surface of the humans are sensitive to these signals.
frontal lobe. Circuits in this brain area function Many nonhumans, notably snakes and
as an integration site for sensory inputs, since it dogs, have a specialized structure in their
also receives projections from visual, taste, and nasal cavity called the vomeronasal
somatosensory cortices. organ, which detects organic compounds
The full extent of the OFC is still under produced by predators and reproduction-
examination, but it is also implicated in decision related hormones produced by the opposite
making and social behaviors. sex. These signals are sent into the brain
via cranial nerve 0, which can then trigger
behavioral changes. Humans have these
anatomical structures, but they are not
believed to carry any functional information.
However, other evidence suggests that
smelling certain compounds influences
mood, alters neuroendocrine signaling, and
even affects mate selection.
9.1.2 Disorders of the Olfactory System

Like other sensory systems, the structures
involved in olfaction can be injured. An injury to
the olfactory system can result in hyposmia, a
reduced ability to smell, or anosmia, a complete
loss of smell.
Figure 9.9 MRI image of a parasagittal section of The most common insult to the olfactory
the brain showing the orbitofrontal cortex (green). system is simple nasal congestion, a temporary,
physical blockage of the entry to the nasal cavity
9-7
that decreases airflow and, therefore, the number Neurodegenerative disorders, such as
of particles that reach the olfactory epithelium. Parkinson’s disease and Alzheimer’s disease,
Congestion can be caused by allergies, the contribute to smell deficiency. Usually, hyposmia
common cold, upper respiratory bacterial or precedes the major clinically observed symptoms
viral infections, or sinus infections. Hyposmia is of these disorders, hinting that smell deficiency
also one of the main neurological symptoms of may serve as an early diagnostic biomarker.
COVID-19. Another olfactory deficit, phantosmia,
Hyposmia is common among healthy, is when a person perceives “phantom” scents,
older adults, affecting about half of the population or in other words, experiences an olfactory
between 65 and 80 years old. As a person ages, hallucination. Phantosmia may be triggered by a
spontaneous calcification causes the holes in the temporal lobe seizure or a stroke. It can also be
cribriform plate to shrink, which can impinge on caused by a brain tumor affecting the olfactory
and damage ORN axons. nerve (CN I), or the subsequent surgical removal
Hyposmia can also be caused by abrupt of the tumor, leading to injury. Schizophrenia, a
head injuries. The ORN axons that project through psychiatric condition characterized by auditory
the holes of the cribriform plate are particularly hallucinations, may also cause phantosmia.
sensitive to blows to the head.
9-8
9.2 Gustatory System
Your gustatory system, which mediates of these receptors, but the number varies by age:
your sense of taste, helps you walk the line Taste bud concentration in the mouth peaks in
between health and illness. It guides you towards childhood and decreases throughout adulthood.
foods that are energy rich, and keeps you away Within each taste bud are approximately
from food that could make you sick. The specific 100 taste receptor cells. Technically, these cells
taste modalities, salt, sweet, sour, bitter, and are not neurons, but are instead derived from
umami, all support this balance. Sweet foods specialized epithelial cells. These cells reach
taste good because foods rich in sugar, such as toward the apical tip of the taste bud and sprout
fruit and wheat, contain large amounts of usable thin projections called taste hairs, which extend
energy, and humans have evolved to find these into taste pores. These tiny pockets at the apical
foods appetizing. In contrast, toxic compounds tip of the taste bud are where taste hairs meet
are often bitter, causing you to respond with saliva. Taste buds also contain basal cells,
feelings of disgust. which reproduce to form supporting cells, and
To further refine this balance, a tastant’s over time, these mature further into taste receptor
appeal varies depending on its concentration. cells. Taste receptor cells turnover every 8–22
For example, we find a small amount of sourness days.
desirable in fruit and candy, but aversive in milk.
Lingual papilla Hair fibers
And while bitterness is often a sign of toxicity in
food, mild bitterness contributes positively to the
taste of coffee and chocolate. Sugar can make
candy, pastries, and drinks very appealing, but
too much can make the food barely palatable.
The same applies to salt: the right amount
makes potato chips and pretzels delicious, but
it also causes sea water to make you vomit. All Taste buds Basal cell
Supporting
of these reactions are adaptations humans have cell
Taste receptor
developed to maintain homeostasis in our body. cell
9.2.1 Anatomy of the gustatory system Figure 9.10 On each lingual papilla are taste
Lingual papillae (singular; papilla) are buds (left). A magnified view of a taste bud (right).
the large anatomical structures that give the
tongue its characteristic rough surface. These Taste receptors cells are responsible for
structures can be seen with the unaided eye. sensing and conveying information about taste in
Each papilla contains up to a hundred taste accordance with the main taste modalities (salty,
buds, which are onion-shaped taste receptors. sweet, sour, etc). Like how the olfactory system
Taste buds can also be found on the palate and is organized, taste receptor cells do not express
in the throat. In total, a person has about 10,000 receptors for more than one taste modality - a salty
9-9
taste receptor cell only carries salty information, tongue gets represented in the left hemisphere of
a sweet taste receptor cell only pass on sweet the brain, and visa versa.
information, and so on. From the medulla, these neurons send
Taste receptor cells communicate with axonal projections into the ventral posteromedial
afferent gustatory neurons. These gustatory (VPM) nucleus of the thalamus. (These represent
nerve fibers originate from three of the twelve the third-order neurons of the gustatory system.)
cranial nerves. These neurons send projections widely across
several areas of the cortex.
● The nerve fibers from the anterior two- The gustatory cortex is the beginning of
thirds of the tongue are part of the facial nerve the processing of taste perception. It is made
(CN VII). up of two different parts: the anterior end of the
● The posterior third of tongue sends insular cortex and the frontal operculum of the
information through the glossopharyngeal nerve frontal lobe. These neurons convey information
(CN IX). such as the taste modality and intensity.
● The back of the palate and the throat
can send taste-related signals through the vagus
nerve (CN X). Insular
cortex
Throat
Vagus nerve (CN X) VPM of

thalamus
Glossopharyngeal nerve
(CN IX) From Solitary nucleus
tongue
Tongue
Medulla
Facial nerve (CN VII)
Figure 9.12 Afferent signaling from the tongue

Figure 9.11 Different cranial nerves communicate passes through medulla, then thalamus, then
information from different areas of the gustatory cortex.
system.
These neurons then form synapses on 9.2.2 Taste modalities of the gustatory
second order neurons in the rostral medulla in system
an area called the solitary nucleus (or gustatory Currently, it is believed that humans sense
nucleus) in the medulla oblongata. Unlike most five basic tastes: Salty, sour, sweet, bitter, and
other sensorimotor systems, the gustatory system umami. Salty and sour taste are both mediated
sends ipsilateral projections into the CNS; that is by ionotropic taste receptors, while sweet, bitter,
to say, taste information from the left half of the and umami taste are mediated by metabotropic
9-10
taste receptors. Besides varying by type, these nutrients. They are critical for maintaining blood
receptors are also not distributed evenly across volume and pressure, for regulating body water, for
the surface of the tongue. For example, the tip maintaining muscle contractions, and mediating
of the tongue is most sensitive to sugars, while action potentials. Cl-, in particular, helps maintain
the back of the tongue is most sensitive to bitter a healthy pH balance. But for these functions to
compounds. be performed optimally, salt must be present at a
specific range of concentrations in the body.
Salt
Sensation of salt taste is primarily driven Sour
by Na ions. When you sprinkle a little table salt
+
Sensation of sour taste is mediated by
(NaCl) onto your tongue, it dissolves in saliva and proton-selective channels, which is why acids
the free sodium ions can passively influx into salt are sour (acids are low pH, which means a high
taste receptor cells through epithelial sodium concentration of H+). Like neurons, taste cells can
channels (ENaCs). This movement of positively depolarize with the entry of positively-charged
charged Na+ ions causes depolarization of the ions, which influences signaling passed through
taste receptor cell, just like in neurons. This the downstream nerve fibers.
depolarization activates voltage-gated calcium The purpose for our ability to sense acids
channels, prompting neurotransmitter release in our food is under debate. Sour tastants do not
that, in turn, activates the afferent gustatory nerve inherently provide any nutritional value, except in
fibers. the case of Vitamin C. Humans and other higher
Salty foods elicit a biphasic response primates cannot synthesize Vitamin C on their
depending on concentration. Foods cooked with own, so it’s possible that we evolved to find a
a low concentration of salt taste bland and are not combination of sourness and sweetness attractive
very appetizing; however, high salt concentrations enough to consistently consume Vitamin C-rich
elicit a strong aversive reaction - imagine how fruits. However, sour can be aversive, motivating
disgusted you were when you first tried to cook us to avoid spoiled or unripe foods that might
and were overly generous with the salt! The taste contain pathogens.
of salt is typically desirable at salt concentrations
lower than 100 mM. Sweet
Additionally, the appeal of salt at a given Sweet taste transduction is carried out
moment depends on our body’s need for salt by the activation of G-protein coupled receptors
at the time. Several hormones such as the expressed on the sweet taste receptor cells.
appetite-stimulating hormone ghrelin contribute The most likely candidate for the primary sweet-
to regulating the concentration of salt in the body sensitive GPCR is a heterodimeric receptor with
by mediating Na+ absorption. Current salt levels the subunits taste receptor type 1 member 2
can also impact appetite for salt. For example, (TAS1R2 or T1R2) and taste receptor type
in chronically-sodium deprived animals, high salt 1 member 3 (TAS1R3 or T1R3). All sweet
solutions are highly rewarding. substances, including carbohydrates and artificial
Why are we so sensitive to the taste of sweeteners, activate the taste pathway through
salt? As it turns out, both Na+ and Cl− are essential these T1R2/T1R3 receptors. Interestingly, these
9-11
receptors are also found in other parts of the body, taste-specific phosphodiesterase, an enzyme
including in the brain, pancreas, gastrointestinal that lowers the intracellular concentration of the
tract, and fat tissue. While its function in these signaling molecule cAMP. Some bitter compounds
areas is not known, it’s theorized that it plays a bypass the T2R receptor altogether, permeating
role in glucose homeostasis. the cell membrane and directly activating the
Sugars like glucose and sucrose are GPCR. The bitter compound quinine, found in
essential for the survival of a species, since they tonic water, does this. In high concentrations,
are the main source of cellular energy. Therefore, quinine can cause disgust and vomiting.
our ability to detect sweetness plays a central Bitter taste prompts avoidance because
role in regulating how much energy we take into bitter tastes often indicate toxicity. For example,
our bodies. Of all the taste modalities, sweet is cucurbitacins, a group of bitter-tasting compounds
the strongest driver of food selection. found naturally in gourds, including cucumbers
and pumpkins, are believed to have evolved as
Bitter an antiherbivory defense mechanism to prevent
Bitter taste is sensed via the T2R receptor. predation. The exact mechanisms that connect
From here, the molecular signaling cascade toxic compounds to disgust and vomiting are
branches off into two distinct pathways. The first unknown; it’s possible that there is not a causative
pathway is similar to the sweet taste pathway; it relationship among these reactions to toxins, but
recruits a similar set of signaling proteins en route rather that humans evolved to respond to toxic
to the afferent gustatory nerves, and knocking compounds at multiple levels in parallel: in the
out any of the receptors along the sweet taste mouth, through bitter taste, in the stomach with
transduction pathway also attenuates bitter vomiting, and in the colon, with diarrhea.
taste transduction. The second pathway uses a
Salt Sour Sweet Bitter Umami
T1R2 T2R
ENaC
T1R3
Na+ H+
Figure 9.13 Taste modalities signal using different populations of receptors. Salt and sour are detected
with ionotropic receptors, while sweet, bitter, and umami are sensed with metabotropic receptors. Many
of the metabotropic receptors signal inside the cell using the α-gustducin molecule.
9-12
Umami the “mouthfeel” of foods, giving foods a creamy,
Umami is the taste of savory deliciousness, rich quality. However, triglycerides themselves
such as the taste of rich chicken broth, a perfect don’t have a taste.
medium-rare steak, or aged cheese. The word In 2015, researchers found that humans
is derived from the Japanese word umai, whicih might be able to sense fatty acid chain molecules
means “delicious.” Like sweet flavor, umami taste in the mouth. It turns out that in their study
is mediated by a heterodimeric metabotropic participants could distinguish between a control
receptor. Umami is signaled when a molecule drink, a bitter drink, a sour drink, and drinks
of glutamate (chemically the same as the containing fat. Participants initially grouped
neurotransmitter!) binds to T1R1/T1R3 receptors. the fatty drinks with the bitter and sour tastes,
The intracellular signaling transduction suggesting that fat by itself is an aversive flavor,
process is similar for sweet, bitter, and umami despite being high in energy content.
sensation. Tastants of these modalities all activate The research on this taste modality, called
GPCRs that use the G protein α-gustducin. This oleogustus, is still in its infancy compared to that
activation increases the activity of phospholipase of the other taste modalities. Researchers have
C-β2 (PLC-β2), which, in turn, activates the not elucidated the mechanisms underlying this
inositol 1,4,5-triphosphate (IP3) receptor, causing pathway.
the release of calcium into the cytoplasm. The
calcium opens the transient receptor potential Spicy
cation channel subfamily M member 5 (TRPMP5), It’s no accident that the word “hot” is
which causes the taste cell membrane to used to describe both the temperature and the
depolarize, generating an action potential. This spiciness of a food. After eating that delicious
causes the release of ATP into the synapse, plate of curry, your body may exhibit a strong
which activates afferent nerve fibers to signal the somatic response: intense salvation, a flushing of
presence of these tastants. the skin, sweating, and sometimes even crying.
Through evolution, we have come to As it turns out, the pain of eating a hot pepper
prefer the taste of umami because glutamate is similar to experiencing other forms of physical
is a byproduct of cooking food. Cooking foods injury. Taste receptor cells send signals to the
changes their chemical properties, thereby brain via C fibers, the same neuronal pathway
improving digestion, reducing toxicity, and that carries afferent painful information (chapter
increasing absorption of nutrients. Glutamate is 8).
one of the byproducts in the process of heating Our ability to detect spicy flavors originates
a food, and so it benefits us to appreciate these at the TRPV1 receptor, a nonselective cation
flavors. channel. Upon activation, these receptors cause
depolarization of the taste cell. Peppers contain
Fat the compound capsaicin, a potent activator of
A triglyceride is a chemical made up of three the TRPV1 receptor. These TRPV1 receptors are
fatty acids bonded to a glycerol molecule. They are also temperature sensitive, opening at around
a large part of our diet, and are commonly found 43C. Because these receptors can be activated
in animal fat and butter. Triglycerides contribute to by either chemical ligands or high temperatures,
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biting into a ghost pepper causes a similar
sensation as if your tongue was literally being
burned - the “heat” of spicy foods is more than
just a colloquialism.
TRPV1 receptors are not only activated
by capsaicin. Ethanol, for example, can also
activate these receptors, which is why a shot of
hard liquor causes a painful, burning sensation.
Since the TRPV1 receptors permit proton
movement into the cell upon activation, acidic
conditions potentiate receptor activation, which
also accounts for why acids often taste “hot.”
Injurious stimulus
Capsaicin
Heat
TRPV1
receptor
Na+ Ca2+
Figure 9.14 TRPV1 recptors are activated by

different stimuli, ranging from physical heat to the
chemical capsaicin.
9-14
In addition to detecting chemicals with our noses
or mouths, we also host a variety of chemosensory
systems that sense various conditions about our
internal environment. These systems contribute
to the maintenance of homeostasis. Whenever
the body is pushed out of it’s ideal operating
range, these chemosensory systems respond
by reflexively adjusting chemical absorption or
behavior.
9.3.1 Respiration
Neural control of the respiratory system
originates in several circuits within the hindbrain.
Of particular relevance is the medulla, the inferior-
most segment of the brain stem. These complex
circuits communicate with descending motor
signals that are critically important for respiration
through the action of two main nerves. The main
driver of respiration is the phrenic nerve, which Figure 9.15 The phrenic nerve (highlighted
is the only nerve that innervates the diaphragm. yellow) is the main driver of respiration.
The other drivers of respiration are the intercostal
nerves, which innervate the intercostal muscles, in the blood. The pH of CSF is essentially a proxy
the set of accessory respiratory muscles found measure for CO2 in the blood: CO2 diffuses
between the ribs that expand the chest cavity easily across the blood brain barrier into the
during inhalation. People with spinal cord injury CSF. Once there, CO2 quickly reacts with H2O
at the level of C5 or higher, which results in to form carbonic acid, which then dissociates into
damage to the phrenic nerve, may need to be a bicarbonate ion and a H+ ion. Because of this
put on a ventilator. These circuits express opioid chemical reaction, when blood CO2 is elevated,
receptors, which is why opioid overdose can lead so is the concentration of H+ (low pH) in CSF.
to fatal respiratory depression. Central chemoreceptors detect changes
Regular respiration is an autonomic in the pH level of the CSF by sensing H+ ions,
function. When CO2 levels rise (a condition which enter the cells through acid-sensing ion
called hypercapnia), these hindbrain neurons channels (ASICs). When ASIC-expressing
drive increased respiratory rate, which helps the neurons detect pH levels less than 7, they send
body expel excess CO2. signals to the nerves that mediate diaphragm and
Respiratory patterns are also regulated intercostal muscle activity to increase respiration.
homeostatically to restore a healthy level of pH This increases the exchange of CO2 out of the
9-15
circumventricular organ, meaning that it is not
isolated from the blood by a blood brain barrier.
Instead, toxins and other large molecules in the
blood are able to influence AP neurons directly.
Additionally, because they are bathed by CSF,
they can also sense the presence of toxins in
CSF.
Figure 9.16 The nervous system regulates blood
pH using the carbonic acid-bicarbonate buffer
system.
lungs, shifting the pH of the blood back towards

more physiological levels of 7.4.
9.3.2. Vomiting
Vomiting (or emesis) is a rapid
contraction of respiratory and abdominal muscles,
compressing the stomach, thereby expelling
stomach contents through the esophagus.
Vomiting is often preceded by nausea, the
unpleasant sensation of stomach discomfort.
Although aversive and painful, vomiting Area
can be a natural and healthy protective response. postrema
For example, when toxins are produced during
bacterial gastroenteritis (food poisoning), it is
beneficial to expel the spoiled or rotten food from
the stomach to minimize further exposure to
bacterial toxins.
The neural signals that lead to vomiting Figure 9.17 Posterior view of the brain stem
originate at the afferent inputs of the vagus showing area postrema, the emetic center of the
nerve (Cranial Nerve X), found in the intestinal brain.
tract. These ascending inputs form connections
within the dorsal vagal complex (DVC), a series
of nuclei found in the medulla of the brain stem. A
region within the DVC that mediates the vomiting
response is area postrema (AP), which is found
on the floor of the fourth ventricle. Within AP
is the chemosensory trigger zone, which is
dense with neurons that sense the presence of
various chemicals. The AP is considered to be a
9-16
Cover: https://pixabay.com/photos/pork-ribs-dinner-pork-food-meat-2157179/
9.1 https://commons.wikimedia.org/wiki/File:Southern_spotted_skunk.jpg
9.2 https://commons.wikimedia.org/wiki/File:1543,Vesalius%27OlfactoryBulbs.jpg
https://commons.wikimedia.org/wiki/File:Anatomy_of_the_woodchuck_(Marmota_monax)_(2005)_(18007398570).jpg
olfactory structures outlined by Austin Lim
9.3 https://commons.wikimedia.org/wiki/File:Head_olfactory_nerve.jpg
9.4 https://commons.wikimedia.org/wiki/File:Location_of_olfactory_ensheathing_cells_(OECs)_within_the_olfactory_
system.png modified by Austin Lim
9.5 https://commons.wikimedia.org/wiki/File:Cribriform_plate_Close-up_view.png
9.6 https://commons.wikimedia.org/wiki/File:Olfactory_Sensory_Neurons_innervating_Olfactory_Glomeruli.jpg modified by
Austin Lim
9.7 https://pixabay.com/photos/grain-bread-bread-rye-bread-cut-3135224/
9.8 https://commons.wikimedia.org/wiki/File:Entorhinal_-_DK_ATLAS.png
9.9 https://commons.wikimedia.org/wiki/File:MRI_of_orbitofrontal_cortex.jpg
9.10 https://commons.wikimedia.org/wiki/File:Anatomy_and_physiology_of_animals_Taste_buds_on_the_tongue.jpg
https://commons.wikimedia.org/wiki/File:1402_The_Tongue.jpg modified by Austin Lim
9.12 https://openbooks.lib.msu.edu/neuroscience/chapter/taste-central-processing/ modified by Austin Lim
9.14 https://commons.wikimedia.org/wiki/File:EMA401_Mechanism_of_Action.jpg
9.15 https://commons.wikimedia.org/wiki/File:Gray806.png phrenic nerve highlighted by Austin Lim
9.16 https://commons.wikimedia.org/wiki/File:Buffer_Part_1.png modified by Austin Lim
9.17 https://commons.wikimedia.org/wiki/File:Human_caudal_brainstem_posterior_view_description.JPG modified by
Austin Lim
DePaul University.
9-17
10-1
Alexander Rajan, PhD
Andrea Gaede, PhD
Editor: Katie Willis, PhD (University of Oklahoma)
The motor system refers to the nerve knowing where you are, it’s difficult to plan a
cells that are used to control our body. The two route to your destination, and getting feedback
key roles of the motor system are to plan, control, along the way helps your brain know if it needs to
and execute voluntary (deliberate) movements, adjust the plan.
and to control involuntary (subconscious or Accordingly, think about motor control as
automatic) functions, such as digesting food. a set of nested loops, where motor and sensory
The motor system is sometimes described processes are closely intertwined. The main loop
as a top-down process: in a voluntary movement, is the descending (from brain to muscle) motor
neural activity in the frontal lobe sends commands command and the ascending (from muscle to
down to motor neurons located in the brainstem brain) sensory feedback. Examples of nested
or spinal cord, which in turn activate muscle loops within this circuit could include spinal cord-
groups. mediated reflexes and communication between
In reality, motor control is more of a loop, areas within the brain.
rapidly communicating between the sensory We will describe the process of motor
cortex and motor cortex. Sensory information control by first describing the signals that originate
about limb position, posture, and objects in in the brain, then tracing that signal down through
contact with the skin inform the descending motor the brain stem, spinal cord, the neuromuscular
plan. Simultaneously, the motor plan provides junction, and finally the muscles.
predictions about upcoming movement. Without
Chapter 10 outline

10.4 The Muscles
10-2
All voluntary (or non-reflexive) for initiation of motor control. Primates have many
movements begin as signals in the brain. cortical areas dedicated to movement, which
Specifically, the neurons involved in motor allows for fine control of small muscle groups,
control are primarily found in the frontal lobe of complicated patterns of movements, and long-
the telencephalon, which includes areas such as term planning of motor action.
primary motor cortex (or M1), premotor cortex, With respect to motor control, the
and supplemental motor areas. The posterior prefrontal cortex (PFC) initiates the long-term
parietal cortex also contributes to movement. planning or cognitive aspects of movements. For
Through this section, we will walk through example, consider the motor actions related to
the brain processes leading to voluntary motor brushing your teeth. PFC signals are more akin
action, beginning at the highest areas of the to “brushing is good for my hygiene and health”,
hierarchy. rather than “move my arm and open my mouth.”
PFC also helps determine if some motor
Association cortices action is appropriate for the specific situation.
Neural control of voluntary movement Think of a behavioral test where you are given
begins with high order thought processes which two clickers, one to hold in each hand. You are
are carried out by two major associative areas, told that when the experimenter shows you a
the prefrontal cortex and the posterior parietal green item, you should click with the right button.
cortex. These areas do not specifically correlate After repeating this behavior multiple times, you
with specific muscle groups, and activation of are told to switch - now, when you see a green
these neurons do not necessarily cause muscle item, you need to click the left button. In this
activity. Instead, these structures are important experiment, PFC is responsible for deciding
which motor pattern (left button or right button
press) is appropriate in response to the stimulus.
PFC also works to weigh the consequences
of motor actions, and makes updates about future
motor actions in similar or different circumstances.
The exact same motor action produces different
results depending on the specific situation, and
PFC contributes to evaluating and predicting
outcomes. For example, the Wisconsin Card
Sorting Task is a human behavioral test that is
strongly dependent on PFC activity. In this task, a
Figure 10.1 Anterior view (left) and lateral view patient is asked to classify cards based on criteria,
(right) of one hemisphere showing the location of such as number, shape, or color. The patient is
the prefrontal cortex (red). told whether they are correct or wrong; however,
the criteria will occasionally change without them
10-3
being explicitly informed. The ability to shift to a M1 Posterior
new set of rules is PFC mediated. SMA parietal cortex
PM
Dorsolateral
PFC
Target FEF V1
S1 A1
Figure 10.2 In the Wisconsin Card Sorting Task, Figure 10.3 The posterior parietal cortex is part
the target card (bottom) could be placed in of the dorsal stream, and integrates sensory
category 1 (matching color), category 2 (matching information with motor commands.
number of objects), or category 4 (matching
shape). Ability to switch to a new set of rules uses are found in the posterior aspect of the frontal
prefrontal cortex. lobe, directly adjacent to the central sulcus. The
PM is the anterior most structure, and SMA is
The other major associative cortex more dorsal to the PM along the medial aspect
contributing to motor function is the posterior of the brain. M1 is posterior to that, bordering the
parietal cortex, which is largely concerned central sulcus. Generally speaking, information
integrating somatosensory with visual information from the associative cortices travel through PM,
and determining an appropriate motor action. then M1, before projecting down through the
For example, if you were planning to get up from brain stem and spinal cord.
your seat to walk across the room, the posterior These three structures are not an
parietal cortex would take in the somatosensory exhaustive list of motor cortex structures,
proprioceptive information about how your body however. For example, the frontal eye field (FEF)
is positioned, and the visual information from the communicates with the extraocular muscles and
objects in the room to avoid running into them mediates saccadic eye movements (chapter
(recall the dorsal stream pathway; chapter 7.4). 7.4). The inferior frontal gyrus, or Broca’s
area, contributes to motor processes related to
Motor cortex language (chapter 14).
The motor cortex is made up of three The premotor area (PM) modulates motor
closely related brain structures that contribute output, and generally activates prior to motor
to execution of movement: premotor area (PM), activity. For example, if monkeys are trained to
supplemental motor area (SMA), and primary press on a button on a delay in response to a
motor cortex (or M1). These motor cortex areas specific light cue, PM neurons will increase activity
10-4
upon presentation to the light cue, even before the The supplemental motor area (SMA) is
arm or hand begins to move. Also, activity of PM upstream of primary motor cortex, but also sends
increases as we imagine performing a complex downward projections through spinal cord. SMA
series of finger patterns, such as during mental communicates bilaterally, and lesioning this area
rehearsal of guitar or violin. causes deficits in manual coordination tasks that
There is debate about the existence of a require both hemispheres to communicate. For
special population of cells in PM called mirror example, in one monkey study, animals were
neurons. These are cells that are active during a presented with a table in which was a hole stuffed
movement, but also when that same movement is with a food reward. In order to obtain the food
observed in another animal or person. Proponents reward, the monkey needed to use one hand to
argue that these neurons are involved in learning push, and the other hand to catch. Lesions of SMA
behaviors and for understanding the behaviors caused the monkey to try to push the food from
of others. However, given the complexity of the both sides simultaneously. This suggests that
task of understanding others, it is unlikely to be SMA is responsible for the proper communication
encoded at the level of individual neurons. between motor commands in both hemispheres.
Primary motor cortex (M1) is a major
motor control center, required for deliberate,
voluntary movements, movements made in
response to a “command.” Furthermore, motor
cortex cells influence motor neurons, neurons
that communicate down into spinal cord that
ultimately influence muscles or glands. This
connection is so strong that the motor cortex cells
are sometimes called upper motor neurons.
In this terminology, a lower motor neuron is
found at the brain stem or spinal cord, and fires
whenever the upper motor neuron sends a signal.
Shank 1 In the 1930s, neurosurgeon Wilder
Penfield conducted several brain operations to
Spikes
treat patients with severe epilepsy. However,

since the brain has no pain receptors, he was
Shank 2
able to remove a portion of the skull under local
anesthesia while the patients were awake and
responding to his questions. During surgery, the
goal was to electrically stimulate portions of the
cortex to determine the origin of the seizures,
Figure 10.4 Surgically implanted electrodes and to ensure that areas critical to speech and
(top) in a marmoset brain. While viewing a fellow hand movement are left untouched so that the
marmoset reaching (bottom left), mirror neuron patient will not have major impairments following
activity increases (bottom right). surgery. This is currently done in neuro-oncology
10-5
M1 control the thumb, and near other populations of
Brain neurons that control the index finger. A graphical
representation of this map is called the “motor
homunculus,” in which body parts with larger
representations in the brain are shown with larger
size (much like the sensory homunculus; chapter
8.3).
Spinal Cord
Upper motor neuron
Muscle Lower motor neuron
Figure 10.5 Relationship between upper motor

neurons in M1 and the lower motor neurons
further down of the signaling pathway.
to reduce the loss of critical motor function and

overall morbidity.
Penfield progressively moved across
different brain areas of M1 while using an electrode
to stimulate patches of the cortex. He had two
major observations. First, stimulation caused
contralateral activity: that is, stimulating the left
side of the brain affects the muscle activity of the
right side of the body. Secondly, by systematically
moving across M1, he observed that different
populations of neurons are responsible for
communicating with specific muscle groups.
For instance, dorsal M1 activates hip and trunk
muscles, while more lateral M1 activates muscles Figure 10.6 Topographical organization of the
of the face. motor cortex (top), showing that neurons that
Penfield discovered that within the motor control adjacent body parts are often adjacent
cortex, different muscle groups are laid out in a themselves. The motor homunculus (bottom) is
rough topography, meaning that neurons that a representation of how much motor cortex is
control the thumb are near other neurons that dedicated to control over a specific body part.
10-6
Clinical connection: Prosthetic limbs
If activation of specific neurons can
produce muscle activity, then decoding
these descending signals could be used
to help amputees control their prosthetic
limbs. This technology is called a brain-
machine interface. In a technique called an
electrocorticogram (eCoG), the surgeon
puts a high-density electrode array capable
of sensing neural activity directly onto the
surface of the cortex of M1. With this strategy,
it is possible to detect electrical activity at
high spatial resolution (hundreds of microns)
and temporal resolution (hundreds of
microseconds), which is critical for movements
as precise and rapid as muscle movement. Figure 10.7 An eCoG allows a machine
ECoG grids have already been successfully to read cortical electrical activity with high
implanted in people with tetraplegia, allowing temporal and spatial precision, which can be
them to control external devices such as a used to control prosthetic limbs.
cursor on a screen or a prosthetic limb.
In the early 2000s, researchers experiments, the researchers delivered long
discovered that complex preprogrammed stimulation trains, similar in duration to that
actions, such as opening the mouth and observed in large muscle group movement
bringing a hand to the mouth, could be - approximately a half a second or longer.
activated from a single parcel of brain Further experiments developed a gestural
regardless of where the hand was located map, and even more complex behaviors such
in space - on your knee, on the table in front as reaching, climbing, and defensive postures.
of you, or to the side, for example. In these
Sensory feedback object, you could do it reasonably well without

An important component of healthy visual feedback. In order to make an accurate
movement is somatosensation, the process of movement, the brain needs to know how well
sensing and perceiving the body (chapter 8.) One the actual movement matches the intended
aspect is proprioception, the perception of our movement. If you are making an error, the sooner
body in the world. For example, if you close your it is discovered, the sooner you can update your
eyes, you can still feel if you are slouching and movement plan and adjust the movement.
if your hands are in front of you or to your sides. Receptors in our muscles, tendons,
Even if you were to move your arms forward, joints, and skin detect contraction, stretch,
such as when reaching out to grab a nearby and vibration. Sensory neurons carrying this
10-7
information synapse onto neurons in the spinal
cord, sending sensory information to both motor
neurons and also up to the brain, particularly the
primary somatosensory cortex (or S1; chapter
8). Here, several bidirectional connections are
made onto neurons in the adjacent motor cortex.
Through these signaling communication routes,
sensory information is used to update the motor
commands and correct movements that go awry.
10-8
Although the descending signals from Since the time of Galen in Ancient Greece
M1 are the major motor command signals that (~200 CE), behavioral functions related to
regulate activity, that signal is fine tuned through sensorimotor control have been ascribed to the
the action of two major brain structures, the cerebellum. In 1824, Marie-Jean-Pierre Flourens
cerebellum and a series of nuclei called the basal demonstrated that pigeons with cerebellar
ganglia. damage have poor wing flap coordination,
resulting in a diminished ability to fly. Anatomist
The Cerebellum Jan Evangelista Purkynĕ (1787–1869) described
The cerebellum (“little brain” in Latin) is the major output cell of the cerebellar cortex,
the most prominent structure of the hindbrain, and histological studies conducted by Santiago
located at the ventral-most part of the brain. The Ramon y Cajal (1909) later described cell
structure is evolutionarily ancient, and the general morphology and the layers of the cerebellum.
architecture and cell types of the cerebellum are The idea that cerebellum is key for
conserved between teleost fish and mammals. coordinated movement remains central to
The human cerebellum contains 69 billion cerebellar research. Cerebellum plays a role
neurons, which represents 80% of the total in integrating sensory information to produce
number of neurons in the human brain, despite coordinated movement, refining motor-related
being physically only 10% of the total brain mass. outputs to learn motor tasks, and processing
cognitive and executive functions.
Nonmotor functions of cerebellar circuits
have not received significant attention until recent
years. Stimulation or lesion of deep cerebellar
nuclei produced various autonomic and complex
Figure 10.8 The cerebellum is relatively small, Figure 10.9 Early illustration by Ramon y Cajal
but contains more neurons than the rest of the of the different types of neurons found in the
brain. cerebellum.
10-9
behavioral outputs, and associative learning organization with different regions of the
occurs in the cerebellum. Cerebellar abnormalities cerebellum receiving afferent fibers from different
like Purkinje cell loss may be involved in autism. sensory systems and projecting to different motor
Furthermore, cerebellar cognitive affective systems.
syndrome (CCAS) is characterized by dysfunction The surface of the cerebellum has a series
in executive tasks (e.g. planning, working memory, of parallel folds called lobules. Two transverse
abstract reasoning), impaired visual-spatial fissures, the primary fissure and the posterolateral
memory, changes to personality and emotional fissure, divide the cerebellum into three lobes.
control, and problems with language production, On the dorsal surface, the primary fissure
demonstrating that cerebellum contributes to separates the anterior and posterior lobes, while
much more than just motor related behaviors. on the ventral surface, the posterolateral fissure
separates the body of the cerebellum from the
Anatomy and function of the cerebellum flocculonodular lobe. The midline region is called
The cerebellum is composed of an external the vermis (Latin for “worm”), and on either side
layer of gray matter (the cerebellar cortex), an of the vermis is a cerebellar hemisphere.
internal core of white matter, and three pairs of Functionally, the cerebellum can be
deep nuclei (the fastigial nucleus, the interposed divided into three defined regions with roles in
nuclei, and the dentate nucleus). The cerebellum distinct types of movement.
is connected to the dorsal brain stem by three
pairs of peduncles, or stalks of tissue: the
inferior cerebellar peduncle, the middle cerebellar
peduncle, and the superior cerebellar peduncle.
The cerebellum is organized in a series
of regular, repeating units. It has a somatotopic
Cerebellar
hemisphere Vermis
Primary fissure Anterior lobe

Posterior lobe
Posterolateral Flocculonodular
fissure lobe
Figure 10.11 A midsagittal view of the cerebellum

Figure 10.10 The cerebellum is attached to the (top) and an “unrolled” view (bottom) labeling the
brain stem via three large pairs of nerve fibers. major anatomical structures.
10-10
1. The vestibulocerebellum, composed of the joint and muscle somatosensory information,
flocculonodular lobe, is the most evolutionarily providing the cerebellum with sensory feedback
-conserved region of the cerebellum. It integrates related to both voluntary and involuntary
visual and vestibular inputs, relaying information movement.
about head and body position in space. It can be The ventral spinocerebellar tract is only
thought of as two components, a medial aspect active during voluntary movements. It sends
and a lateral aspect. a “copy” of spinal motor neuron activity to the
Medial vestibulocerebellum controls cerebellum, informing the movement commands
muscles of the trunk and head, which regulate assembled at the spinal cord level.
posture. It also communicates with the limb Together, these spinocerebellar
extensor muscles, which help maintain balance connections are important for motor learning.
at rest and during locomotion. Sensory information from the actual movement
Lateral vestibulocerebellum controls (dorsal) is compared with the expected
eye movements and coordinates head and eye movement (ventral). If there is a mismatch, the
movements. In clinical observations, patients with motor command gets modification to achieve the
lesions in the lateral vestibulocerebellum display desired output.
deficits in smooth pursuit eye movement towards The cerebellum also initiates feed-forward
the side with the lesion. control of muscle activity to regulate the timing
of movements. This is anticipatory activity that
2. The spinocerebellum, which includes causes muscle contractions to generate smooth
the vermis and intermediate regions of the and accurate motion.
hemispheres, receives somatosensory and
proprioceptive inputs from the spinal cord and is 3. The cerebrocerebellum, composed of the
important for locomotion and extremity movement. lateral portions of the cerebellar hemispheres, is
The distal muscles of the limbs and digits are the most evolutionarily recent region, and is much
controlled by neurons in the intermediate regions larger in humans and apes than other basal-order
of the cerebellar hemispheres that receive mammals. As the name implies, these structures
somatosensory inputs from the limb.
Somatosensory information (touch, Spinocerebellum
pressure, proprioception; chapter 8) is passed to
the spinocerebellum from the spinal cord. These Cerebrocerebellum
connections provide feedback to the organism
about its changing position and environment
so that comparisons and adjustments can be
made. Projections into the spinocerebellum
display approximate somatotopy. There are two
functionally distinct ascending pathways into
Vestibulocerebellum
spinocerebellum, both carrying information from
spinal interneurons. Figure 10.12 Functional divisions of the
The dorsal spinocerebellar tract carries cerebellum.
10-11
Clinical connection: Ataxia
Ataxia is a condition characterized by
poor coordination of voluntary movements,
atypical eye movements, poor balance, or
changes in gait. They may exhibit dysarthria,
a speech disorder resulting in difficulty with
articulating language. Acute alcohol intoxication
produces an approximation of the symptoms of
ataxia. Figure 10.12 MRI showing a healthy cerebellum
A wide variety of causes can result in (left) and one experiencing degeneration from
ataxia, such as cerebellar injury from a stroke ataxia (right).
or tumor, toxin exposure, radiation poisoning,
hereditary diseases, or diet-induced (gluten) cause is addressed, and may be completely
autoimmune mediate cell death. Treatment of reversible or untreatable. Medication and physical
ataxia is most effective when the underlying therapy may also help treat the symptoms.
communicate with the cerebral cortex. Outputs Lugaro cells and chandelier cells) as well as
of the cerebrocerebellum travel to motor and excitatory interneurons (unipolar brush cells).
premotor cortices, and function in planning and Mossy fibers, one of the two major types of
executing movement. The cerebrocerebellum afferent projections into the cerebellum, terminate
also targets nonmotor associative areas, such in the granular layer. Mossy fibers form synaptic
as prefrontal and posterior parietal cortex, complexes with granule cells and Golgi cells called
contributing to cognitive functions. Neuroimaging cerebellar glomeruli that allow neurotransmitter
and neuropsychological studies demonstrate spillover and crosstalk.
cerebellar activation during tasks designed to The middle layer is called the Purkinje
evaluate attention, planning, working memory, cell layer and constitutes the output layer of the
abstract reasoning, language, pain, emotion and cerebellar cortex. It consists of a single layer of
addiction. Purkinje cells, which have giant cell bodies and
a broad dendritic arbor that stems from a central
Cellular organization of the cerebellum dendrite and fans in a single plane, extending
The cerebellar cortex is arranged into upward into the outer layer of the cerebellar
three layers with distinct populations of neurons. cortex. Purkinje cell axons are responsible for the
The deepest layer, called the granular output of the cerebellar cortex, projecting to deep
layer, is the input layer of the cerebellar cortex. It cerebellar nuclei in the white matter or vestibular
contains a substantial number of small, densely nuclei in the brain stem where GABA is released.
packed excitatory neurons called granule The external layer of the cerebellar cortex
cells, which are the primary unit of this layer. is the molecular layer, which contains the apical
The granular layer also includes more sparsely dendrites of the Purkinje cells and parallel fibers,
distributed inhibitory interneurons (Golgi cells, the axons of granule cells. These parallel fibers
10-12
Cerebellar
glomerus
Figure 10.14 Cartoon illustrating the cellular organization of the neurons of the cerebellum.
ascend from the granular layer to the molecular Also in the molecular layer are two populations
layer where they bifurcate to form branches that of inhibitory interneurons, the stellate cells
extend mediolaterally, parallel to the long axis and basket cells, which provide feed-forward
of the folia/lobules, thus giving them their name. inhibition to Purkinje cells.
10-13
The Basal Ganglia Diseases of the basal ganglia include
The basal ganglia are a series of subcortical movement disorders such as Parkinson’s disease,
brain structures that are intimately involved with dystonia, Huntington’s disease, and Tourette’s, as
various aspects of movement, such as voluntary well as complex psychiatric disorders including
motor activity, habit learning, and the selection of addiction and obsessive-compulsive disorder
actions. Despite being major structures involved (OCD).
in motor functions, none of the components of
the basal ganglia directly send projections down Striatum
the spinal cord. Rather, they communicate mostly The striatum is the largest of the basal
within themselves before signaling through the ganglia structures. It is the main input site of the
motor cortex. While the connections between basal ganglia, with projections coming from both
basal ganglia structures have been largely cortical and limbic structures such as thalamus
mapped out, the specific functions of each and amygdala.
individual structure in isolation is not entirely On a cellular level, the majority of neurons
clear. in the striatum are GABAergic cells called spiny
projection neurons (SPNs), or medium spiny
Cortex neurons (MSNs). These neurons express
different subtypes of dopamine receptors, and
some of them are excited by dopamine while
others are inhibited. Mixed within the SPNs are
Striatum
several populations of interneurons with various
GPe
STN
GPi
SNpr
SNpc
Thalamus
Dopamine GABA Glutamate
Figure 10.15 Diagram showing the connectivity Figure 10.16 Confocal image of a striatal spiny
and the nature of the signaling between different projection neuron identified with green fluorescent
nuclei of the basal ganglia. protein (GFP).
10-14
electrophysiological properties that utilize
different neurotransmitter systems, such as
GABA, acetylcholine, and nitric oxide.
The striatum is divided into two anatomically
and functionally different structures, a dorsal and
ventral striatum.
Dorsal Striatum
The dorsal striatum is made up of two
components, the caudate nucleus and putamen.
In rodents, the two are indistinguishable.
Functionally, dorsal striatum contributes to
learning of habitual behaviors. Habits are learned
motor patterns that can be performed without full
attention and generally inflexible due to repeated
training. Habits can either be adaptive (such as
changing physical stance in response to different Figure 10.17 Skinner box can be used to measure
environmental threats) or maladaptive (such operant conditioning, a dorsal striatum-mediated
as compulsive hair pulling or in substance use behavior.
disorder).
An example of a behavioral test of habit Putamen contributes to motor-associated
learning is a serial reaction time test, where one procedural learning tasks, like a mirror tracing
of four visual stimuli are presented and the patient task (chapter 13.1), which involves learning
is expected to make a motor response, such as how to draw with a pencil while watching only a
pushing on a corresponding button. If the pattern reflection of your hand. As with the serial reaction
of stimuli repeat with some regularity (button 2 is time test, improving at these behaviors happens
often followed by button 4, for example) patients unconsciously.
can unconsciously learn the repetition of the Anatomically, the dorsal striatum receives
pattern, decreasing reaction time. excitatory glutamatergic inputs from both
The caudate is particularly important motor cortex and thalamus. It also receives
for goal-directed actions, which are sets of dopaminergic projections from another basal
motor behaviors that are made in response ganglia structure, the substantia nigra pars
to knowledge of which actions lead to which compacta, a communication route called the
outcomes. such as the complex motor actions nigrostriatal pathway.
made while performing an operant conditioning The only output of the dorsal striatum
task. An experimental paradigm for this behavior are the GABAergic spiny projection neurons
would be a Skinner box, where an animal lever- (SPNs), which exist in two different types with
presses or nose-pokes for a food or sugar reward two different targets. One population, the direct
(chapter 11.2). SPNs (dSPNs), express dopamine D1 receptors
and send axons into the internal globus
10-15
pallidus (GPi). When this direct pathway is imbalance of this signaling (such as in Parkinson’s
activated, it increases motor activity. The other disease) leads to motor disturbances.
output neurons, the indirect SPNs (iSPNs),
express dopamine D2 receptors and project into Ventral Striatum
the external globus pallidus (GPe). Activation The ventral striatum includes the olfactory
of this indirect pathway decreases motor activity. tubercule and the nucleus accumbens, which
For healthy behavioral output, the dSPNs is further subdivided into core and shell.
drive the intended motor action, while the iSPNs Importantly, these ventral striatum
shut down competing motor actions. The balance structures are important for reward, motivation,
of these systems is closely regulated, and and aversion. As with dorsal striatum, dopamine
Clinical connection: Huntington’s Disease

Huntington’s disease is a rare Huntington’s disease passed through
neurodegenerative movement disorder resulting families in an autosomal dominant manner. A
from various dysfunctional signaling pathways protein called huntingtin (htt) is implicated, and
of the basal ganglia. Symptoms include mutant huntingtin has several repeats of the
hyperkinesia (uncontrolled movement), poor amino acid glutamine. The greater the number of
coordination, and cognitive and psychiatric repeats, the more severe the symptoms and the
changes eventually leading to dementia. The earlier the onset of the disease. A leading theory
onset of symptoms happens when a person suggests that mutant htt accumulates inside
is in their 30s-50s, and prognosis is generally neurons, leading to neurodegeneration.
fatal within 15 years after diagnosis. There is
currently no cure for the disease.
Normal Htt protein
Healthy Htt gene

10-26 repeats CAGCAGCAG...
CAGCAGCAGCAGCAGCAG...
Abnormal Htt
protein
HD gene
37-80 repeats
Figure 10.18 Longer CAG repeats in the Htt gene code for abnormal proteins. Greater number of
repeats are associated with earlier age of onset of symptom presentation.
10-16
signaling is critical for mediating these behaviors. functionally different connections. The internal
Increased dopamine signaling in ventral striatum globus pallidus (GPi) is movement promoting,
is a “learning signal” that encourages the organism and receives inputs from the dSPNs of the dorsal
to repeat that behavior again. Dopamine is striatum. On the other hand, the external globus
released in response to unexpected rewarding pallidus (GPe) is movement inhibiting, and
stimuli, such as getting a sip of a sugary drink or receives dorsal striatal afferents from iSPNs.
engaging in sexual contact. Many drugs of abuse,
such as nicotine and cocaine, artificially drive up Subthalamic Nucleus (STN)
this dopamine signal, which leads to repeated The STN is part of the indirect pathway,
use and drug seeking (chapter 11). downstream of the GPe. The GPe makes up the
The major inputs into the ventral striatum axonal inputs into the STN, which are inhibitory
are glutamatergic afferents from prefrontal GABAergic projections. The output of the STN
cortex and limbic areas, such as hippocampus, are glutamatergic signals into the GPi.
amygdala, and thalamus. The dopaminergic In a medical intervention called deep
inputs come from the ventral tegmental area in brain stimulation (DBS), a surgeon implants
the midbrain. permanently indwelling electrodes directly into
brain tissue. These electrodes are controlled
Globus Pallidus (GP) by an external battery pack that delivers pre-
In dissection, the GP appears as a pale programmed stimulation protocols. DBS in
globe. It is subdivided into two components with the STN is used to alleviate the symptoms of
Parkinson’s disease.
Electrode
Battery
Figure 10.19 A deep brain stimulator (left) is controlled by an external battery. During surgery, the STN
(right) can be targeted as a treatment for Parkinson’s disease.
10-17
Substantia Nigra significance, these neurons experience selective
The SN is a midbrain structure that appears neurodegeneration in Parkinson’s disease.
darker in dissection due to heavy expression of The substantia nigra pars reticulata
neuromelanin across cells in these areas. It is the (SNpr) is an anatomically distinct area of the SN.
largest midbrain structure. It receives GABA-ergic inputs from the dorsal
SN is divided into two areas. The striatum and excitatory inputs from STN. The
substantia nigra pars compacta (SNpc) major output of SNpr is GABAergic; these axons
contains several dopamine expressing neurons terminate in the thalamus
that project into the dorsal striatum. Of clinical
Clinical connection: Parkinson’s Disease percentage of cases are early onset (21 - 50
Parkinson’s disease is a years old; Michael J. Fox was diagnosed at
neurodegenerative movement disorder that 30), and have a strong genetic component. The
causes bradykinesia (slowness of movement), disease causes significant decreases in life
a resting tremor, muscle rigidity, and changes expectancy and quality of life.
to posture and locomotion. Although most A loss of dopaminergic neurons of the
symptoms are motor, there are mild cognitive SNpc contributes to basal ganglia circuitry
and psychiatric changes, such as apathy, disruption. When less dopamine is released
anhedonia, mood disturbances, or depression. into dorsal striatum, the dSPNs are less active
Advanced age is the primary risk factor, as while the iSPNs are more active. This imbalance
an estimated 1% of people over the age of in the output leads to the motor symptoms of
60 develop PD. Other environmental factors the disease. However, the cause of PD is still
contribute to risk, such as repeated traumatic unknown; the formation of intracellular protein
brain injury (suspected in Muhammad Ali) aggregates called Lewy bodies and oxidative
or occupational exposure to heavy metals, stress leading to neurodegeneration are among
insecticides, or other neurotoxins. A small some of the proposed mechanisms.
Healthy midbrain
Substantia nigra
Parkinson’s midbrain
Figure 10.20 The substantia nigra selectively degrades in PD (left), possibly due to accumulation
of Lewy bodies inside the neurons (right, arrow head).
10-18
Spinal cord anatomy several cranial nerves, particularly those with

The spinal cord extends posteriorly from motor function: The trigeminal nucleus (CN
the brain stem, surrounded by the vertebrae. In V) modulates muscles of chewing, the facial
a typical human, the spinal cord is about 1 cm nucleus (CN VII) regulates facial expressions,
in diameter. Generally, the diameter of the spinal the glossopharyngeal nucleus (CN IX) controls
cord decreases from anterior to posterior, with two the muscles involved in speech and swallowing,
exceptions: an enlargement in the mid-cervical and the hypoglossal nucleus (CN XII) controls
region to accommodate the extra nerves of the the muscles of the tongue.
arms and hands, and a smaller enlargement in
the lumbar region to accommodate extra nerves Corticobulbar tract
Upper motor
of the legs and feet (chapter 2.1). neuron
The output neurons of the motor cortex
Cranial nerve
carry voluntary motor information and send motor nuclei
their axons down through two major descending
communication routes. At the level of the
brain stem, both pass through the medullary
pyramids, paired anatomical structures found
on the ventral surface of the medulla. Because
of this, both descending axonal tracts are also
called the pyramidal tracts.
The corticobulbar tract is made up of
axons that terminate in various brain stem motor
nuclei. These nuclei communicate directly with
Figure 10.22 The corticobulbar tract originates in

M1 and projects into the brain stem motor cranial
nerve nuclei that control facial muscles.
The other major output of M1 are the

upper motor neurons whose axons are the
corticospinal tract, which runs down the spinal
cord through white matter. This pathway has two
different communication components.
Figure 10.21 Position of the pyramids in the Upwards of 90% of the corticospinal tract
ventral spinal cord (left, green) and its location are axons of the lateral corticospinal tract, which
along the midline (right). sends voluntary motor control to the contralateral
10-19
distal limbs, such as in the arms, hands, legs, neurons then send nerve rootlets out of the
and feet. Some neurons of M1 are Betz cells, ventral surface of the spinal cord, then form a
the largest known neurons in the brain. Most of neuromuscular junction with the muscles.
this tract crosses hemispheres at the pyramidal The remaining output is the anterior
decussation, runs down the contralateral spinal corticospinal tract, which carries information to
cord, then forms synapses onto the lower motor the muscles of the trunk, such as our shoulders
neurons in the ventral horn. These lower motor or pectorals. This signaling from the brain stem
descends ipsilaterally, but eventually decussates
Primary at the spinal cord, resulting in contralateral control.
motor Here, as above, the neuron forms synapses with
cortex
the lower motor neurons found in the ventral horn.
Reflexes
Reflexes are involuntary motor
responses that are performed automatically and
independent of brain signals (although some
can be suppressed voluntarily, with extra effort).
Reflexes involve very simple circuits, sometimes
consisting of only two populations of neurons:
Midbrain Sensory information comes in from the periphery,
synapsing onto motor neurons in the brainstem
or spinal cord. Reflexes can take place as quickly
as 1/100th of a second!
A simple reflex is the patellar reflex, or
Medulla
the “knee-jerk” or myotatic reflex (described
Pyramids in more depth in chapter 8; figure 8.27). The
stretching of the tendon causes the muscle to
Pyramidal elongate, sensory receptors detect this change
decussation in muscle length, and the corresponding signal
Anterior is sent into the spinal cord. This sensory neuron
corticospinal
Lateral synapses directly onto a motoneuron, which then
tract
corticospinal tells the thigh muscle to contract, making the
tract Spinal cord
decussation kicking “knee-jerk” movement. Since only one
To muscle synapse is involved in producing this response,
Spinal cord this is an example of a monosynaptic reflex arc.
The reflexive kick is controlled at the level
Lower motor
neuron of the spinal cord and cannot be intentionally
suppressed by descending motor pathways no
Figure 10.23 Connectivity of descending motor matter how hard you concentrate.
control pathways.
10-20
Central pattern generators (CPG) muscles through CPG activation is likely an
Central pattern generators (CPGs) are evolutionary older mechanism. Respiratory
networks of cells that are capable of producing control circuits are found at the level of the brain
intrinsic motor responses even in the absence of stem, specifically, the medulla and pons. One
sensory or brain inputs. These motor responses suspected CPG is a population of medullary
are usually well-rehearsed, repetitive, and cells called the pre-Bötzinger complex, which
happen at the unconscious level, meaning that contains cells that change their activity in a cyclic
certain behavioral outputs can be performed pattern. Neurons in these areas are also sensitive
independently of signals upstream in the to changes in blood chemistry (Chapter 9.3).
motor cortex. Some example motor responses The major nerves involved with respiration
driven by CPGs include diaphragm movement are the phrenic nerve, which innervates the
(respiration), alternating leg swinging and foot diaphragm, and the intercostal nerves, which
flexing (walking), and the progressive contraction predictably innervate the intercostal muscles.
of up to 25 pairs of muscles in the tongue and When we inhale (inspiration), the diaphragm
mouth (swallowing). Some CPGs are located in contracts and the intercostals move the rib cage
the brain stem (respiration) and others throughout to increase the volume of the chest cavity, which
the spinal cord (locomotion). allows the lungs to expand. During exhalation,
CPGs have been observed in several the reverse process is true. These nerves receive
organisms, ranging from insects, crayfish, birds, innervation from neurons of the CPGs in the
and mammals including humans, hinting that respiratory centers of the hindbrain (medulla and
their evolution was highly adaptive for survival. pons, specifically.)
Imagine how difficult it would be to survive if every The activity of the respiratory CPGs is so
breath required a conscious thought! potent, that they can sometimes function while
The CPG is not a standalone driver of unconscious. Some deficits in respiratory CPGs
motor activity, however. The circuits receive are believed to be one cause of central sleep
signals from higher brain areas which can modify apnea, a disorder where a person stops breathing
their characteristics. Imagine that you want to while asleep (chapter 12).
consciously hold your breath, or intentionally walk
in some unusual or goofy way. In both cases, CPGs of locomotion
the descending signals from the brain are able It is much more complex to describe the
to override the output motor command pattern action of the muscle groups needed for a simple
that the CPG normally produces. Once you stop behavior of just walking down the sidewalk: the
intentionally changing your motor behavior, the ankle dorsiflexors, the hamstrings, hip flexors,
muscles return to their normal activity in response gluteus maximus and many more function at
to CPG output. very precise moments, allowing us to propel
ourselves forward. Importantly, this pattern of
CPGs of respiration activity is rhythmic, and repeats at the frequency
Getting oxygen is one of the most essential of stepping.
functions that an animal needs to perform for Many earlier studies of spinal cord CPGs
survival. As such, involuntary control of respiratory were conducted in different animal groups with
10-21
the following years, he gradually
recovered a small amount of function.
Fine manipulation skills and bladder
bowel control never recovered, and
he had not walked unassisted for
ten years, experiencing tremendous
weakness after taking a few steps.
Just days after beginning a
physical therapy regimen consisting
of assisted upright walking, upon lying
down, the man reported alternating
muscle flexion and relaxation of the
hips, knees, and ankles similar to the
pattern of activity seen in locomotion.
He was unable to voluntarily stop
Figure 10.24 Locomotor CPGs produce alternating cyclic these motions, and could only get
activity of motor neurons, which simplify walking. some rest by turning to the side.
This muscle activity was smooth and
unique locomotor patterns. Mollusks have rhythmic, as would be seen in a healthy person
crawling activity that is rhythmic, fish swim by walking.
sending alternative patterns of muscle activity
through their body, and birds fly by rhythmic
flapping of their wings.
In mammals, spinal CPGs were
demonstrated in cats with a thoracic-level
Walking Running
spinal cord transection. Following this surgery,
the signals from the brain were unable to be Figure 10.25 Six-legged animals like insects
communicated down to the hind legs, eliminating have central pattern generators that simplify
voluntary movement. They exhibited weakened locomotion through coordinated neural activity
muscular power, but were still able to stand for that regulates muscle movement.
short times. If their front paws were put onto a
stable platform while their hindlegs were put on a
moving treadmill, the cat would involuntarily walk
to keep up.
Humans also have CPGs for movement.
One remarkable study looked at 37-year-old
man who had injured his spinal cord in a football
accident as a young man. His injury was at the
level of C5, resulting in complete paralysis and
a loss of sensation from the neck down. Over
10-22
10.4 The Muscles
Neuromuscular junction (NMJ) The axons of the lower motor neurons

The signal from lower motor neurons synthesize and release acetylcholine. Densely
communicate with the muscle at the expressed in the sarcolemma are nicotinic
neuromuscular junction (NMJ). The NMJ is acetylcholine receptors (nAChRs), ionotropic
similar to other chemical synapses, however receptors that allow sodium influx and subsequent
the postsynaptic cell is a muscle cell separated muscle cell depolarization upon acetylcholine
by about 30 nm. The postsynaptic site is the binding. This depolarization results in muscle cell
sarcolemma, the cell membrane of muscle cells, contraction.
which has several folds to increase surface area.
Muscle anatomy
As mentioned above, motor functions can
either be voluntary (moving your arm above your
head) or involuntary (muscle contraction that leads
to bowel motility, or heart beating). Although the
nervous system influences both types of muscle
activity, most of our discussion revolves around
deliberate, voluntary skeletal muscle movement.
The main action of muscles is to contract, a
physical change of their shape where they
1 become wider and shorter. For example, as you
flex your arm, your bicep changes from long and
thin to short and thick.
2 Different muscles have different
characteristics driven by their shape and
3
composition. For example, some muscles can
be active for a long time without getting tired
4
(maintaining your posture in your chair as you
read this) while others can exert a lot of force but
5
get tired quickly (lifting weights in the gym).
In studying muscles, some of the key
Figure 10.26 Electron micrograph image of an measurements are where they connect to the
NMJ (top; T = axon terminal, M = muscle cell). bone, how long they are, how thick they are,
Cartoon depicting the phases of signaling at an and what type of muscle fibers they are made of.
NMJ (bottom). The action potential (1) allows These measurements can be used to calculate
release of aceylcholine (2), activating nAChRs how much force a muscle can generate and how
(3), allowing depolarization of muscle cells (4) quickly the joint can move.
and the contraction (5).
10-23
Individual muscles, such as your
Clinical connection: Myasthenia biceps brachii, are made up of several muscle
gravis (MG) fascicles, which in turn are made up of muscle
Myasthenia gravis (MG) is an autoimmune fibers. Muscle fibers are the individual cells in
disorder characterized by muscle weakness, which contraction occurs. The functional units
resulting in difficulty with speech, trouble with for contraction are called sarcomeres. It is the
movement and swallowing, drooping eyelids, aggregated activity of hundreds of thousands
and double vision. Each year, an estimated 20 of sarcomeres within each muscle fiber that
out of a million people get diagnosed with MG. generates the force with which you walk your
The muscle weakness seen in MG results dog or chew your food.
from immune system-mediated destruction The contraction within sarcomeres
of the nAChRs expressed at the NMJ. Thus, happens between two proteins actin and
when the lower motor neuron releases ACh, the myosin. Actin are the thin filaments that form
muscle cells are unable to detect this release, the scaffolding, and myosin are thick filaments
so they fail to contract appropriately. that pull the actin together, shortening the
One therapeutic strategy involves sarcomere and contracting the muscle.
inhibition of acetylcholinesterase, the enzyme Although each sarcomere is small (1.5 to 3.5
that degrades ACh. This causes the synaptic µm), many are stacked back to back along the
ACh to remain in the synapse longer, increasing length of each fiber, pulling against each other
the chance that receptors get activated. to contract through the whole range of your
Alternatively, autoimmune diseases like MG can joints. Many sarcomeres bundled in parallel
be improved with immunosuppressant therapy. provide the combined force that give muscles
With successful treatment, MG usually does not strength. The strength in all of your muscles
result in changes in lifespan. comes from these tiny threads pulling against
each other.
Actin
Myosin
Relaxed
Flexed
Figure 10.27 A patient with MG may show

weakness of facial muscles. Figure 10.28 In a sarcomere, myosin (purple)
and actin (red) overlap when the muscle flexes.
10-24
Muscle types
There are two key characteristics of voluntarily contracted (and in reflexes) to move
muscles: their structure (striated due to the your body by moving your skeleton. There are
presence of sarcomeres or smooth), and whether two types of skeletal muscles.
they can be voluntarily controlled. Based on these Fast twitch muscles generate a lot of
characteristics, there are three types of muscles force quickly, but also tire quickly. They are used
in humans and other vertebrates. mostly in high intensity exercise like lifting weights
and sprinting. Slow twitch muscles generate
Striated Smooth less force, but can work for a long time. They are
Voluntary Skeletal used in endurance exercise like jogging. Many
Involuntary Cardiac Smooth exercises use a combination of both.
Muscles come in several different shapes,
Skeletal muscle is what most people defined by the arrangement of their fibers and how
think of when they think “muscle.” They attach they connect to tendons. The different shapes
to bones with tendons, and exert force on your allow for different properties: some can change
skeleton to create movement and exert force on length quickly, others change shape less but are
objects. stronger. Another consideration for shape is the
Skeletal muscles are also called “voluntary geometry of the joint they cover: for example, the
muscles” because they are the muscles that move pectoralis muscle reaches from your chest across
when you choose to make a movement. They are your shoulder, and so the muscle is wide and flat
Skeletal Cardiac Smooth
Figure 10.29 Different types of muscle as seen at 400x magnification. Muscle fibers are seen running
from left to right. In skeletal and cardiac muscles, striations can be seen perpendicular to the muscle
fibers.
10-25
where it connects to your sternum, and narrows at the elbow. It’s movement is supported by
to a point where it connects to your upper arm. synergistic muscles, including the brachialis
Skeletal muscles work to move the body and brachioradialis. These can also be fixators,
through a combination of cooperation and providing stability and preventing or allowing
opposition. The agonist muscle is the main rotation of the wrist while flexing at the elbow.
mover, like the biceps brachii when you flex Antagonist muscles are those that move in
the opposite direction to the agonist. For the
elbow, the antagonist is the triceps bracii, which
Bicep contract
lengthens during the bicep flex. Another example
Bicep relax
of an agonist-antagonist pair are the hamstrings
to flex the leg, and the quadriceps to extend it.
Smooth muscles are the muscles
Tricep
Tricep relax contract embedded within organs like your stomach and
intestines, blood vessels, and bladder. They are
also known as “involuntary” muscles because
they are not under direct conscious control.
Cardiac muscle can be thought of as a
Figure 10.30 Skeletal muscles may be paired and hybrid between skeletal muscles and smooth
produce opposing effects on a particular motion. muscles, in that they are striated like skeletal
muscles but not under conscious control.
DePaul University.
10-26
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10.4 Suzuki W, Banno T, Miyakawa N, Abe H, Goda N and Ichinohe N (2015) Mirror Neurons in a New World Monkey,
Common Marmoset. Front. Neurosci. 9:459. doi: 10.3389/fnins.2015.00459
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10.14 Consalez GG, Goldowitz D, Casoni F and Hawkes R (2021) Origins, Development, and Compartmentation of the
Granule Cells of the Cerebellum. Front. Neural Circuits 14:611841. doi: 10.3389/fncir.2020.611841
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ParkinsonsDisease.png Blausen.com staff (2014). “Medical gallery of Blausen Medical 2014”. WikiJournal of Medicine 1
(2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436. - Own work
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10.22 https://commons.wikimedia.org/wiki/File:Motor_Facial_Route.png Patrick J. Lynch; illustrator; C. Carl Jaffe; MD;
cardiologist Yale University Center for Advanced Instructional Media Medical Illustrations by Patrick Lynch, generated for
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10.25 Espinal A, Rostro-Gonzalez H, Carpio M, Guerra-Hernandez EI, Ornelas-Rodriguez M and Sotelo-Figueroa M (2016)
Design of Spiking Central Pattern Generators for Multiple Locomotion Gaits in Hexapod Robots by Christiansen Grammar
Evolution. Front. Neurorobot. 10:6. doi: 10.3389/fnbot.2016.00006
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11-1
Editor: Harriet de Wit, PhD (University of Chicago)
More than 275 million people worldwide have misused drugs such as heroin or cocaine at least
once in 2016. Use of some of these drugs carry significant health risks, and their use has led to
hundreds of thousands of deaths, making drug use one of the highest preventable causes of mortality.
For some people, drug use turns into a substance use disorder, such as addiction. These
disorders are prevalent worldwide, affecting some 30 million people globally. On top of the direct health
risks associated with compulsive drug use, drug addiction has a tremendous financial burden: Alcohol,
tobacco, and illicit drugs cost the US more than $740 billion dollars in lost productivity, health care
costs, and legal related fees and fines.
This chapter introduces you to some of the basics of neuropharmacology, the study of drugs
that affect the nervous system. Drugs are defined as some chemical substance that comes from outside
the body; drugs are exogenous substances that can influence a person’s physical or mental state. The
field of study of the effect of drugs on the body is called pharmacodynamics, while the reverse study,
the effects of the body on the drugs, is called pharmacokinetics.
Chapter 11 outline


For a drug to influence the nervous system, brain more quickly are more likely to produce
it has to find a way to get into the body. Drugs can pleasurable feelings, and thus be misused.
be used by several routes of administration, The most common route of administration is
which can be roughly divided into two main by oral administration, by mouth. Drugs consumed
classifications: enteral, which means they have orally can come in a variety of preparations, with
to be absorbed through the gastrointestinal tract, a pill being the most common, but they can also
or parenteral, which avoids the digestive tract. be foods or drinks. Swallowing substances is
Routes of administration are particularly important one of the most natural processes, making oral
in substance use, because drugs that reach the administration one of the most convenient ways
11-2
Figure 11.1 Pills, one of the most common
preparations for oral administration of drugs.
to take a drug, generally very simple requiring no

additional supplies. Orally administered drugs can
be designed to release over a prolonged period of
time, even up to a day, which makes it a preferred
route of administration for substances that need
to be present for extended periods of time. The
substance can also be expelled from the body
through vomiting or stomach pumping in case it
is suspected as causing toxicity or in overdose.
Absorption of the drug into the bloodstream can Figure 11.2 The hepatic portal system moves
also be modified by other substances, such as substances taken orally through the liver for
foods in the stomach. enzymatic processing before entering total
One of the major considerations of oral circulation.
administration is the slow onset of effect of the
drug. It requires digestive processes which work absorbed through the gut wall and into the hepatic
on the time scale of tens of minutes to hours, portal system, a branch of the circulatory system
making it less effective in the case of major that surrounds the gastrointestinal tract. Before
emergencies where speed of treatment effect entering systemic circulation, this blood is passed
is the difference between life and death. It also through the liver, where a variety of degradation
requires the conscious action of swallowing, enzymes destroy some amount of the drug. This
so oral administration will not be useful when process is called first-pass metabolism, and
a person is unconscious. And if a person has causes a decrease in difference between the
nausea, they may be unable to keep the drug in consumed amount of drug and the amount of
their system long enough for it to be digested and drug that gets to its target of action.
absorbed. On the contrary, some drugs are inactive
Substances that are ingested orally are until they get converted into another substance
11-3
11-3
detected within seconds. When a needle
is used to deliver the drug directly
into the bloodstream, the drug is not
subject to any first-pass metabolism,
meaning that the dosage delivered
is similar to the dosage experienced.
Many substances, in particular heroin,
are delivered via IV injection since it
produces the most rapid onset high. In
general, drugs that are taken via rapid
routes of administration have a higher
misuse potential. Clinically, the speed
of an IV injection drug effect makes
Figure 11.3 Hypodermic needle for drug delivery via it preferable when time is essential,
intravenous injection, a very rapid route of administration notably, when injecting substances like
that can cause a drug effect within seconds. Narcan (naloxone) that can reverse
the respiratory depressive symptoms of
after enzymatic processing. These substances opioid overdose. Alternatively, it is also possible
are called prodrugs. One well known prodrug to deliver a pain-killer drug slowly and as needed
is psilocybin, a chemical found in “magic using an IV drip, which minimizes the risks of
mushrooms.” Psilocybin itself is inactive, but overdose due to a sudden influx of drug.
once it is exposed to highly acidic conditions, IV injections are sort of a one-way street:
like the inside of the stomach, it becomes the the concentration of drug that enters the blood
psychoactive substance psilocin. cannot be decreased. The drug rapidly mixes
One other enteric route of administration with blood, and can only be decreased with
avoids some of the issues with oral preparations. biological modifying agents or through natural
Rectal administration avoids a majority of the enzymatic degradation. IV injections require
first-pass metabolism, and can be delivered even syringes, which are an added cost to drug use,
if a patient has severe nausea. There are two and bring with it a variety of health risks, including
other related enteric methods worth mentioning. the potential transmission of bloodborne illnesses
Sublingual refers to placement of the substance and infections at the injection site. Repeated
under the tongue, and may be seen with some injections can be painful and can lead to deflated
preparations of LSD. Transbuccal administra- veins, which is why some IV drug addicts resort
tion refers to drugs that are absorbed by the vas- to shooting drugs into other smaller veins such as
culature in the gums as in oral nicotine prepara- the veins on their hands or between the toes.
tions such as dip or Swedish snus. Alternative injection routes are less
common for misused drugs, and each has
Intravenous (IV) injection is the fastest slightly different advantages and disadvantages.
route of administration, with drug effects being Intramuscular (IM) injections, like a flu shot
11-4
into the deltoid muscle of the arm, are
somewhat slower than IV injections (tens
of minutes rather than tens of seconds)
but are much easier to perform than an
IV injection. In a subcutaneous (SC)
injection, solution is injected into the
fat layer underneath the skin, making it
ideal for lipid-soluble drugs.
Inhalation is another rapid

Figure 11.4 Inhalation allows for exchange of gases at the
route of administration. Drug effects
alveoli, so drug enters the bloodstream rapidly.
are experienced on the scale of tens
of seconds. For a substance to have an effect the smoke is inhaled, while liquids are turned into
on the brain through inhalation, it must first be a vapor either through a heating element like vape
volatilized then taken into the lungs through the or naturally because of the chemical properties of
nose or mouth. To inhale solids (such as with the liquid.
tobacco or marijuana), they are often burned and
In some cases, drugs interact with foods

in a way that changes their effectiveness. A
common example of this is the compound
bergamottin, commonly found in grapefruits.
Bergamottin inhibits the activity enzymes
called cytochrome P450s (CYP), a class of
enzymes in the liver and the small intestines
that metabolize a wide variety of substances
that enter the body. When we drink grapefruit
juice, inhibition of CYP can decrease the
dosage of drug that gets into the brain. For example, the analgesic drug codeine is a prodrug, a
substance that exerts influence on the body after it is modified during metabolism. CYP normally
degrades codeine into the more potent analgesic morphine, but in the presence of grapefruit juice
in the body less morphine is produced, resulting in less effect than expected.
On the other hand, other drugs are degraded by the CYP-3A4 enzyme before they are
even able to affect the brain, like the anti anxiety drug buspirone. Usually, only 4% of the dosage
of buspirone actually has an effect. But, when a CYP-3A4 inhibitor like grapefruit juice is present, a
regular dosage of the drug results in a greatly elevated concentration in the brain, which may start
to produce symptoms of overdose. More than 85 pharmaceuticals interact with grapefruit juice;
some of the interactions can lead to life-threatening cardiovascular / respiratory side effects (like a
buildup of the opioid fentanyl) or permanent kidney damage.
11-5
Physiologically, the lungs are extremely the gases, thus making exposure to the substance
effective at transporting inhaled gases into the highly undesirable. The dangers of this route of
bloodstream, the same process that allows us administration is that a person may experience
to capture oxygen from the air and expel carbon hypoxia, low blood levels of oxygen, which can
dioxide as we exhale. Gas exchange occurs at the cause permanent brain damage. Many of the
pulmonary capillaries, the dense network of blood “rewarding” sensations associated with inhalant
vessels that surrounds the alveoli of the lungs. misuse are due to hypoxia.
Inhaled air fills these alveoli and exchanges gases
in the time span of each breath. This remarkable Insufflation represents a different route
efficiency of exchanging inspired gases with the of administration from inhalation because there
dissolved gases in the bloodstream provides one are a few major differences of how the drug
of the major clinical advantages of inhalation gets into the bloodstream. The substance is first
as a route of administration, especially during pulverized into a fine powder then inhaled through
surgery. Inhalable anesthetics are very quickly the nostrils. Most of the solid sticks to the inside
cleared out of the body when a person goes from of the nasal cavity, where the chemical can then
breathing the anesthesia to breathing normal be absorbed by the thin blood vessels that line
air. Breathing is also one of the most natural, the inside of the nose. Insufflation, or “snorting,”
unconscious functions that our body possesses, is a very common route of administration for the
which makes inhalation a very convenient route recreational use of cocaine, producing a very
of administration. rapid drug effect within minutes. Because drugs
However, inhalation of hot burnt solids that are insufflated are protected from first-pass
causes significant damage to the airways. metabolism, they yield a higher dose that affects
Inhalation of the chemicals in the propellants in the brain.
compressed gases has been on the decline since
manufacturers began adding bittering agents to Transdermal is another parenteral route
of administration that avoids processing by the
digestive tract. In transdermal administration,
a substance is placed on the skin surface, and
over time the chemical diffuses through the
skin into the blood vessels. The most common
and well-known example of transdermal drug
administration is the nicotine patch, a nicotine-
replacement therapy. Transdermal patches
have the advantage that the drug diffuses slowly
over a prolonged period of time, up to 24 hours,
minimizing the abuse potential of drugs taken in
this route. However, because the skin is such an
Figure 11.5 Inhalation is often used for
effective protective barrier against the outside
inducing anesthesia before surgery because of
world, there are major limitations to the types
it’s ease of administration and rapid onset.
of drugs that can be delivered via transdermal
11-6
application: only small molecules and fatty lipids
that are effective at milligram concentrations can
be used.
Topical administration is closely related
to transdermal administration, with the major
difference being that topical administration does
not significantly increase the blood concentration
of the drug. Topical administration acts only
locally, and some common substances that are
applied topically include Tiger balm or Icy-Hot.
Because chemicals introduced topically do not
Figure 11.6 A transdermal patch that steadily
significantly get alter brain activity, they are not
delivers nicotine into the bloodstream.
psychoactive.
The pharmacokinetic profiles of drugs are
important for understanding their abuse potential,
and potential strategies to develop effective
treatments and medications to treat overdose.
11-7
Having a sense of reward is a valuable our reward signaling neural circuitry starts with
adaptive trait. Consider two similar organisms the ventral tegmental area (VTA). Located
living in the distant geologic past, both involved in the midbrain, the VTA contains neurons that
in Darwin’s struggle to pass their genetic synthesize the neurotransmitter dopamine (DA),
material to the following generation. One of and is the largest group of DA cells (citation) in
these creatures gets an internal rewarding the brain. They are also called the A10 neurons.
sensation whenever it drinks water while thirsty, This population of DA cells similar to the cells in
eats high caloric-content food, or successfully the substantia nigra, the midbrain neurons that
reproduces. As can be expected, this organism are lost in Parkinson’s disease (see chapter 10).
is highly motivated to seek out those rewarding These VTA DA neurons send their axonal
stimuli in the world. It is are more likely to crave projections predominantly into two main areas.
sugary foods to maximize daily caloric intake The mesolimbic pathway consists of dopamine
necessary for activity and growth. The other producing neurons that release dopamine onto
creature does not experience pleasure from its the cells in the nucleus accumbens (NAc,
actions, resulting in little motivation to seek out sometimes also called the ventral striatum). This
calories or to reproduce, for example. It stands seems to be the major pathway by which reward
to reason that the first of these two creatures has is mediated by the brain. Using microdialysis, it is
an evolutionary advantage to survive. possible to measure the dopamine concentration
As can be expected, the regions of the in the NAc during performance of some behavioral
brain that are concerned with reward are highly tasks. In studies with rats, engaging in rewarding
conserved through evolution. For us humans, activities such as eating or sex results in increased
release of dopamine in the NAc. Similarly we
Figure 11.7 Neural structures involved in reward
see that release of dopamine into the human
and aversion.
NAc is enhanced when we engage in activities
we enjoy: binge eating sugary stuff, having sex,
even playing video games. Notably, many drugs
of abuse such as cocaine or amphetamine can
induce a similar overflow of dopamine release
PFC
when an animal is exposed to the drug.
The second area that receives VTA
LHb
NAc innervation is the prefrontal cortex (PFC),
VTA and this projection is called the mesocortical
pathway. We think of the PFC as being involved
in the conscious, decision making and inhibition
of actions. It is likely that maladaptive changes
in the dopamine projections into the PFC may
explain the poor decision making and loss of
11-8
One of the earliest experiments demonstrating functional evidence of a “reward circuit”
was conducted at McGill University in the early 1950’s. Drs. James Olds and Peter Milner
carried out surgery on anesthetized rats to implant metal electrodes into different areas of
the brain. After recovery, the rats were placed into an operant conditioning chamber, also
called a Skinner box. These special cages are equipped with a device which the subject can
physically manipulate. For example, the cage may have a lever which the animal can push,
or a hole into which they can poke their nose. In the case of Olds and Milner’s experiments, a
lever press led to activation of the implanted electrodes, resulting in neuronal activation. They
had found that when the electrode was implanted into brain areas such as the corpus callosum
or the hippocampus, the rats did not spend significant time pressing on the lever. However,
the rats which had the electrodes implanted in the septal nucleus responded frequently on the
lever. One such rat pressed the lever almost 2000 times in less than an hour, averaging nearly
one response every two seconds! Electrical activation of
reward centers is so desirable, rats will choose electrical Figure 11.8 An operant conditioning
stimulation over food even to the point of starvation. chamber, where pushing a button or
This experimental paradigm is also called lever results in a response such as
intracranial-self stimulation (ICSS). And while the electrical activation of the brain.
original studies were conducted on rats, clinicians soon
after tested their model in humans, with similar indwelling
electrodes in different brain regions. Unsurprisingly,
humans also have areas of the brain that are responsible
for encoding reward, and when given the chance to
electrically activate those areas, they do so extensively.
When the experimenters brought in a tray of delicious
food to the test chamber, the hungry patients - who
hadn’t eaten for upwards of seven hours - simply looked
at the meal, but couldn’t pull themselves away from the
stimulation button long enough to eat. Artificial stimulation
of these reward centers of the brain was more valuable to
the patients than nutrition.
control that addicts experience - their prioritization Opposite of the reward pathway is a related
of immediate reward despite bad long term set of neural circuits that signal an opposite
consequences (losing their job, alienating reaction: aversion. If eating a sugary, chocolatey
family, immediate health risks, for example). treat activates the reward circuitry, then eating a
This connection has been heavily studied in the bitter-tasting bug activates the aversion circuitry.
context of schizophrenia and other psychological Just as with the VTA and related structures of
pathologies. the reward pathway, the ability to detect aversive
stimuli is highly conserved throughout evolution.
11-9
For example, we know that noxious plant toxins,
the kinds of foods that would have made our
proto-human ancestors sick, are often bitter (see
Chapter 9). Being able to detect these flavors as
disgusting would be a pro-survival adaptation.
If the VTA to NAc projection is the reward
pathway, the projections between the neurons in
the lateral habenula (LHb) to the VTA is the “anti-
reward” pathway. The LHb sends inhibitory GABA
projections onto the VTA DA neurons, so when an
aversive stimulus is presented, the LHb neurons
increase in their activity, which decreases DA
neuron excitability through GABA release, thus
resulting in less DA in the NAc. These results were
conducted with electrophysiological techniques
and first demonstrated in monkeys in 2009. The
researchers found that when a monkey was given
a squirt of delicious fruit juice, LHb neurons spiked
less, which relieved the inhibition on the VTA
neurons, allowing them to increase in spiking - as
can be expected when a rewarding stimulus is
presented. On the other hand, when an aversive
stimulus was presented, in this case an air puff to
the face, the LHb increased in activity while the
VTA neurons decreased in activity. Relatedly, if
an animal is trained to expect a reward after some
innocuous stimulus (Pavlovian conditioning), and
that reward is withheld after presentation of the
stimulus, the LHb increases in activity.
11-10
To talk more accurately about the action
100%
of drugs on a molecular level, it’s important to
establish some of the vocabulary that is used
in pharmacology. As we begin discussing the
Response
action and movement of molecules, it’s important
to remember that the physical movement of 50%
molecules is more random than guided. When
neurotransmitter molecules are released into
the synapse, they move around in that space
randomly. At many points in time, they float around 0%
the synapse, causing no effect. But sometimes, 10-7 10-6 10-5 10-4 10-3
molecules will bump into a receptor, activating it Drug concentration
as long as the molecule remains attached. Other
Figure 11.9 Generic dose response curve
times, those molecules will bump into reuptake
showing that drug effect (y-axis) increases as the
proteins, large transmembrane proteins that
dosage of drug (x-axis) increases.
decrease the concentration of neurotransmitters
in the synapse by pulling the neurotransmitter
back into the presynaptic axon terminal. And at 1. Agonists are chemical substances that
other times, the molecule can even float outside can activate receptors. Receptors themselves
of the synaptic space. Pharmacologists use the are large, transmembrane protein structures with
word stochastic to describe this randomness. a surface that is exposed to the extracellular
The location of a molecule has no influence on side. On this exposed side, there is some
where it will go next. three-dimensional arrangement of amino acids
It is also helpful to become familiar with that the agonist is able to bind to. When the
the dose-response curve, which is a graph agonist-receptor complex is formed, the receptor
that plots the activation of a receptor on the physically changes conformation, which can
y-axis, and increasing dosage of a drug on then trigger a downstream reaction. In the case
the x-axis. In most cases, as neurotransmitter of an ionotropic receptor, the protein changes
concentration increases, so does the activation to either allow or hinder ion movement across
of the corresponding receptor. The shape of the the cell membrane. Nicotine is an example of
dose-response curve is described as sigmoidal, an agonist that binds to ionotropic acetylcholine
the S-shaped curve that is common to many receptors. For metabotropic receptors, the
fields of science, including ecology, microbiology, activated agonist-receptor complex results in
physics, and chemistry. downstream activation of G-proteins, which then
In molecular pharmacodynamics, we signal the cell to behave in a variety of ways.
will describe three main categories of ligands, Morphine acts as an agonist at opioid receptors,
substances that are able to bind to receptors to which are metabotropic. The specific site on the
form a ligand-receptor complex. receptor protein where agonists bind is called the
11-11
orthosteric site, or active site. Full Partial
agonist Antagonist
The interaction between a receptor and agonist
an agonist can be described by the analogy of
a lock and key. The receptor is represented by
a lock. Receptors are large protein complexes
that span the cell membrane, just like a lock sits
at the interface between two rooms. Receptors
have an outward facing side that responds to the
presence of an agonist by physically changing
shape, similar to the way a lock will physically
change when the correct key is inserted into
the keyhole. Finally, receptors are very specific 100%
and will only respond to chemical structures that Full
agonist
“match” the active site - the lock won’t just open Partial
agonist
Response
in the presence of any random key.
Agonists themselves can be divided 50%
into three different classes. A full agonist is a
substance that can activate the receptor to the
maximal degree at high concentrations. When Antagonist
0%
we think of an exogenous neurotransmitter that
is released by a neuron, such as glutamate,
Inverse
it activates the nearby glutamate receptors
agonist
maximally. In a dose-response curve, full agonists
-50%
substances that set the 100% value. The phrase
Increasing drug concentration →
partial agonist is used to describe substances
that can also activate the receptor by binding to Figure 11.10 Different classes of ligands and
the orthosteric site, but are unable to fully activate their action on the receptors.
the receptor, even at increasingly higher doses. More specifically, competitive antagonists
On a dose response curve, the partial agonist are substances that bind to the orthosteric site,
activates the receptor to a lesser degree than the same site on the receptor where an agonist
the full agonist. Some partial agonists can be would bind. Because competitive antagonists
used clinically for treating a variety of disorders physically block the active site, and because
including anxiety, psychosis, and chronic pain. molecules move around randomly, the presence
Another class of agonists are the inverse of the antagonist can prevent the agonist
agonists, which causes an opposite response from activating the receptor in a concentration
as an agonist. dependent manner: The more antagonist present,
the higher the concentration of agonist must be in
2. If agonists are the chemical substances the synapse for activation. Therefore, adding a
that activate receptors, antagonists are the competitive antagonist to the system will shift the
substances that prevent agonists from acting. dose response curve to the right.
11-12
molecules that are still acting on the receptors.
100% Agonist When Narcan is given via an IV injection or nasal
alone
spray, it works within minutes to block the action
of opioid drugs that are affecting respiratory
Response
Agonist
50% with control, thus restoring normal breathing.
antagonist It is important to note that in the absence of
an agonist, an antagonist alone will have no effect
on cell excitation. Therefore, if an antagonist alone
0% induces a change in some cellular property such
Increasing drug concentration → as excitability, then it is reasonable to conclude
that the cell is being acted upon by some agonist
Figure 11.11 Dose response curves for agonist
at rest.
and for agonist plus competitive antagonist.
Separate from agonists and antagonists
One of the most well known competitive are a different class of chemical substances
antagonists is the drug Narcan (naloxone) which called allosteric modulators that also interact
inhibits certain opioid receptors. One reason with neurotransmitter signaling. These chemicals
opioid overdose can be fatal is the drugs are able belong to a unique classification of substances
to shut down CNS drive of the respiratory system distinct from agonists and antagonists. Instead of
through acting as agonists at opioid receptors. In binding to the orthosteric active site, they target
order to treat the person in this situation, you will a different region of the receptor, a site called the
have to find a way to block the action of the opioid allosteric site. The allosteric site generally can
Figure 11.12 A receptor interacting with an allosteric modulator changes it’s response following agonist
binding to the orthosteric site.
Agonist Agonist Agonist PAM or

alone + PAM + NAM NAM alone
Allosteric Orthosteric
site site
No
response
Dimished
response
Normal Enhanced
response response
11-13
be found on the extracellular side of the receptor, at a different population of serotonin receptors.
and like the active site, consists of a special In pharmacology, drugs with many sites of action
three-dimensional arrangement of amino acids. are commonly called dirty drugs.
When allosteric modulators bind to the receptor,
they change the potency of agonists that activate
the receptor. They can either increase the action
of the agonist (positive allosteric modulator, or
PAM) or decrease the action (negative allosteric
modulator, or NAM.) In either case, some
agonist, either endogenous neurotransmitter or
exogenously-introduced drug, must be present
for the allosteric modulator to have any effect.
Allosteric modulators act at the level of the
receptor to modulate excitability of the neurons.
For example, consider an ionotropic receptor that
allows Na+ to move across the cell membrane
when an agonist is present. When a PAM is
present simultaneously with the agonist, more
Na+ ions will move across the receptor than if the
agonist was acting alone. But, when a NAM is
present with that same agonist, fewer Na+ ions
will move across the membrane, resulting in
decreased excitability.
Many of these allosteric modulators are
used experimentally but some are used clinically.
The most well known allosteric modulators are
the barbiturates and benzodiazepines. Both are
PAMs which act at the GABA receptor, meaning
that when a benzodiazepine (like Valium) is
present, the same amount of GABA will have
a stronger effect. Since GABA is an inhibitory
neurotransmitter, enhancing this inhibition of
neural circuitry can be an effective way to decrease
brain disorders that result from overexcitation of
the brain: anxiety, epilepsy, and insomnia.
A single pharmaceutical agent can have
different actions at different classes of receptors.
For example, the common antipsychotic clozapine
is an antagonist at some dopamine and serotonin
receptors, while also acting as a partial agonist
11-14
In the early 1900s, US laws regulating the
manufacture, distribution, possession, and use
of drugs were complicated. Certain substances
were banned, but regulation of the substances
was left largely to individual states. It wasn’t until
1970 when a nationwide proposed regulatory
measure would combine all of the current federal
mandates regarding misused drugs into a single
bill, and Richard Nixon signed the Controlled
Substances Act (CSA) into law.
Under the terms of the CSA, the Drug
Enforcement Agency and the Food and Drug
Administration would be responsible for
developing regulations about a wide variety of
chemical substances. For each drug, they would
be tasked with evaluating the health related
properties of the drug:
Figure 11.13 The Controlled Substances Act was

1. Impact on health, including toxicity
signed by President Richard Nixon in 1970.
harms and addiction potential
2. Applications in the medical field is regulated under the terms of the CSA, despite
these drugs being among the most misused in the
With these characteristics in mind, the US with tremendous health risks, high addiction
substances were classified into one of five potential, and little medical application.
categories, rated Schedule I through Schedule There are probably thousands and
V. Drugs put into Schedule I are substances that thousands of psychoactive substances,
were perceived to have the highest addiction chemicals that can act on the nervous system
potential, most severe health risks, and no medical which can induce a change in behavior or
applications. On the other end of the spectrum are mindstate. Here, we will focus largely on six
Schedule V substances, drugs with low addiction classes of drugs.
potential, few health risks, and legitimate uses
within the clinical setting. Substances classified Alcohol
under Schedule I include heroin, for example,
while a Schedule V substance might be an According to the 2015 National Survey on
antiepileptic drug like Lyrica. Today, the list of Drug Use a nd Health, alcohol is the most widely
controlled substances contains more than 400 used substance among these drugs, with more
chemicals. Interesting, neither tobacco or alcohol than 85% of adults reporting having used alcohol
11-15
at some point in their lives. Chemically speaking, related violence or injuries.
many substances are classified as “alcohols,” but Ethanol is a metabolic byproduct
the most common misused is ethyl alcohol or
Yeast
ethanol. Ethanol is the easily-obtained substance
with a highly intoxicating effect. The overwhelming
majority of ethanol use is recreational. The World
Health Organization reports that alcohol use is
the leading risk factor for premature death among
males aged 15-59 globally, making it one of the
overall top causes of preventable death.
Carbon
Acute exposure to ethanol has effects dioxide
Ethanol
that differ depending on dosage. At low
concentrations, ethanol can induce an elevation Sugar
in mood, decreased anxiety, increased risk taking,
slowing of reflexes, and impaired judgment. At Figure 11.15 Ethanol is a byproduct of yeast
high concentrations, ethanol can cause memory metabolism. As carbon dioxide is dissolved
deficits, loss of consciousness, analgesia and into the solution, fermented products like beer
areflexia, and possible death through respiratory become fizzy.
depression. Chronic exposure to low levels of
alcohol has some pro-health benefits such as synthesized by yeast as they break down sugars.
decreased risk of death by cardiovascular events, It has the chemical structure of C2H6O, making
but in general, these benefits are outweighed by ethanol a tiny molecule with properties similar
negative health outcomes, such as the elevated to water, meaning that ethanol can diffuse
risks of liver disease or cancer and alcohol- easily through cell membranes. Whereas other
chemical substances often have highly specific
molecular or protein targets, ethanol has several:
GABA receptors, glutamate receptors, potassium
channels, serotonin receptors, and more. In
general, ethanol has a depressant effect on
neurons, but it has been demonstrated to activate
DA neurons in the VTA.
Nicotine
Nicotine is the main psychoactive

ingredient of tobacco products. Nicotine is an
Figure 11.14 Ethanol is the most commonly alkaloid compound that is synthesized in nature
misused drugs, easily accessible in public by a variety of plants, with the tobacco plant
settings, at grocery stores, sporting events, and having the highest nicotine content. Other plants
others. of the Solanaceae family (Nightshade family),
11-16
such as eggplants and tomatoes, also contains induces release of norepinephrine by activating
nicotine, as it was probably an anti-herbivory the sympathetic nervous system. When a person
evolutionary adaptation. The most common routes smokes a cigarette, they experience a rapid
of administration for nicotine include inhalation rush or a high within tens of seconds. Chronic
(cigarettes, cigars, vape), transbuccal (chew, dip, smoking greatly increases the risk of developing
snuff), or transdermal (in the case of the nicotine lung, throat, and mouth cancers, coronary heart
replacement therapeutic strategy, the nicotine disease, or stroke.
patch). Nicotine is a highly addictive substance, Cigarette smoking over the past several
often rated as addictive as cocaine or heroin. It is decades has seen a sharp decline, in part due
currently the leading cause of preventable death to the success of anti-smoking campaigns in
in the US, causing nearly one out of every five changing public opinion toward smoking, and
deaths. government-led changes in legislation resulting
Pharmacologically, nicotine has specificity in stricter marketing laws, especially in regards
as an agonist at nicotinic acetylcholine to targeted advertising aimed at youth. In the
receptors (nAChRs). These receptors are mid 1970’s, almost 30% of 12th graders reported
excitatory ionotropic receptors, and are expressed smoking cigarettes daily, and that number has
widely across the body. Nicotine is a stimulant, and decreased to only 4% in 2018. On the other hand,
the rising popularity of vape among teenagers
has encouraged nicotine consumption through an
alternate route of administration: Teen e-cigarette
users are more than 3 times more likely to start
smoking cigarettes compared to non e-cigarette
users.
Figure 11.17 E-cigarettes are a popular smoking

cessation strategy, but many younger people
Figure 11.16 NAChRs are transmembrane
have started using e-cigarettes recreationally.
receptors made up of five subunits.
11-17
Cannabis understanding of cannabis is that it is far less
harmful than once believed, although it does
Cannabis is a drug that is derived have a negative impact on the developing brain,
from the flowering buds or other parts of the as significant adolescent exposure to cannabis
Cannabis sativa plant. The most common route increases the likelihood of developing psychiatric
of administration is inhalation, as when people conditions such as schizophrenia later in life.
smoke a joint or a blunt. As cannabis becomes
decriminalized or outright legalized across
the US, oral preparations are becoming more
commonplace. The effects of cannabis are often
felt within minutes, and can include a sense of
euphoria, relaxation, distortion in the sense of
perception, and potentially a lightness (high) or a
heaviness of body (stoned).
Although the cannabis plant contains several
chemical substances, the main psychoactive
ingredient is delta-9-tetrohydrocannabinol,
or THC for short. THC, once it enters the
bloodstream, is capable of activating receptors
that our body uses endogenously, called the
Figure 11.18 The flowering buds of the cannabis
cannabinoid receptors (CB receptors). There
plant contain high concentrations of the
are two types of CB receptors, with CB1 exerting
psychoactive substance THC.
the majority of the psychoactive effect and
CB2 expressed mostly throughout the immune
system. Our bodies naturally produce substances Opioids
that activate these receptors; these substances
are called the endocannabinoids, or eCBs. Opioids are a class of drugs, either natural
Activation of the CB1 receptors, either through or synthetic, that can bind to and activate the
eCBs or THC, produces the elevation of mood. body’s endogenous complement of opioid
Cannabis is currently classified as a receptors. The most well known natural opioid is
Schedule I drug federally, but as of 2019, 10 states opium, but the other popular drugs of this class
have legalized recreational use of cannabis, and include the street drug heroin or the medicinal
20 other states permit cannabis for medicinal use. substances morphine or fentanyl. Derived from
Recently, Illinois has permitted the 55 medical the poppy plant, evidence of human use of opioids
dispensaries to sell recreational cannabis starting for both medical and recreational use dates back
in January, 2020. The stigma surrounding the more than 5000 years to ancient Sumer.
“evils” of cannabis use are largely a remnant of As with the endocannabinoids described
a morality propaganda campaign driven by the above, the body naturally produces opioid
publishing of such “educational” films as Reefer substances, endorphin being the most well-
Madness in 1936. Much of our current medical known. Activation of opioid receptors, either by
11-18
the leaves of the plant.
Cocaine is considered to be a
potent sympathomimetic, meaning the
substance activates the sympathetic
nervous system. Therefore, the
physiology of a person on cocaine will
be similar to an activated “fight-or-flight”
response: elevated heart rate and blood
pressure, dilated pupils, and increased
respiration.
Figure 11.19 Opioid-overdose related deaths in the US Cocaine acts on a molecular
have risen steadily over the past few decades, with a steep level by functioning as an inhibitor of
rise over the past five years. reuptake proteins. At the synapse,
there are often presynaptically
endogenously produced opioids or exogenous expressed proteins called transporters. These
opioids, induce a potent analgesia, dampening large membrane-spanning proteins function to
the sensation of pain. Opioid drugs the current move molecules from the extracellular space
gold standard for pain relief. They also cause back into the presynaptic terminal, where they
sedation and feelings of euphoria. Heroin and are then repackaged into vesicles for release at
morphine are frequently taken via IV injection, a later time. Cocaine is a reuptake inhibitor,
but many prescription opioids, particularly for physically preventing the transporter protein
long-term pain conditions, are consumed orally. from clearing the neurotransmitters dopamine,
Over the past 20 years, there has been norepinephrine, and serotonin out of the synapse.
a dramatic increase in the number of opioid- This leads to an elevation of the concentration
overdose related deaths. The most recent spike of those neurotransmitters, which results in a
in deaths is due to overdose on synthetic opioids greater likelihood that the synaptic receptors get
such as the extremely potent painkiller fentanyl, activated.
which saw a 10-fold increase between 2013 and
2017. The so-called opioid epidemic kills an
estimated 130 Americans each day.
NT
Cocaine NT NT
NT
Cocaine is a psychostimulant that is
derived from the coca plant. The most common
routes of administration are insufflation (powder
cocaine), inhalation (crack cocaine), but it can Control Cocaine
also be solubilized and injected or taken via Figure 11.20 Cocaine blocks reuptake of
transbuccal and oral administration by chewing neurotransmitters, increasing signaling.
11-19
Cocaine is a Schedule II substance. 1970’s, secret CIA funded research, and some
Although it has a very high addiction and harm loosely-regulated research ethics in the clinical
potential, it has a handful of medicinal applications setting all led to notoriously negative press
as well. For example, it is a potent local anesthetic regarding the substance, tainted the general
and vasoconstrictor, so it is often used in surgery, public opinion about this class of drugs.
especially in facial or nose surgeries. Since 2010, there has been a growing
body of evidence supporting the notion that
Psychedelics psychedelics can serve a therapeutic purpose,
most notably in treating psychiatric conditions such
Psychedelics are the class of drugs as PTSD, terminal illness-related depression,
formerly called hallucinogens. They can be either and drug addiction.
natural, such as psilocybin which is derived from
mushrooms, or man-made, in the case of lysergic
acid diethylamide (LSD). Psychedelics can
cause a person to experience visual distortions,
synesthesia, an altered sense of self (ego
dissolution), or sometimes a sudden connection
with nature or a higher power. Chemically,
many psychedelics are similar in structure to
the endogenous neurotransmitter serotonin and
therefore activate serotonin receptors.
Although psychedelics have been used for
centuries in religious ceremonies, they have had
a troubled history in the US. The adoption of LSD
(acid) by the counterculture movement during the
Serotonin LSD
Figure 11.21 LSD is chemically very similar to

the endogenous neurotransmitter serotonin.
11-20
Pharmacologically speaking, tolerance the amount of the substance that is capable of
can be defined as a decrease in the action of a acting.
drug due to repeat exposure. This phenomenon The most common example of metabolic
happens as a result of homeostatic adaptations tolerance is seen in frequent alcohol use. The
that the body undergoes when it has been main psychoactive substance found in alcoholic
exposed to a substance for a prolonged period beverages like beer, wine, or liquor is ethanol.
of time. In a person who is tolerant, they must Our liver, which filters circulating blood, contains
take progressively higher doses of the drug to enzymes which break down chemicals in the
experience a desired effect. blood. Specifically, the standard degradation
Tolerance can be represented graphically process of ethanol uses two enzymes. The first
by a rightward shift in the dose response curve. of which, called alcohol dehydrogenase, oxidizes
For a drug naive person, someone with no molecules of ethanol into the toxic byproduct
experience with the drug, a low dose of drug may acetaldehyde. The second step uses the enzyme
have a strong effect. However, for a person who acetaldehyde dehydrogenase to convert the
has become tolerant to the effects of the drug, acetaldehyde into acetic acid, a generally
that same low dose will produce a small drug harmless compound (the same chemical
effect. (The other way to think about the dose structure as vinegar) that is used by the body
response curve is the following: For two people to in a biochemical reaction that drives the citric
experience the same magnitude of effect, a drug acid cycle. Because most alcohol is taken via
tolerant person would require a higher dose than oral consumption, ethanol is subject to first-pass
someone who has never taken the
drug before.)
There are different forms ADH ALDH
of tolerance that a person can
experience.
In metabolic tolerance
(sometimes also called
dispositional tolerance, or
pharmacokinetic tolerance), there
is a decrease in the amount of the
drug that gets to the site of action. Ethanol Acetaldehyde Acetic acid
The body becomes more efficient
at eliminating the substance. Since
exogenous substances usually get
degraded by enzymatic reactions, Figure 11.22 The liver breaks down alcohol in a two-step
an increase in the activity or enzymatic process. Frequent alcohol use upregulates the
number of enzymes will decrease speed by which degradation happens, causing tolerance.
11-21
metabolism before reaching systemic circulation. This functional tolerance can be characterized
However, after prolonged exposure by a decrease in receptor expression after
to alcohol, the body undergoes homeostatic chronic exposure to an agonist. When the opioid
compensatory changes. The two liver enzymes etorphine is present in the body, it activates the
responsible for degradation of ethanol increase in opioid receptors. Frequent exposure to etorphine
either function or amount. When these metabolic causes a molecular change in the receptors,
enzymes become upregulated, the circulating which leads to internalization, the process by
ethanol in the bloodstream becomes broken down which cell surface-expressed receptors become
more rapidly and more efficiently, resulting in a taken into the cell. Since etorphine is only able
decrease in the amount of ethanol that reaches to activate receptors on the surface, these
general circulation, and consequently, the brain. internalized receptors diminish the strength of the
This explains why people who have never drank etorphine signal, which manifests as tolerance.
alcohol (low amounts / function of enzymes) may By downregulating the number of receptors that
experience a stronger drug effect compared to are expressed on the surface, the cell reacts to
someone who drinks regularly. It also accounts the environment by becoming less responsive in
for why there is some genetic variation between the face of drug.
a person’s sensitivity to alcohol’s intoxicating
effect, as enzyme efficiency is partially encoded Sometimes, the body physiologically
by genetics. prepares for the drug effect before the drug is
even present. The way it does this is to initiate
Another way by which tolerance can an opposite somatic effect from what the drug
manifest itself is through changes at the level of is expected to do. This “reverse” effect is likely
the molecular components of cells. This type of a protective mechanism to minimize the drug
tolerance is called a functional tolerance, or effect, and these anticipatory bodily changes
pharmacodynamic tolerance. This tolerance can be precipitated by drug-associated cues.
leads to a decreased sensitivity to the substance. For example, heroin causes analgesia. Cues
that predict administration of the drug, such
as preparation for an intravenous injection or
being in a physical environment where drug is
frequently administered, can cause the reverse
physiological effect, hyperalgesia. Because
of this, a person may need to take more drug
to overcome the anticipatory changes. This
unconscious form of learning leads to a form of
tolerance that is dependent on Pavolvian cues;
Synapse before Functionally tolerant
this is called conditional tolerance.
tolerance synapse
If not accounted for, conditioned tolerance
Figure 11.23 Pharmacodynamic or functional can have potentially lethal side effects. A clinical
tolerance causes a synapse to be less sensitive description (Siegel, 2001) of a patient with
to drug. pancreatic cancer describes one such “failure”
11-22
of tolerance. Bedridden and suffering from drug. The symptoms of withdrawal are frequently
tremendous pain, a man was regularly given the opposite of the side effects of the drug. One
morphine in his bedroom, dark and filled with example is the physiological response to heroin.
humming apparatus for his medical care. As When heroin is present, a person may experience
expected, he developed a tolerance towards the euphoria, analgesia, relaxation, and constipation.
morphine, requiring higher and higher doses in But after the homeostatic changes have taken
order to inhibit pain. One day, he went into the place resulting in downregulation of opioid
brightly lit living room to receive his normal dose receptors, a person may experience withdrawal
of painkiller. Soon after, he died from opioid symptoms such as dysphoria (depression), pain
overdose. hypersensitivity, restlessness, and diarrhea.
It is good to note that tolerance does not only
Sensitization is a phenomenon related to happen in the presence of agonists like ethanol
tolerance, but the polar opposite: instead of a drug or morphine. In fact, antagonists are well known
effect being lessened after chronic exposure, a to produce tolerance and withdrawal. If you have
sensitized person experiences an increase in drug ever had difficulty staying alert a headache or
effect. It is sometimes called “reverse tolerance.” without your morning coffee, you are experiencing
Nicotine as well as many psychostimulants the effects of withdrawal. Caffeine is an antagonist
such as cocaine or amphetamine can produce for the adenosine receptors. When the body is
psychomotor sensitization after repeated dosings. used to a certain amount of caffeine that blocks
200 adenosine signaling, there are mechanisms that
Locomotor activity / min
lead to homeostatic upregulation of adenosine

150 receptors. And so when caffeine is no longer
present, the endogenous levels of adenosine
100 overactivate adenosine signaling, leading to the
withdrawal symptoms.
50
0
2 4 6
Days of treatment
Synapse when Synapse following
Figure 11.24 A rat exposed to amphetamine over caffeine is present caffeine withdrawal
multiple days shows locomotor sensitization, an
increase in activity in response to drug. Figure 11.25 The regular presence of an
antagonist like caffeine may cause increases of
Since mechanisms of tolerance result in
adenosine receptor levels postsynaptically.
long lasting homeostatic changes, they may lead
to withdrawal, a set of symptoms that a person When someone is withdrawing from a
experiences when they are abstinent from the drug, they often feel the urge to take the drug.
substance. This produces a highly aversive state This is a sign of drug dependence. A physical
that can be relieved by administration of more dependence can be a physical dependence,
11-23
where the person seeks drug in order to either
relieve the physical symptoms of withdrawal, or
to experience the positive sensations associated
with the drug. Alternatively, a psychological
dependence can also develop, where the person
has intense cravings for the drug such as a
fixation on drug acquisition, or mood or behavioral
changes in the absence of drug.
Long term drug use may cause people to
become heavily dependent. These people often
engage in recurring patterns of drug seeking and
drug taking. Their patterns of use can be highly
destructive, as they make drug acquisition as their
main objective, fixating on drug taking even at the
cost of their jobs, relationships, and even their
own health. Because this form of pathological
drug use is extremely harmful, much attention is
focused on understanding the mechanisms that
underlie this condition.
11-24
“Why do some people transition from user experiment, the subject (usually a monkey, rat,
to addict?” or mouse) gets a surgical implantation of an
indwelling intravenous tube that is connected to
Many people are able to use the most a pump. Then, the subject is put into an operant
addictive substances such as cocaine or heroin conditioning chamber. When they press the lever
casually without ever becoming an addict. For or poke their nose into a hole, the pump triggers,
these people, their drug use pattern can remain resulting in an infusion of drug directly into the
recreational, even though they may use the bloodstream.
substance frequently and report a great sense
of satisfaction when they use the drug. On the
other hand, there are some people who have
a very high propensity to quickly becoming a
pathological addict. One of the big challenges
in drug abuse research is to understand the
differences between these two populations -
what factors, either environmental or genetic, are
protective and prevent the transition from casual
drug user to compulsive drug addict? And what
are some ways we can use this knowledge to Figure 11.26 In a Skinner box, animals can be
help addicts find ways to break their pattern of trained to give themselves a variety of drugs.
harmful compulsive drug seeking and drug use?
One possible way to get at the answer This experimental paradigm closely
is to create animal models of drug dependence mimics human drug seeking behavior. For
and try to determine the nature of the underlying example, rats and mice will very quickly learn to
biological changes that contribute to the press on the levers for intravenous infusions of
addiction-like pattern: Do some cellular circuits cocaine and morphine. Many of them will give
change permanently? Are certain genes or themselves drugs even despite severe adverse
proteins upregulated or downregulated? Can consequences, such as enduring foot shock -
pharmacological or behavioral interventions arguably similar to human behavioral patterns
change drug-taking or drug-seeking behavior? where addicts may do all kinds of behaviors for
access to drug. Monkeys, if given the option to self
Non-human models of administer for cocaine, must be restricted in the
addiction amount of drug they receive: if given unrestricted
access, they give themselves so much cocaine
One of the most instructive non-human that they have seizures and die.
animal models of drug use disorder is called A second experimental test created to
self-administration. In a self-administration study drug abuse is called conditioned place
11-25
preference (CPP). A CPP test works on the feelings associated with that room, they will avoid
principle that animals learn to associate certain being in the room. Whereas self-administration
environments with positive feelings, and will assesses “drug seeking,” CPP measures “drug
prefer to spend significantly more time in those liking.”
environments. To conduct CPP, a three-room
testing chamber is used. This experimental Below are three major biology-driven
chamber has two large rooms, each with hypotheses that have been proposed to explain
characteristics that are unique to that room. For drug addiction. It’s important to note that none
example, one room may have mesh flooring with of them tell the complete story - otherwise drug
dark-colored walls, while the other room may addiction will have already been cured! Also,
have woodchip flooring with light-colored walls. these theories are not mutually exclusive from
The two rooms are connected by a smaller, one another. A likely answer to curing addiction
neutral room, and the rooms can be isolated probably incorporates some combination of
from another by means of a dividing door. To these approaches in addition to societal policy
conduct CPP, an animal will be given the drug of changes.
interest, then placed into one of the two rooms,
where they are free to explore the room, but The “hedonia hypothesis”
cannot leave. As a control, at a different time,
they will be injected with an innocuous solution What drives addicts to behave in the way
and placed into the other room. On test day, the they do? One of the earlier theories put forward
animal will be put into the neutral middle room, to explain addiction is the hedonia hypothesis
and given the opportunity to move freely between proposed in the late 1970s by Roy Wise. The
the two chambers. If the animal developed hedonia hypothesis hinges on the assumption
positive associations with the room where they that dopamine is the “pleasure neurotransmitter,”
experienced the drug effect, then they will choose and that any substance or behavior that increases
to spend significantly more time in that room. dopamine will be desirable. The theory is
On the other hand, if they experienced negative supported by some behavioral data. For example,
60%
Preference index
40%
20%
0%
Post-drug
Pre-drug
-20%
Figure 11.27 In a conditioned place preference test, increased time spent (preference index) in a
chamber previously paired with drug is interpreted as an increase in drug liking.
11-26
using microdialysis, it was found that dopamine and Kent Berridge. Under their model of drug
release by the mesolimbic pathway increases in use, initially a person takes a drug because they
the presence of many drugs of abuse. Additionally, like the positive, euphoria-producing side effects
administration of dopamine antagonists are of the substance. But after chronic exposure
able to block some drug taking behavior. This to the substance, the person becomes fixated
dopamine-centric approach to drug use disorder on obtaining the drug rather than how the drug
was so influential that pharmaceutical companies, makes them feel. At this point, they continue to
while developing novel antidepressants, quickly use the drug even though they no longer enjoy
dismissed drugs that increased dopamine out of the drug to the same degree that they once did.
fear of the risk of addiction potential. Instead of “liking” the drug, the addict fixates on
Despite the attractiveness of the “wanting” the drug.
straightforward “pleasure neurotransmitter” The incentive sensitization model
model, the dopamine hypothesis does not give suggests that the drug-exposed brain develops
us the whole picture. For one, dopamine release an increased sensitivity to drugs, but also more
at the mesolimbic pathway is only notable importantly, drug related cues. Pavlovian learning
for psychostimulant drugs, such as cocaine takes place when an addict takes a drug. Each
and methamphetamine. But there are plenty drug has an associated set of cues, and re-
of stimulants that still produce the significant exposure to those cues can trigger relapse.
overflow of dopamine without causing any
rewarding sensation. Furthermore, if dopamine
is the signal that mediates the positive hedonic
Relative effect
“Wanting”
feelings, one might predict that by blocking
dopamine receptors chronically, you can also
prevent long-term cocaine addiction, but this
therapeutic strategy isn’t very useful. Many of the “Liking”
most popular misconceptions about dopamine
that you frequently see in the media take this early Time
hypothesis as the truth. It even was featured as
Figure 11.28 The incentive sensitization model
the cover of a 1997 Time magazine. That same
suggests a difference between “wanting” and
year in an interview with the original proponent
“liking” the effects of a drug.
of the hedonia hypothesis published in Science,
Roy Wise agreed with recent results that his Over repeated pairings, those cues trigger a
model was incomplete. progressively stronger response.
Their model accounts for why it is difficult
The incentive sensitization to remain abstinent from an addictive drug for
model long durations of time. Despite a decrease in
drug seeking behaviors, many addicts eventually
A more recent theory to explain drug relapse, or return to the previous destructive
addiction is a model developed by researchers pattern of drug use. One phenomenon that makes
from the University of Michigan, Terry Robinson staying drug free difficult is the observation that
11-27
prolonged abstinence can increase the intensity One of the major implications of the BDMA
of drug cravings. This is called incubation is that compulsive drug use and seeking is not a
of craving, and is seen with several different choice that a person makes. Addicts are not the
classes of drugs, notably, nicotine. way they are because of some poor moral guidance
or a weakness of willpower. Addicts compulsively
100
seek drug because of some underlying circuitry
80 of their brain that makes cessation difficult. One
Lever presses (1 h)
substantial accomplishment of the BDMA is that

60 public policy has adjusted to increase access to
mental health resources for addicts to help cover
40 the financial challenges of recovery programs
(Mental Health Parity and Addiction Equity Act
20 of 2008), and to improve the outcomes of non-
violent drug offenders as they reintegrate with
0
1 7 14 society outside of prisons.
Withdrawal day(s) The BDMA is not without fault, however.
The major criticism of this framework to explain
Figure 11.29 In a self-administration paradigm,
compulsive drug use is that most people stop
lever pressing increases the longer an animal is
their addictive use patterns by themselves
abstinent from drug.
spontaneously without any treatment. Another
harm of the BDMA is that it puts heavy emphasis
The Brain Disease Model of on biochemical therapies rather than on a public
Addiction (BDMA) policy approach to drug addiction treatment.
Lastly, the BDMA has not produced a successful
Much of our current understanding of therapeutic strategy to help with addiction.
addiction is based on the principles that repeated
drug use leads to biological changes in the brain
that resemble aberrant learning. This model for
drug addiction is called the Brain Disease Model
of Addiction. Genetics has a strong influence on
the likelihood that someone develops a disease,
and addiction is no different. Inherent risk-taking
behaviors, magnitude of a drug effect, and risk of
relapse are all modified by genetics.
DePaul University.
11-28
Image credits
Cover https://pixabay.com/photos/poppy-poppy-butt-plant-flower-1540284/
11.1 https://pixabay.com/photos/hand-tablets-encapsulate-health-3632914/
11.2 The New Student’s Reference Work, 1914
11.3 https://pixabay.com/photos/syringe-needle-medical-medicine-3902915/
11.4 https://pixabay.com/vectors/lungs-diagram-anatomy-body-human-41562/, https://upload.
wikimedia.org/wikipedia/commons/7/7d/Gas_exchange_in_the_aveolus.svg modified by Austin Lim
(Grapefruit) https://pixabay.com/photos/grapefruit-grapefruit-red-citrus-3434196/
11.5 https://upload.wikimedia.org/wikipedia/commons/3/3d/Preoxygenation_before_anesthetic_
induction.jpg
11.6 https://upload.wikimedia.org/wikipedia/commons/9/94/Nicoderm.JPG
11.7 https://commons.wikimedia.org/wiki/File:Human_brain_midsagittal_cut.JPG modified by Austin
Lim
11.8 https://commons.wikimedia.org/wiki/File:Operant_Conditioning_Involves_Choice.png modified by
Austin Lim
11.10 https://commons.wikimedia.org/wiki/File:Scheme_simple_diffusion_in_cell_membrane-ca.svg
11.12 https://commons.wikimedia.org/wiki/File:Scheme_simple_diffusion_in_cell_membrane-ca.svg
11.13 https://commons.wikimedia.org/wiki/File:Richard_M._Nixon_signing_-_NARA_-_194618.tif
11.14 https://pixabay.com/photos/alcoholic-beverages-bar-beer-1845295/
11.15 https://upload.wikimedia.org/wikipedia/commons/0/04/Yeast_%28PSF%29.png
https://pixabay.com/photos/craft-beer-dark-beer-porter-brewery-2468985/
11.16 https://upload.wikimedia.org/wikipedia/commons/4/46/NAchR_2BG9.png
11.17 https://pixabay.com/photos/ecigarette-juul-electronic-cigarette-3576177/
11.18 https://pixabay.com/photos/northern-lights-medical-marijuana-1826032/
11.19 NIH
11.24 Reprinted with consent of Dr. Eugenia Gurevich. https://www.sciencedirect.com/science/article/
pii/S0028390817301715?via%3Dihub#undfig1
11.26 https://upload.wikimedia.org/wikipedia/commons/c/c4/SelfAdmin-2.jpg
11.27 https://upload.wikimedia.org/wikipedia/commons/0/0a/Conditioned_Place_Preference_-_Floor_
Texture.JPG
Reprinted with consent of Dr. Ewa Niedzielska-Andres
https://www.sciencedirect.com/science/article/pii/S0166432819302803?via%3Dihub
11.29 Reprinted with consent of Dr. Xia Li https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446935/
11-29
Edited by: Dana Simmons, PhD (University of Chicago)
Ben Marcus, PhD (University of Chicago)
Sleep is such an important part of our lives It is possible to study sleep using a
that a lack of it strongly correlates with negative combination of techniques; the output of sleep
outcomes on nearly every measure of health. studies are visualized on a polysomnogram (pahl-
People who sleep less than approximately 7 e-SOM-nuh-gram; somn- is the prefix referring to
hours a night are at a greater risk for heart sleep). Several physiological measures are taken
disease, stroke, asthma, arthritis, depression, in a polysomnogram, including heart rate, blood
and diabetes. Nearly 20% of all car crashes, both pressure and oxygenation level, respiratory depth
fatal and nonfatal, are attributed to drowsy driving. and pattern, muscle activity, eye movement, and
The cancer research branch of the World Health one of major interest to neuroscientists, brain
Organization has determined that disruption wave activity.
of regular sleep is “probably carcinogenic to While everyone knows what sleep is, it is
humans,” putting it in the same risk category useful to try to more precisely define sleep as a
as the infectious agents malaria and human biological function. Sleep is characterized by the
papillomavirus (HPV), as well as the biochemical following:
weapon mustard gas. Sexual health is affected by
sleep deprivation as well, as men with the worst A decrease in physical activity
sleeping habits have significantly lower sperm Compared to waking behavior, a person’s
counts, decreased circulating testosterone, and physical activity is greatly decreased when they
even testicular shrinkage. sleep. While asleep, people are relatively inactive,
Despite all that we know about the benefits and as a result the body uses about 10% less
of sleep, sleep is often the first time commitment energy.
to get cut, often getting squeezed as people stay This is not to say that people do not
awake later while waking up sooner. Consider completely cease all movement during sleep.
that the CDC estimates that more than a third of It is very common to readjust posture many
American adults fail to get enough sleep each times in the middle of the night. Some people
night. Almost 70% of college students fail to get may grind their teeth together or talk in their
the recommended amount of nightly sleep, and sleep, sometimes carrying on full conversations
half of all college students report experiencing by themselves! About 15% of people have
daytime sleepiness as a result. experienced somnambulism, or sleepwalking:
The current medical recommendation is full on wake-like behaviors such as navigating
7-9 hours of sleep each night. But why is sleep down a flight of stairs or preparing a sandwich,
so important? performed entirely in the absence of intent of
12-2
A decoupling from external inputs
When we sleep, our conscious brains are
“distanced” from the outside world. Sleep causes
a heightened threshold for detection of stimuli, so
we do not receive the same magnitude of inputs
from our sensory systems as when we’re awake.
This is why someone else might have to talk
loudly or even shake you physically to wake you
up.
Changes in brain wave activity

Sleep was once thought to be a period
of time characterized by low brain activity.
After all, the person looks like they are not
moving. Shouldn’t brain activity be reflective
of that decreased state of activity? With the
Figure 12.1 Sleep is usually characterized by a advancement of EEG technology in 1924, and the
decrease in physical activity, but some people rise of sleep laboratories in the 1970s, scientists
experience somnambulism. Delacroix, Eugene. who studied brain activity noticed that, at different
Lady Macbeth Sleepwalking. 1849-1850. times throughout the night, the brain of a sleeping
person was very similar in activity to the brain of
memory recall. Despite these rare occurrences an awake person!
of physical activity, the average movement of the
person over a night’s rest is still less than their
average activity when awake.

12-3
Chapter 12 outline
12.1 Phases of sleep

12.2 Why do we sleep?
12.3 The circadian rhythm
12.4 Neurochemical signals of sleep and wake
12.5 Brain structures involved in sleep
12.6 Sleep disorders
12.1 Phases of sleep
Each night when we go to sleep, our behaviors. Respiration rate and heart rate both
brains undergo a very stereotyped pattern of increased during the REM phase of sleep and
activity changes. At times, neurons in the cortex dipped during NREM sleep. They also (rudely)
exhibit synchronized patterns of firing. And at woke up patients throughout the two phases of
other times, cortical activity looks very similar to sleep, and found that patients were more likely
an awake brain. to recall dreams with visual imagery if their REM
We can divide sleep roughly into two sleep was interrupted. Those woken during
different phases depending on one of the first NREM sleep were less likely to recall dreams,
physiological measures that sleep scientists hinting that dreaming is more likely to happen
studied: eye movement. A study published in during REM sleep.
1953 used a device to detect eye movement While eye movement could differentiate
while a person was asleep. Interestingly, they between two phases of sleep, another common
noticed that at some points in the night, usually diagnostic technique, electroencephalography
first occurring around three hours after falling (EEG), could further subdivide NREM sleep. EEG
asleep, the patient’s eyes would dart rapidly and measures electrical activity at the scalp, detecting
jerkily back and forth, a pattern of activity that the the firing of large numbers of cortical neurons.
University of Chicago researchers called rapid Using EEG, scientists discovered three distinct
eye movement (REM). This first period of REM NREM phases based on neuron activity patterns:
activity lasted for about 20 minutes, after which NREM1, NREM2, and NREM3 sleep. Currently,
the eyes would stop moving again. This activity readings collected via EEG are considered to be
pattern repeated every hour or two for the rest of the gold standard for measuring the stages of
the night. They used eye movement to separate sleep.
sleep into two phases: REM sleep, and non- But before we describe EEG traces
REM sleep (NREM sleep.) while asleep, we should describe the EEG of a
In addition to eye movement, they person who is awake. Usually, the awake EEG
observed and measured other physiological is dominated by high-frequency waves, falling in
12-4
Awake
NREM1
NREM2
Sleep spindle
K-complex
NREM3
REM
Figure 12.2 In an EEG, electrodes are placed
on the head that can detect and record neuronal
activity of the cortex. Figure 12.3 Throughout the night, the EEG
shows that the brain cycles through different
the beta band range of frequencies: between 13 patterns of activity.
and 30 Hz. The proportion of neurons firing at
the beta frequency increases with attention and patterns of activity that interrupt theta activity.
mental activity: When a person is concentrating K-complexes are large amplitude events that
on a task, such as reading a textbook, the beta are observed about every minute. These are
wave frequency dominates. the largest amplitude events in a healthy human
NREM1 is the earliest stage of sleep. EEG. Following a K-complex you may see a
It’s also described as relaxed wakefulness, sleep spindle, a high-frequency burst of rapid
drowsiness, or light sleep. During NREM1, a neural activity in the low beta range that lasts
person’s muscles are still somewhat active, their for about a second. It is unknown exactly what
eyelids may open and close every so often, and the function of these sleep spindles are, but
they may still respond to questions. In NREM1 some research suggests they may be involved
sleep, the beta frequency amplitude decrease in memory processes or to minimize perception
as the slower frequency alpha waves (8-13 Hz) of outside noises, which can help a person stay
increase in amplitude. Late in NREM1, theta asleep even in the face of disruptive stimuli.
waves (4-8 Hz) become more prevalent. Basically, NREM3 is also called deep sleep. At
the deeper into NREM1 sleep a person becomes, this phase of the night, a person’s physiological
more waves with lower and lower frequencies activity drops to its lowest point of the night:
start to emerge. heart rate, respiration, blood pressure, and
During NREM2 sleep, theta waves metabolism all reach minimum during NREM3. In
predominate. In a healthy adult, about 50% this stage of sleep, many of the cortical neurons
of a night’s sleep is spent in NREM2. NREM2 fire in synchronicity with one another, and the
is characterized by the appearance of two subsequent change in potentials cause large
12-5
amplitude deflections in the EEG, at the low- represented at the top, and deep sleep is at the
frequency delta band (1 - 4Hz). Because the bottom.
delta frequency is much slower than frequencies For an average night’s rest, neural activity
detected in lighter stages of sleep or wake, NREM will fluctuate through the four phases relatively
3 is also called slow wave sleep. predictably. When a person first falls asleep,
The EEG trace of a person in REM sleep they will move from NREM1 down through
is quite the opposite of what is seen in deep NREM2 then NREM3, before coming back out
sleep. Instead of large amplitude events at a of deep sleep progressively back to NREM1.
low frequency, the REM brain has a lot of low After NREM1, they may enter REM sleep before
amplitude events at a high frequency. In fact, transitioning back through the stages to NREM3
the brain in REM sleep has a pattern of activity again. This cycle of activity repeats roughly every
that is more similar to a person who is awake one and a half hours.
than asleep! Because of this asynchronous firing People spend a larger percentage of each
activity, REM sleep is sometimes also called cycle in deep sleep and very little time in REM
paradoxical sleep. sleep early in the night. On the other hand, in
To illustrate the stages of sleep that a the last few cycles before waking up from a full
person experiences each night, we can use a night’s rest, people spend a larger percentage of
hypnogram. These charts to plot time on the of each cycle in REM sleep, and almost no time
x-axis, and stage of sleep on the y-axis. Awake is in deep sleep.
REM REM REM REM

NREM1
NREM2
NREM3
0 1 2 3 4 5 6 7 8
Figure 12.4 A hypnogram can be used to visualize the time spent

in each phase of sleep over the night.
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12.2 Why do we sleep?
All organisms that we know of experience Evidence for the recuperation theory
some type of sleep. But we still haven’t figured out comes from experiments tailored around the
exactly why animals sleep. Here, we will discuss idea of looking at what happens when a person
three theories that have been proposed to explain doesn’t get sufficient sleep. As anyone who has
sleep. None of these theories alone fully explains ever pulled an all-nighter can attest, a single night
the complex phenomenon of sleep, and they are of sleep deprivation often leads to significant
not mutually exclusive. The most likely reason psychological changes, including anxiety,
we sleep is probably some combination of the irritability, and mood swings. Staying awake even
following three theories. longer than 24 hours can cause more severe
changes in mind state, such as temporary
Recuperation Theory psychosis, hallucinations, or delusions.
The recuperation theory of sleep is The recuperation theory is supported by
centered around the idea that being awake is several pieces of evidence, three of which we will
stressful and exerts a physically demanding toll discuss.
on the body. The body therefore needs a period 1. Enhanced metabolic cleaning
of time when energy usage decreases and the during sleep. When you’re awake, your cells
body’s natural repair systems can work without produce several biological waste products during
disruption. Sleep is how the body “wipes the slate cellular respiration. These chemical byproducts
clean” and resets. can be potentially toxic to the body when they
Case study: Peter Tripp Peter’s body for a funeral. Tripp even began
In 1959, New York City radio DJ Peter hallucinating, seeing spiders and rodents in
Tripp ran a publicity stunt to raise money for his clothes - prompting him to strip naked and
the charity March of Dimes: he stayed awake run into the street screaming.
for 201 hours. Sitting inside a glass booth in the Some believe the long-term sleep
middle of Times Square, Peter played music deprivation severely affected his brain beyond
and broadcasted his experiences across the this temporary psychosis. After the experiment,
airwaves. The first night of sleep deprivation Tripp was involved in a huge commercial
wasn’t awful, but the next seven consecutive bribery scandal, lost his job, and got divorced
days and nights were a real challenge, for (Of course, life has many variables, so we’ll
both Tripp and the doctors who kept an eye on never be completely sure of the precise effect
him. long-term sleep deprivation may have had on
Just a few days in, Peter began his relationships and decisions.) Today, the
experiencing severe psychological side Guinness Book of World Records no longer
effects. Tripp developed intense paranoia: He allows people to compete for the prolonged-
mistook his psychiatrist, who was wearing all wakefulness record due to health concerns.
black, for being the undertaker here to collect
12-7
cells die and get replaced. One
of the signaling molecules that
encourages the replacement
process is growth hormone
(GH), which enhances cellular
repair, muscle and bone
growth, and protein synthesis.
Wake Sleep
Normally, throughout a 24-
Figure 12.5 During sleep, the glymphatic system increases flow hour day, GH is produced and
of CSF (green waves) that are able to wash out the amyloid-beta released throughout the body
protein (black dots) from the interstitial space. by the hypothalamus. The
largest wave of GH production
accumulate. The glymphatic system, a sort of occurs early in sleep, during NREM 3 sleep.
cellular rinse that floods the extracellular space During this huge burst of GH release, a person’s
with CSF, clears these cellular waste byproducts circulating plasma GH concentration may be 10
when they accumulate in the brain. When we times higher than at baseline.
sleep, the extracellular space expands by about While the support for the recuperation
60%, which increases the ability for CSF to theory is generally true for almost all people,
penetrate deeper into the brain tissue. there are about 1% of people who seemingly
One byproduct of interest is the molecule gain the restorative benefits of sleep, even with
beta-amyloid, a protein that exists in the healthy fewer than 6 hours of sleep each night. They may
brain. But, accumulations of beta-amyloid are wake up at 4:30 in the morning feeling completely
found at high levels in the post-mortem analysis refreshed. And yet, despite getting so little
of brains from patients with Alzherimer’s disease. sleep, these short sleepers have similar health
During sleep, the glymphatic system’s “rinsing” outcomes with respect to body mass index and
activity washes away beta-amyloid from the psychiatric measures such as depression and
interstitial space and degrades the protein. overall optimism.
2. Immune system function improved
Growth hormone blood μg/mL
with sleep.
30
Sleeping more enhances your ability to
fight pathogens. Sleeping for fewer than 6 hours
20
per night increases the likelihood of catching
a variety of transmissible illnesses, such as
10
cold, flu, or gastroenteritis. Sleep increases the
effectiveness of vaccines, and each hour of sleep 0
over 6 hours increases said effectiveness by 8PM 12AM 4AM 8AM 12PM
about 50%. Time
3. Increased production of growth
Figure 12.6 Growth hormone levels peak early in
hormone during deep sleep.
the night during deep sleep.
Most cells of the body are turned over regularly as
12-8
Something about the circadian rhythms of inactivity until the sun rises. During this inactive
these short sleepers allows them to “maximize” period, sleeping decreases our metabolism and
their sleep efficiency. Many have very short sleep our body’s need for energy.
latencies, meaning they fall asleep within minutes Humans are just one animal that has an
after lying down - as quickly as someone with evolutionarily fine-tuned sleep pattern. If you look
narcolepsy. They also spend a larger percentage across the animal kingdom, you’ll find all varieties
of their night in deep sleep and REM sleep while of sleep behaviors that are best fitted to the needs
minimizing NREM1 and NREM2. of the individual species. In the wild, for example,
dolphins are generally prey. They evolved with
Evolutionary Adaptation Theory the ability to put one half of their brain to “sleep”
The evolutionary adaptation theory is the at a time, allowing the “awake” half to keep an eye
idea that animal sleep patterns are different across out for potential predators. Small prey animals,
species for reasons that most efficiently benefit like squirrels, are faced with the threat of being
each animal. Over millions of years of evolution, attacked at night. For them, remaining very still,
individuals with the most ideal sleep patterns quiet, and hidden improves their survival. Tigers,
have an advantage, and their sleep habits will be the top alpha predators in any ecological niche,
selected for in the following generation. have almost no predators to hide from, allowing
For example, consider humans. As an them the luxury of sleeping up to 20 hours a day.
animal highly dependent on light and the visual This evolutionary adaptation theory
system for navigation and accurate performance argument has a major weakness, however. In
of tasks, the dark is a very dangerous time to be almost all animals, sleep represents a period
active. The risks of wandering off a cliff, running of time when an organism’s ability to use their
head-first into a tree while escaping a predator, sensory organs to detect the hallmark signs of an
or eating a wrong-colored poisonous berry would approaching predator, like the flurry of feathers
all be elevated in the dark. We benefit from from a hungry owl or the soft padding of a wolf
behaviors that minimize those risks, such as footsteps, decreases drastically. For an animal
that can’t hide very effectively, sleep represents a
period of vulnerability, as they would be unable to
sense incoming threats.
Figure 12.7 In a traveling pod of dolphins, the Figure 12.8 Alpha predators have no fear of
animals on the edges sleep with half of their brain being attacked, and are given the luxury to sleep
in order to remain a vigilant lookout. for prolonged periods of time.
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Brain Plasticity Theory
The brain plasticity theory suggests that
the brain needs some period of time for critical
changes to occur. During sleep, circuits in the
brain undergo consolidation processes that are
important for memory formation. For example,
academic performance and examination grades
worsen as a person’s nightly sleep decreases.
Both the REM and NREM3 phases of sleep
are important for different types of memories, and
studies suggest that declarative memory, pieces Figure 12.9 According to the brain plasticity
of information about facts, benefits more from theory of sleep, newborns spend most of their
slow-wave sleep while procedural memory, day sleeping in order for their brains to adapt to
the learning of motor skills, is enhanced by REM all the new senses they are experiencing.
sleep. Although the exact mechanisms about
how sleep improves memory are unknown, we
theorize that brain activity during sleep helps
move memories held in “temporary” areas into
areas of stable, long-term storage.
The evidence in support of this theory
starts with looking at the brains of newborns.
When you were first born, during those first few
weeks of life, you slept close to nearly 70% of
the day, almost 17 hours! At this point in your life,
your brain starts to experience all sorts of new
sensations: your eyes detect visible light for the
first time, the skin feels the air blow past it, and the
ears sense new frequencies and combinations
of sound waves. As a result of these stimuli,
scientists hypothesize that your brain undergoes
as many learning events as rapidly as possible.
This rapid learning helps you remember what
you learned each day so you can respond to your
environment as you grow up.
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12.3 The circadian rhythm
Almost every living organism that we know of clock. His work laid the foundations for future
on Earth exhibits some sort of cyclic pattern chronobiologists, scientists who study day-
of activity that closely matches the rising and night dependent periodic phenomena in living
setting of the sun. The discovery of 24 hour beings.
patterns of behaviors began in 1729 with the Any behavior or physiological measure
French scientist Jean-Jacque d’Ortous de that intrinsically cycles on a 24-hour pattern
Mairan, who documented the movement of the is said to be a circadian rhythm. The word
Mimosa pudica plant. This unique organism was circadian comes from the Latin words circa-
chosen since the plant exhibits heliotropism, meaning “around”, and diem meaning “day”.
light-seeking movements. In particular, this Compare this with an ultradian rhythm, any cycle
plant opened up the leaves in the daytime to that is faster than 24 hours, such as the cycling
capture sunlight, then closed at night, minimizing between deep sleep and REM sleep every 90
predation. When the plants were put into a dark minutes. Alternatively, compare with infradian
room with no exposure to sunlight, to his surprise rhythms, patterns that are longer than 24 hours,
they still opened and closed their leaves in time like the 4-week-long human menstrual cycle.
with the clock. Mairan concluded that the plant Although we mostly think of the circadian
did not change its behavior in response to light, rhythm in the context of sleep and wake, many
but rather in response to some internal 24-hour other physiological measures fluctuate reliably
throughout the day. Blood pressure peaks at
11 AM, making the morning the time with the
highest risk for cardiac events. Body temperature
dips late in the evening, putting the body into
a low-energy state that helps promote sleep.
Withdrawal reflexes peak around midnight,
hunger-driving hormone production rises before
lunch and dinner, attention is usually highest in
the morning - all manner of behaviors that rise
Leaf extension
and fall depending on the time of day can be said

to be a part of a circadian rhythm.
Bizarrely, even organisms with a life span
shorter than a full day still exhibit 24 hour cycling
patterns of circadian rhythm-like behaviors.
8:00 8:00 8:00 8:00 8:00
AM PM AM PM AM Cyanobacteria, or blue-green algae, are capable
of a process called nitrogen fixation, where
Figure 12.10 The leaves of the Mimosa pudica
they convert atmospheric nitrogen into organic
plant open and close their leaves in time with the
compounds like amino acids. These organisms
24-hour cycle of sun rising and setting, even in
are capable of asexual reproduction every 6
complete darkness.
12-11
hours or so, but they still have nitrogen fixation
patterns that align with daily patterns of light and
dark.
Circadian rhythms on a behavioral level

Luckily, a person’s circadian rhythm is not
permanent. Anyone who has traveled overseas
to a different time zone for more than a few days
has experienced that uncomfortable sensation
called jet lag, where a person experiences
psychological symptoms such as difficulty
concentrating and mood swings, and physical
symptoms like daytime fatigue, insomnia, and Figure 12.11 Traveling to a part of the world
gastrointestinal distress (nausea, constipation, where day and night misalign with your internal
or diarrhea). Jet lag happens when there’s a circadian rhythm can cause jet lag.
mismatch between the internal environment
and the signals that the brain receives from the you. A rise in the neurohormone melatonin is an
outside world. If you flew east from Chicago to important signal that contributes to helping the
Cairo, for example, your circadian clock will be off brain entrain, which is why taking a melatonin
by 7 hours. When your internal “Chicago” clock supplement late at night when in a new time zone
is telling you to start getting sleepy around 11 may help someone get over jet lag more quickly.
PM, the sun will be rising in Cairo, as the locals If sunlight is a trigger that helps a
are starting to wake up. You may be eating when person entrain their circadian rhythm to new
you’re not hungry or laying down in bed when environments, what would happen if a person is
you’re not sleepy, and this mismatch contributes completely isolated from sunlight? In other words,
to jet lag. what does a free-running circadian rhythm look
However, with a few days of adjustment, like? One of the early documented case studies
you will be able to overcome jet lag. You will start addressing this curiosity was conducted by a
sleeping as the sun sets, you will get hungry French cave explorer named Michel Siffre. In
at the same time as the Egyptians, and your 1972, Siffre (voluntarily) spent six months deep in
physiological measures will start to align with a Texan cave to evaluate what would happen to
your time zone. This adjustment is only possible a person completely isolated from zeitgebers. At
because our circadian rhythms are entrainable, the end of the experiment, he found his circadian
meaning they are able to change and fit the cycle was much longer than 24 hours, and very
surroundings. Our circadian rhythms entrain unpredictable - some of his so-called days would
in response to zeitgebers, the German word consist of being awake for 36 hours and asleep
for “time givers”: environmental cues, such as for 12.
increased light exposure when the sun comes up, A more rigorous scientific study, conducted
or social cues, such as increased sensory input in a group of people living in an underground
from heightened activity of the people around bunker with unchanging lighting conditions for
12-12
severeal days estimates the typical free-running Drosophila melanogaster. Normal fruit flies are
circadian cycle to be close to 26 hours. In other no exception to 24-hour cycles of behavior, as
words, a person absent from external cues begin they generally exhibit periods of wakefulness that
to fall asleep and awaken 2 hours later each day. are paralleled by the rising and setting of the sun.
Free-running circadian disruption is But, if this period gene was mutated, there was an
a potential issue for scientists aboard the unusual change in the sleeping habits of the flies.
International Space Station, who experience Some of them slept on a 29-hour cycle, some
about 16 sunsets and sunrises per day, since the had a shorter rhythm at 19 hours, and some had
orbiting space vessel completes one trip around no predictable sleep-wake pattern whatsoever.
the earth every 90 minutes. In order to minimize Later, it was discovered that another gene
the negative effects of jet lag on the researchers was related to the cycle of sleep and wake, called
aboard, NASA has the inside of the vessel set timeless. This gene codes for a protein called
to an artificial 24-hour cycle. Bright blue LEDs TIM, which interacts closely with the protein
illuminate the cockpit in the “daytime,” while dim, coded by period, the protein PER. When PER and
red-shifted wavelengths are used in the evening TIM interact with each other, they form a dimer
to induce sleepiness. (a pair of molecules) with the ability to enter into
the nucleus, bind to a specific sequence on the
genome, and prevent further transcription of both
PER and TIM. Therefore, the paired proteins
function as a negative feedback regulatory
system.
Figure 12.12 The free-running circadian rhythm

is slightly longer than 24 hours. In conditions
with unusual light conditions, such as aboard the
International Space Station’s research laboratory,
“night-time” is mimicked every 24 hours. Figure 12.13 The molecular basis for the circadian
cycle depends on transcriptional repressors.
Circadian rhythms on a molecular level The TIM protein, however, is degraded by

The circadian cycle functions on light, so during the daytime, the concentration of
the molecular scale at the level of cellular TIM in the cell is very low. As a result, the PER
transcription. In the mid 1980s, the gene period protein is left by itself, where it can no longer
was discovered in the genome of the fruit fly, repress transcription. The cells, without the
12-13
active repression of transcription, then proceed
to create more protein. Once night falls, light
no longer breaks down TIM, and TIM begins to
accumulate again, forming the dimer with PER,
which prevents further protein transcription. The
cycle repeats itself the next morning.
Since behavior can be driven or modified
based on protein levels, the capacity for an
organism to change transcriptional activity on
a 24-hour cycle suggests that genetic level
changes can possibly influence the activity of the
whole organism. These gene transcription-level
changes were discovered in Drosophila in 1990,
and three scientists, Hall, Rosbash, and Young,
were recently awarded the 2017 Nobel Prize in
Physiology or Medicine.
12-14
12.4 Neurochemical signals
Many of the neurotransmitters that the we are sleepy.
brain uses for signaling are capable of modifying If you are able to chemically block the
some aspects of sleep. For example: action of adenosine, you can stave off sleepiness,
• Glutamatergic signaling is heightened during increasing alertness and ability to focus. Odds
the awake state, and many glutamatergic are good that you have used a psychostimulant
neurons increase their activity during REM to block adenosine signaling this morning,
sleep. or are drinking some right now. Caffeine, for
• Drugs that increase the action of GABA by example, is an adenosine receptor antagonist,
acting as positive allosteric modulators are and is the world’s most popular unregulated
used as sedatives and sleep aids. psychostimulant drug. Other common adenosine
• Norepinephrine, acting through increasing receptor antagonists include theobromine and
activity of the sympathetic nervous system, theophylline, both of which can be found in tea
enhances alertness. and chocolate. They are chemically very similar
Be aware that many neurotransmitters to caffeine and adenine, part of the chemical
can affect sleep behavior. However, we are only structure of adenosine.
going to describe the function and actions of three
sleep-related neurochemicals. Adenosine + Caffeine
Adenosine
Adenosine is a molecule that has a variety
of functions in the body. In addition to being one
of the four main building blocks of DNA (the “A”
of the A:T G:C base pairing combinations), it
acts as a signaling molecule in the body that is
involved in inflammation, the immune response,
and modulation of heart rate.
It is also used as part of the molecule
that stores cellular energy: ATP, or adenosine
triphosphate. Each molecule of ATP has phosphate
Sleep promoting Sleep inhibited
bonds that release tremendous energy when the
bonds get hydrolyzed (broken apart). Vesicles,
in addition to containing neurotransmitters, have
many molecules of ATP. Throughout the day,
as the body uses up cellular energy, there is an
increase of adenosine as a result. Therefore,
as our energy consumption increases, so do Figure 12.14 Caffeine acts as an antagonist for
adenosine levels, thus signaling to the brain that adenosine signaling.
12-15
Melatonin the hypothalamus called the suprachiasmatic
Melatonin is an endogenous hormone nucleus (SCN). In turn, these cells of the SCN
that helps the brain regulate the sleep-wake send inhibitory projections to the pineal gland. In
cycle. Melatonin is produced by a single gland in the day time, the SCN tonically inhibits activity
the brain called the pineal gland, so named for of the pineal gland, resulting in low production of
its pinecone-like shape. Specialized cells in the
pineal gland convert the amino acid tryptophan
into melatonin, which is then secreted into the Pineal gland
bloodstream. Increased melatonin levels helps to
SCN
signal the body to prepare for sleep.
The production of melatonin is heavily
dependent on exposure to sunlight. While some
of the cells in the retina are responsible for
passing specific visual information into the brain,
other cells (such as the photosensitive retinal
ganglion cells) communicate whether or not it is
daytime. These cells send their axonal projections Figure 12.15 Exposure to light sends information
separately from the optic nerve that sends most via the retinohypothalamic tract and signals to the
visual information. Rather, they project through suprachiasmatic nucleus of the hypothalamus,
a pathway called the retinohypothalamic which inhibits pineal gland production of
tract (RHT), synapsing on a clump of cells in melatonin.
Half-life
Exogenous substances that enter the half-lives, the substance has effectively been
body usually get degraded over time through eliminated from a clinically relevant perspective.
natural enzymatic processes. The half-life, 100%
also written as t1/2, is the time that it takes
for the concentration of the substance to be
Caffeine remaining
75%
degraded to one half of what it originally was.
The half-life of caffeine is about 5 hours.
50%
This implies that if you drink a full cup of coffee
at 2 PM and plan on going to bed at midnight,
the caffeine in your bloodstream is similar as 25%
if you just chugged a fourth of a cup of coffee
before trying to sleep. 0%
5 10 15 20
The half-life was originally used to hours hours hours hours
describe the decay of radioactive atoms,
but has also been adopted by biologists and Figure 12.16 Exponential decay of caffeine
pharmacologists. It is safe to say that after 5 given a half life of 5 hours.
12-16
melatonin. But when daylight starts to decrease, histamine is a neurotransmitter that acts as a pro-
the RHT sends a weaker excitatory signal onto wakefulness signal (the opposite of adenosine
the SCN, which allows increased pineal gland and melatonin, which both increase drowsiness.)
activity. Most people understand the role of
Light exposure is the main environmental histamine in the context of allergies. Seasonal
influence that decreases melatonin levels. But, allergy sufferers often take a histamine antagonist
not all wavelengths of light are equally potent at (antihistamine) to decrease the severity of
dampening melatonin production. The shorter allergen exposure. Many antihistamines warn
wavelengths of light, down in the violet-blue against operating heavy machinery while taking
range, are much more efficient at activating the these drugs, since drowsiness is one of the major
RHT compared to longer, yellow-red wavelengths. side effects. Newer generations of antihistamines
Increased RHT activation leads to decreased are more effective at minimizing drowsiness,
melatonin production, which can delay the onset so they often advertise “non-drowsy” on the
of sleep. Fluorescent or LED lighting and digital packaging.
devices, such as computer screens and cell
phone screens, use blue wavelengths of light.
Therefore, the best advice to optimize your
sleep habits is to eliminate exposure to all digital
devices about one hour before your intended bed
time.
Relative energy (%)
100
80
60
40
20
400 500 600 700

Wavelength (nm)
Figure 12.17 Production of melatonin is most

strongly suppressed by blue wavelenghts of light,
which are emitted by the LEDs that backlight
digital devices like computer or cellphone
screens.
Histamine
Histamine is a small signaling molecule
that has a variety of functions. In the body,
histamine mediates the sensation of itch,
participates in the inflammatory response, and
activates the immune system. In the brain,
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12.5 Brain structures involved in sleep
When scientists use an EEG to measure
electrical activity, they look at the activity of Clinical connection: Encephalitis lethargica
neurons in the cortex, the outermost layer of In the midst of World War I, a strange
brain cells. However, sleep and wake behaviors disease of unknown origin called encephalitis
are driven by the action of cells that lie buried lethargica ravaged the globe. A worldwide
deep within the phylogenetically older areas pandemic, an estimated five million people
of the brain. The signals that originate here were affected. About half of the patients died
communicate broadly throughout the rest of the from early stage symptoms, and those who
brain, and these signals are the ones that cause survived often failed to recover fully.
us to sleep or wake. Encephalitis lethargica was also called
It is not just a single part of the brain that “sleeping sickness” because of the symptoms
controls sleep behavior, but most likely a network that patients experienced: a lack of energy,
of communication activity between different extreme muscle weakness, and loss of all
areas. Here, we will only address a few of the desires. Neurologist Oliver Sacks described
brain areas that are heavily involved with sleep. these patients as being “insubstantial as
ghosts, and as passive as zombies.”
Hypothalamus Today, cases of encephalitis lethargica
Early studies on the role of the are extremely rare. The cause of the disease
hypothalamus in sleep began with Viennese was never figured out, but one theory suggests
neurologist Constantin von Economo. He that malfunctions in the immune system are
described a series of patients with a disease related to the onset of the disease, since a
called encephalitis lethargica in 1917. In his major outbreak appeared in the wake of the
observations, patients presented with one of Spanish flu pandemic of 1918.
two sets of symptoms. Some had progressive
lethargy, starting with drowsiness, moving to
extended sleeping periods, worsening to coma.
On the complete opposite end of the spectrum,
some patients had severe insomnia - a clinically
significant difficulty with falling asleep.
When von Economo performed the autopsy
on the patients, he found very specific injuries in
the hypothalamus that correlated with symptoms.
Among those with persistent sleepiness, the
posterior hypothalamus was severely damaged.
Von Economo concluded therefore that the Figure 12.18 Hypothalamus damage was
posterior hypothalamus contained structures that found in people who experienced encephalitis
are needed for maintenance of wakefulness in the lethargica (sleeping sickness).
12-18
healthy individual. In the patients with insomnia as of consciousness or coma.
their main symptom, their anterior hypothalamus Information flow through the reticular
was injured, leading von Economo to conclude formation passes in the upwards (towards the
that this area was important for promoting sleep. cortex) and downwards (towards the body)
Von Economo’s findings represented a directions. The upward pathway, also called the
shift in the way scientists thought of sleep. Most ascending reticular activating system (ARAS),
researchers believed that sleep was brought receives inputs from all the sensory systems
on simply by an overall decrease in brain before sending wide projections all across the
activity. However, his discovery of hypothalamic cortex. (For your curiosity, the downward pathway
localization of a “sleep center” demonstrated that is the reticulospinal tract that is involved with
for normal sleep to happen, certain areas in the motor control of the skeletal muscles, and is not
anterior hypothalamus actually need to increase strongly involved with sleep behaviors.)
their activity.
The hypothalamus can be subdivided
further into populations of neurons that have
previously been addressed in some context. The
suprachiasmatic nucleus (SCN), the neurons that
receive light information via the retinohypothalamic
tract and help regulate melatonin release,
is part of the hypothalamus. Elsewhere in
the hypothalamus is the tuberomammillary
nucleus, the major site of neuronal production
of the wakefulness signal histamine. The lateral
hypothalamus has neurons that produce the
pro-wakefulness signaling molecule orexin Reticular
(sometimes also called hypocretin), and these formation
neurons are lost in people with severe narcolepsy.
Reticular formation
The reticular formation is found in the Figure 12.19 The reticular formation in the brain
brainstem. Like a large net of interconnected stem is a series of interconnected neurons that
clumps of neurons, it is difficult to anatomically control some functions of consciousness.
classify the structures of the reticular formation,
since they do not have a clearly defined border or
boundary. Activity of these neurons contribute to
a variety of behavioral states, such as alertness
and consciousness. The reticular formation
is vulnerable to ischemia, lesions, or physical
trauma. Often, severe injuries may result in a loss
12-19
12.6 Sleep disorders
Insomnia patterns.
Almost everyone has experienced difficulty We can describe insomnia as acting at two
sleeping at some point in their lives, often as a stages. Onset insomnia is defined as a difficulty
result of stress or anxiety. For example, it might with initially falling asleep. People with onset
be difficult to fall asleep the night before a big insomnia will frequently lie in bed for a long time
interview, or you may wake periodically in the before finally drifting off. Maintenance insomnia,
hours before an important early morning flight. however, is a difficulty with remaining asleep.
There is no strict definition for insomnia. People with maintenance insomnia experience
The major clinical symptoms are self-reported many waking events throughout the middle of
measures, such as a dissatisfaction with nightly the night, or they may wake up very early in the
sleep or a change in daytime behavior, such as morning and be unable to get back to sleep. The
sleepiness, difficulty concentrating, or altered two are not exclusive, and people may experience
mood states. The lack of clear diagnostic criteria both forms of insomnia in a single night.
makes estimating prevalence difficult, but some The most effective treatments for insomnia
guesses put the number of people with insomnia begin at the level of behavioral changes. Improving
close to one third of the US population. sleep habits, such as minimizing arousal states
Common triggers for insomnia include before bedtime, developing a reliable pattern of
heightened anxiety, stress, or advanced age. It sleep-wake timing, eliminating caffeine intake
may also be downstream of other diseases, such in the afternoon and evening, and increasing
as Parkinson’s disease, diabetes, depression, daytime physical activity can decrease insomnia.
or chronic pain conditions. Lifestyle can also Prescription medications are less preferred for
be a major risk factor for insomnia, as jet lag insomnia treatment, since these drugs are more
and working late-night shifts can disrupt sleep effective at inducing unconsciousness rather
Clinical connection: Fatal familial insomnia a diagnosis is made.

While many cases of sleeplessness The cause of FFI is unknown. There is
last a day or two, and some cases are a strong genetic component associated with it,
clinically significant and treatable with as it appears frequently within certain family
behavioral changes, a very small fraction of trees. But, there have also been a few cases
cases of insomnia are incurable and deadly. of sporadic FFI, people with no apparent family
In people with fatal familial insomnia (FFI), members with the disease. One observation in
they experience severe insomnia. Some common among people with FFI is significant
patients stay awake for up to six months at a damage to the thalamus, as a result of
time. As a result of either the disease or the misshapen proteins called prions, a similar
sleep deprivation, they experience altered disease-causing agent that is responsible for
mood states, hallucinations, dementia, and mad cow disease.
eventually death, usually within two years after
12-20
than biological sleep. These drugs can also
have adverse psychological side effects such as
mood swings and depression, and those adverse
effects may be more severe than insomnia itself.
Prolonged use of prescription sleep medications
can lead to a “rebound effect,” causing a person
to experience even worse insomnia when they
are unable to get sleep drugs. This is called
iatrogenic insomnia, and can lead to a cycle of
dependence.
Sleep apnea
Sleep apnea is characterized by nightly
sleep that is frequently interrupted by the
inability to breathe (a- meaning none, and pneu
referring to wind, air, or breath, as in pneumonia
or pneumatic pump). In turn, this lowers blood
oxygen levels, causing the brain to wake the
person in panic. Each wake event may only last a
few seconds, but these disruptions are significant
enough to prevent a person from getting the
appropriate amount of restorative deep sleep. A
person with sleep apnea may wake 30 times an
hour, despite having no recollection of waking.
The immediate result of sleep apnea is excessive
daytime sleepiness, but over long periods of time,
sleep apnea contributes to the development of
heart disease and an increased risk for stroke. Figure 12.20 Sleep apnea is a blockage of the
There are two forms of sleep apnea, both airway during sleep, causing patients to wake in
of which may be seen in a person with this sleep the middle of the night (top). It can be treated by
disorder. Obstructive sleep apnea is the more wearing a CPAP device (bottom).
common of the two. This happens when soft tissue to sleep apnea, which are often a combination of
in the back of the throat temporarily collapses, genetic and environmental influences. Obesity
which can decrease or completely block airflow is a major risk factor, resulting in increased soft
into the lungs. On the other hand, central sleep tissue mass around the neck and torso, which
apnea is mediated by some biological change in can increase the likelihood of airway blockage.
the brain that results in a decrease in involuntary Advanced age contributes to sleep apnea, as
breathing patterns at night, possibly due to some the muscles that keep the airway open weaken
damage in the respiratory centers of the brain. and lose tone over time. Exposure to chemical
There are several risk factors that contribute irritants, such as cigarette smoke, contribute to
12-21
inflammation and increased water retention in the timing, and physical activity). Drugs such as
soft tissue, both of which can decrease the size amphetamines (Modafinil) can be used in the
of the airway. daytime to stimulate activity in the CNS, and can
Sleep apnea is most often treated with a be prescribed to treat severe cases of narcolepsy.
portable machine called a continuous positive Some antidepressant drugs can be used to treat
airway pressure device, or a CPAP device. cataplexy.
These machines are basically air pumps that The exact cause of narcolepsy has not yet
connect to a mask that is worn over the nose and been identified. However, there are many clues
mouth. When used correctly, the CPAP forcibly that point to a dysregulation of the signaling
pushes air into the person’s respiratory system, molecule orexin produced by cells in the lateral
acting as an external lung. However, the CPAP hypothalamus. These neurons die off in people
can be loud and bulky, and the mask must be with narcolepsy, but the cause of why the
airtight for the treatment to be effective, making neurons die is unknown. Also, having a genetic
the treatment very uncomfortable. Because of
this, CPAPs can cause more difficulty with sleep Clinical connection: REM sleep behavior
compared to sleep apnea itself, so they often disorder
have a low compliance rate. One very rare parasomnia (sleep
disorder) called REM sleep behavior
Narcolepsy disorder (RBD) can cause people to carry
Unlike the previous two sleep disorders, out complex, highly coordinated motor
which result in a deficit of sleep, narcolepsy actions while they are sleeping, sometimes
can be thought of as an “excess” of sleep. More acting out their dreams as if they were
accurately, narcolepsy is inappropriate sleep, and reality. People with RBD are at risk of
it manifests as frequent sleep attacks throughout injuring themselves or others.Their sleep
the day, each event lasting for seconds or actions may be in response to a violent
minutes at a time. An estimated 1 in 2000 people nightmare, causing them to jump out of bed,
experience narcolepsy. kick or punch the air, run through the house,
One of the life-threatening symptoms or throw things.
that appears in narcolepsy is cataplexy, which One of the most shocking instances
is the sudden weakening of muscle tone that of parasomnia-induced sleepwalking was
accompanies a sleep attack. A cataplectic attack the 1987 case of Kenneth James Parks, a
may cause someone to physically fall over during Canadian man who, in his sleep, drove 23
a narcoleptic incident. Cataplexy often happens km to the house of his in-laws and stabbed
during high emotional states, such as excitement. both of them with a kitchen knife. After his
As with other sleep disorders, changes in arrest, scientists discovered that his brain
lifestyle can improve the course of narcolepsy. activity was highly abnormal during sleep.
Introducing short daily naps can be helpful, as As a result of the medical examination, the
can general good sleep habits (minimal digital Supreme Court of Canada acquitted him of
device usage before sleep, regular sleep-wake murder in 1992.
12-22
predisposition to narcolepsy does not guarantee Major risk factors for RLS are iron deficiency and
that a person will experience the symptoms, dopamine dysregulation. The exact pathogenesis
indicating that there is some combination of is unknown, but it does have some genetic
genetic and environmental factors that lead to component.
narcolepsy.
Periodic limb movement disorder
Restless legs syndrome Periodic limb movement disorder (PLMD)
A person with restless legs syndrome is a motor disorder that causes abrupt limb
(RLS) experiences frequent unusual sensations movement such as kicking, flexing, or jerking.
in their limbs, such as a tingling or buzzing. Usually, the limb movement is in the legs, but
Because these uncomfortable sensations arm movement can also be seen. Since motor
disappear with movement, people with RLS often activity is actively suppressed during REM sleep,
want to move their legs around. Technically, RLS limb movement is most often seen in the first half
is not exclusively a sleep disorder, since patients of sleep when NREM sleep dominates the sleep
experience similar symptoms when they are cycle. Each series of limb activity repeats at about
simply at rest, while sitting and watching TV or a 30 second interval.
studying. But, the sensation happens frequently PLMD is different from RLS, since PLMD
as a person is lying down in bed, thus delaying results in involuntary movements that a person
the onset of sleep. may not be aware of, while RLS related-movement
RLS is likely underdiagnosed, since it is a is voluntary. As a movement disorder, the course
disease that exists on a spectrum. Those who are of PLMD can be modified by dopaminergic
minimally affected probably do not experience drugs. Alternatively, sedatives can help minimize
significant changes in sleep. Estimates of nighttime movement.
prevalence of RLS range from 2.5% to 15%.
Figure 12.21 Polysomnogram showing repeated muscle activity in both left and right legs (bottom two
traces) during sleep.
DePaul University.
12-23
Cover: https://pixabay.com/photos/cat-sleep-wall-blue-grey-leisure-4358985/
12.1 Eugene Delacroix, lady Macbeth sleepwalking
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Pancrat [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)]
12.11 Image by Arek Socha from Pixabay
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at_%27night%27.jpg
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12.14 https://pixabay.com/photos/asleep-sleep-bored-tired-nap-3126444/ https://pixabay.com/photos/crazy-fun-person-
happy-girl-funny-2840240/
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licenses/by/4.0)]
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Kipala [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
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by-sa/2.1/jp/deed.en)]
12.19 https://commons.wikimedia.org/wiki/File:Reticular_formation.svg modified by Austin Lim
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wikimedia.org/wiki/File:CPAP.png?wprov=srpw1_26
12.21 https://commons.wikimedia.org/wiki/File:PLMD_Polysomnogram.png
12-24
13-1
David Graykowski (DePaul University)
Editor: Alexandrina Guran, PhD (Universität Wien)
Think back to your favorite birthday party. several brain areas. Our ability to learn new facts,
Which of your friends were there? What did you recount the events of last week, or to perform
do, where did you go, and did you have cake? new motor skills is the result of learning-induced
Did you get gifts? neural plasticity. In this chapter, we will consider
The ability to perform this task depends different aspects of learning and memory, starting
on our ability to create and recall memories. from the behavioral level down to the molecular
According to our current best understanding of changes responsible for memory formation,
the neuroscience of learning, the underlying as well as some disorders that disrupt healthy
biology of a memory mainly consists of subtle memory processes.
changes among synapses distributed across
Chapter 13 outline
13.1 Patient HM
13.2 Neural Structures Involved in Learning
13.5 Disorders of Memory
13.1 Patient HM
One of the most influential case studies in extension). In his early adulthood, he was having
the neuroscience of memory is the story of Patient a tonic-clonic seizure monthly and several minor
HM. HM was born in 1926 in a small Connecticut seizures daily, preventing him from working a
town. He had a mostly regular childhood: taking normal job or living a normal life - despite taking
family road trips, riding bicycles, and learning a cocktail of anti-epileptic medications.
about American presidents in school. Neurosurgeon William Scoville proposed
In his childhood, HM began having a “frankly experimental operation” to treat HM.
severe seizures, possibly the result of a head It was known that most epilepsy originates in
injury. In his teenage years, he started having patches of neurons of the medial temporal
tonic-clonic seizures, the most severe form of lobe (MTL), and HM’s epilepsy was typical in
seizures that produces a loss of consciousness this respect. Scoville suggested to surgically
and convulsions (extreme muscle contraction or resect the MTL. In 1953, Scoville removed about
13-2
Hippocampus
Figure 13.1 Patient HM at 27 years old.
8 cm of the MTL bilaterally, including part of the

amygdala, and notably the hippocampus, the
seahorse-shaped structure of the brain.
The surgery succeeded at its primary goal:
HM’s seizures were less frequent and less severe.
However, HM was left with a highly unusual and
life-altering side effect: He was unable to create
new discrete memories, a memory deficit called Figure 13.2 The location of the hippocampus
anterograde amnesia. For example, he could in the medial temporal lobe (top). A dissected
not remember what he had eaten for lunch just hippocampus and fornix (bottom left) looks like a
minutes after finishing the last bite. Despite seahorse (bottom right).
being an avid fan of watching the news, HM
couldn’t remember the names or the faces of are different form of memory called procedural
different celebrities or public figures. It was as memory; see below). He was also capable of
if he was permanently living in the present. (In recalling things from his early childhood, such as
contrast, retrograde amnesia affects the ability geography facts he had learned in elementary
to successfully retrieve memory from one’s past.) school.
However, despite his pervasive memory
deficits, HM did not display any deficits in Types of memories
intelligence. His language and speech were The fact that HM’s MTL surgery disrupted
unaffected, and word recall was excellent, as he some types of memories (e.g., memory for facts)
loved completing crossword puzzles and often did while others were still intact (e.g., motor skills)
so successfully late in life, with only the occasional inspired neuropsychiatrists to try to define the
spelling errors. He could learn to acquire new different forms of memory. Much of the research
skills, such as keeping a pen still on a moving was led by Dr. Brenda Milner, who carried out
circular platform, or a tapping task (these skills several behavioral tests on HM to figure out what
13-3
types of memories are dependent on the intact Several tests concluded that HM had lost
MTL and which ones can function without MTL. his ability to create new semantic memories. In
The most profound deficit was HM’s one such study, HM was asked to determine if a
inability to create new declarative memories. word was made up or real. He was shown words
Declarative memories, also called explicit with very old origins, such as “shepherd” or
memories, are the pieces of information that “butcher.” On these words, he performed as well
can be consciously declared or stated explicitly. as the control group. When he was shown words
Declarative memories are thought of as a that are made up, such as “phlage” or “thweise”,
“knowing what”. Declarative memories can be he likewise performed as well as the controls.
further subdivided into semantic memory and However, when shown words that were added
episodic memory. into the dictionary after his 1953-surgery, such
Semantic memories are pieces of factual as “granola” or “jacuzzi,” he scored about 50%
information. Some examples include: correct - consistent with guessing at random, as
1. “Jupiter is the largest planet of our solar if he never acquired the knowledge that these
system.” words have a meaning.
2. “Rosalind Franklin discovered the double- HM was also unable to create
helix structure of a DNA molecule.” autobiographical memories. When asked to
3. “The actor Keanu Reeves played the recall one of his birthday celebrations as an adult,
protagonist of the movie The Matrix.” he wouldn’t be able to give any significant details
An episodic memory, sometimes also about the event. Instead, his answers were often
called an autobiographical memory, is the vague and generic.
recollection of a discrete moment in a person’s One interesting observation was that HM’s
life. It can be thought of as “mental-time travel” memory about details from his childhood were
- what was it like when. The following memories still intact. The inability to recall memories from
are examples of episodic memories: the past, in this case, from before HM´s surgery,
• “When I got home, I put my wallet and phone is called retrograde amnesia. Patient HM’s
on the table.” retrograde amnesia was temporally graded,
• “I ordered pizza last night.” meaning that the farther back you examine,
• “In 2019, I went to see my favorite musicians the more complete his memories were. Many
perform live.” of his memories for the two years before his
Memory
Declarative Procedural
Working
(explicit) (implicit)
Episodic
Semantic Kinesthetic Priming Associative
(autobiographical)
Figure 13.3 Summary diagram of some of the major subtypes of memory.
13-4
Memories how”. Some examples of procedural memories
retained include, for example, performance of a series of
Anterograde amnesia
100% motor actions without conscious thought such as
an experienced musician playing a simple scale
50% (sometimes commonly called “muscle memory”,
even though the muscles do not store any actual
0% Time memory!), or a priming effect (such as when a
Lesion
Memories person sees pictures of bananas, they are more
retained likely to answer the fill-in-the-blank prompt “b _ _
Retrograde amnesia
100% _ _ _” with “banana”, whereas other people might
guess “bubble” or “badger”).
50%
The original test of procedural memory
0% conducted by Dr. Brenda Milner was called the
Time
Lesion mirror tracing task. In this test, the patient is told
to draw a third star in between the two stars as
Figure 13.4 In anterograde amnesia, a person is quickly as possible without making any mistakes.
unable to create new memories following a lesion The challenge is that the tracing is to be done
(top). In temporally-graded retrograde amnesia, while watching their hand and the star in their
older memories are better retained while recent reflection in a mirror. Because of these unusual
memories are more likely lost. circumstances, completing this task is difficult.
But over multiple days of practice, people become
surgery were completely lost, but memories
from his youth and teenage years were intact as
much as healthy individuals (there is contention
about this observation, because HM was
taking several anti-epileptic drugs, which may
have impacted memory formation.) From this
observation, memory researchers concluded that
the MTL functions as short-term storage site for
memories, but after some years, those memories
Day 1 Day 2 Day 3
get relocated to other brain areas outside of the
Errors
MTL. Currently, the scientific evidence suggests

that memories are distributed across several
Trials Trials Trials
networks of cortical and subcortical brain areas.
While HM lost the ability to create new
declarative memories, he was still able to maintain Figure 13.5 Patient HM performed poorly on the
a different class of memories, called procedural mirror tracing task (top), but improved at the task
memories (or implicit memories). They are over time despite having no memory of performing
unconscious memories, and can’t be explicitly the task (bottom).
stated. These can be thought of as “knowing
13-5
better at this mirror tracing task, completing it dogs begin to salivate, a conditioned response
faster with fewer errors. Improvement on this (CR), independent of any food being presented.
task indicates that a person is learning or gaining Separate from declarative or procedural
some memory about how to better perform the memories, a different form of memory called
task. working memory was tested in HM. Working
After practicing this mirror tracing task, HM memory involves processes of storing information
was able to finish drawing the star about ten times temporarily while simultaneously manipulating
faster than when he first began. He improved his those pieces of information. This type of memory
performance within each day’s worth of training,
and he also improved day-to-day. There is
Stimulus Response
evidence that he maintained these skills up to one
year later, despite not having regular training on
this task. Surprisingly, each day Milner examined
HM, she would need to reintroduce herself Food:
since he forgot who she was. She also had to Unconditioned
stimulus (US) Salivation:
re-explain what HM was supposed to do in the Unconditioned
mirror tracing task. Hence, while HM was unable response (UR)
to form declarative memory about the experiment
or the people involved, learning of the procedural
memories and motor actions involved in this task
remained intact. Bell: Neutral
stimulus No response
Another type of procedural memory is an
associative memory. Associative memories are
the types of information that we learn through
traditional Pavlovian conditioning. For example,
recall the classic Nobel prize-winning experiment
Pairing of bell with
in physiology conducted by Ivan Pavlov in the Salivation
food
late 1800s. Normally, the presentation of dog
food, an unconditioned stimulus (US), causes
a dog to salivate, a naturally happening behavior,
called the unconditioned response (UR). Dogs
are not particularly interested in the sound of a
whistle: this neutral stimulus will produce a minor Bell: Conditioned
stimulus (CS) Salivation:
response, such as a head turn and attentional Conditioned
shift towards the origin of the sound, but not much response (CR)
more than that. However, when this stimulus is
repeatedly paired with the presentation of food, Figure 13.6 A CR after exposure to a CS, such as
dogs quickly learn to associate that the whistle in classical Pavlovian conditioning, is an example
signals food. After multiple pairings, upon hearing of an associative memory, one type of procedural
the whistle, a conditioned stimulus (CS), the memory.
13-6
can be thought of as a “short-term memory on Trial 1: Prompt 4826
overdrive.” Although HM struggled with working Expected response 6284
memory immediately after his surgery, several
years later HM performed as well as age-matched Trial 2: Prompt 28791
control patients on these tasks. Expected response 19782
For example, a test of working memory
Trial 3: Prompt 841186
is the digit span test, where a person is given
Expected response 681148
a series of numbers to remember, then they are
asked to repeat the numbers in reverse order.
After successfully completing this task, a different Prompt Expected response
series of numbers, this time one digit longer, is 4 1 2
3 4
presented to the patient until they first start making 1
errors in recall. A related task is called the Corsi
2 3
block tapping test, where an experimenter sets
up several blocks on a table. The experimenter
then taps a series of blocks in a specific order,
then the subject is asked to tap on the blocks Figure 13.7 The digit span test (top) and the
in reverse order. As with the digit-span test, the Corsi block tapping test (bottom) are measures
experimenter then makes the series of blocks of working memory.
longer until they make mistakes in the tapping.
Patient HM died in 2008 at age 82 of
respiratory failure. His name was Henry Molaison.
13-7
13.2 Neural Structures Involved in
The Hippocampus (HPC)

The hippocampus (HPC), meaning
“seahorse” in Greek, was named based on its
morphology. The HPC is located along the ventral
and medial surface of the brain. The HPC is one
of the critical structures of the limbic system,
a series of subcortical brain structures that are
involved in several different complex behaviors,
such as emotions and memory. The limbic system Schaffer
is an evolutionarily ancient brain network. collaterals CA1
The synaptic connectivity of the
hippocampus is very well characterized. CA3
Hippocampal synaptic connectivity was first
Dentate Entorhinal
described by Ramon y Cajal, and is made up Mossy gyrus cortex
fibers Perforant
of three main synaptic connections; sometimes
pathway
called the trisynaptic circuit. First, the axonal
outputs of layers 2 and 3 from the entorhinal Figure 13.8 The circuitry of the hippocampus
cortex make up the inputs into the HPC. This as illustrated by Ramon y Cajal (top) and as a
white matter signaling tract is called the perforant schematic diagram (bottom). Structures are
pathway, and they synapse onto the granule labeled in red and communication pathways are
cells of the dentate gyrus. These neurons send in black.
axons, called mossy fibers, to the pyramidal
cells of the Cornu ammonis (CA) 3 region of the spatial memory whenever we are walking around
HPC. The axonal projections from here, called campus, making our way from one building to
Schaffer collaterals, project into CA1, which another, thinking about the streets you’d need to
are the neurons that make up the output of the cross or the buildings you can cut through. While
hippocampus. These outputs project out to layer the volume of the hippocampus is not a reliable
5 and 6 of entorhinal cortex. While the three indicator of the strength of a healthy person’s
main neuronal projections are glutamatergic, spatial memory, injury to the hippocampus causes
the trisynaptic circuit is modulated by GABA, deficits in spatial memory.
acetylcholine, norepinephrine, and serotonin. To test spatial memory behaviorally in non-
The HPC is involved in spatial memories, human animals, one test that is regularly used
memories involved in navigation of our in rodents is called the Morris water maze. In
surroundings and the creation of a mental map of this test, a shallow pool is filled with an opaque
our world. Spatial memories are developed when liquid, making it difficult to see through. Hidden
we enter a new building for the first time, and we somewhere in this pool is a clear plexiglass
search for a new classroom. We also use our platform, surrounding the pool are different
13-8
environmental cues that can be seen from the find the platform decreases. When the HPC is
surface of the water, such as different shapes surgically removed from rodents or inactivated,
or colors. The water is deep enough that when they perform poorly in the Morris water maze.
a rodent is put into the Morris water maze, they Another non-human behavioral test used
have to swim to stay afloat. The rodents swim to assess the capacity for learning navigational
around aimlessly until they find the platform, the cues is the radial arm maze. In this test, a rodent
time it takes for this to happen is recorded, and is placed on a circular platform. Extending from
the trial ends. Over time, the animals learn that this platform are eight or more “arms”, at the
the platform is located near certain navigational end of each is a small dish. In one of the dishes
cues, and on future trials, the animals spend is a morsel of food (“rewarded arm”), while the
more time near those cues, and the latency to other dishes contain nothing (“non-rewarded
arms”). The maze is designed so that the food
cannot be seen from the end of each arm, so the
Camera
animal must return to the starting platform before
exploring another arm. The number of entries
Starting location
Environmental into a non-rewarded arms is counted as an error.
cues Over time, the animals make fewer errors as they
learn which arm is rewarded and which ones
are not. Alzheimer’s disease model organisms
Hidden platform perform poorly on this task.
Based on the deficits seen in Patient HM
and other experimental manipulations of the HPC,
we conclude that the HPC is strongly implicated
in the process of declarative memories and
spatial navigation. Since some of HM’s memory
functions were still intact, such as procedural
memories and working memory, it is believed that
these functions are independent of HPC function.
The Amygdala
The amygdala is another limbic system
structure found in the medial temporal lobe
adjacent to the HPC. Amygdala comes from the
Greek word meaning “almond,” which roughly
describes its shape. While the amygdala is
often spoken of as a single structure, it is more
accurately divided into several subnuclei, each
Figure 13.9 The Morris water maze (top) and the with different cell populations and functions.
radial arm maze (bottom) are behavioral tests to One broad division distinguishes the basolateral
assess spatial memory. amygdala (BLA) versus the central nucleus of
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amygdala (CeA): The BLA contributes to both fear fear conditioning. This test involves putting a
memories and reward processing, while the CeA rodent into a chamber with floors made of metal
contributes more to the physiological response in rods, which are connected to an electric current
emotions as well the perception of emotion. generator. The metal rods can deliver a non-
lethal but painful electric shock to the rodent’s
foot. In this learning paradigm, a combination of
sound and light cues is presented to the animal.
Shortly after, the painful foot shock is delivered.
If the animal learns that the cues are associated
with the negative painful memory, they exhibit
freezing after exposure to the cues. Amygdala
lesions prevent the animal from freezing, while
hippocampal lesions have no effect on this
Figure 13.10 The amygdala are temporal lobe
emotional learning. Changing cellular signaling
structures that contribute to the salience of
in the amygdala alters the learning of fear
emotional stimuli.
conditioning. The foot-shock paradigm is often
used as a non-human model of post-traumatic
The amygdala is strongly involved with the stress disorder.
formation and storage of emotional memories,
memories or associations that have a strong Inferotemporal cortex (IT)
emotional connection. Both positive and negative Structures of the inferotemporal cortex (IT)
emotional states are represented here. For are part of the ventral stream of visual perception
example, a whiff of grandmother’s cooking may (chapter 7). The IT stores some components of
cause you to reminisce back to a fun childhood visual memory. We use these functions when
summer. Alternatively, the smell of vomit may elicit we see a classmate outside the classroom
the unpleasant emotions and nausea associated and recognize them from our Introduction to
with a nasty food poisoning incident. Neuroscience class, or when we see a parody of
One non-human test of emotional a famous painting and recognize the similarities
memory is the foot-shock paradigm, a form of to the original work. A simple behavioral task to
assess visual memory would start by
viewing a series of abstract shapes,
and when a shape appears that you
have already seen, you push on a
button. The human capacity for visual
memory is massive: After viewing
Figure 13.11 In the fear conditioning paradigm, a rodent is put 10,000 images for a few seconds
into a room with medal rods as the floor (left). Then, a sound apiece, people were able to identify
tone is repeatedly paired with a foot shock (middle). When a previously seen image successfully
the sound is played again, the rodent may exhibit freezing about 83% of the time.
behavior (right).
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match those facial features with someone they
have seen before, which is a memory related
process.
The parahippocampal place area (PPA),
also found in IT, contributes to visual memories
associated with locations and environmental
scenes. Imaging studies have demonstrated that
activity of the PPA increases specifically when
people view place-related images, including
scenic landscapes like mountains, man-made
structures like campus buildings, or the interiors
Figure 13.12 The inferotemporal cortex is one of rooms, both furnished and completely empty.
of the signaling pathways important for visual To serve as control stimuli, viewing faces or
memories. objects does not increase the activity of the PPA.
A bit more specifically, one part of the IT is Prefrontal Cortex (PFC)

the fusiform gyrus, which has been previously As part of the frontal lobe, the PFC is involved
described in the context of facial recognition. in high order decision making and personality. In
People with prosopagnosia, a visual perceptual the context of memory, neural circuits in PFC are
disorder affecting the fusiform gyrus, can perceive important for short-term and working memory.
the different parts of a person’s face, but have Patients with injuries to their prefrontal cortex
a difficult time putting the whole picture together after stroke, tumors or aneurysm, performed
and matching those features to a specific person. worse on a variety of working memory tasks such
For facial recognition to be accurate, there must as the digit span test. Additionally, people with
be some memory that allows for a person to frontotemporal dementia, a neurodegenerative
Figure 13.13 The inferotemporal cortex (left, sagittal view) is part of the ventral stream of visual
perception, and is likely one site of visual information storage. Within the IT is the fusiform gyrus
(middle), which is specifically activated strongly in imaging studies when a person is shown with a facial
stimulus (right).
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disorder characterized by a degradation of the set of circumstances without incorporating and
frontal lobe, often have difficulty with working evaluating the present circumstances.
memory. Habitual action performance is likely
The PFC also has strong projections with related to a variety of neuropsychiatric disorders.
the hippocampus, and these circuits are likely Obsessive compulsive disorder (OCD), for
also involved in the formation of hippocampal- example, is characterized by the presence of
dependent memories. recurring, intrusive thoughts, which can lead to
repetitive actions. Commonly observed is the
Striatum thought that one’s hands are unclean, which
The striatum is a structure of the basal leads to repeated handwashing.
ganglia, a series of brain structures that contribute A rodent behavioral test of habitual activity
to behaviors such as motor activity (chapter 10) is the observation of self-grooming, a natural and
and procedural memories. The striatum likely healthy series of stereotyped actions that consists
holds memories involved in habits. Habitual of licking the paws and moving them through the
behaviors help us preserve cognitive bandwidth, fur of the nose, caudally down the body. Mouse
reducing the “mental energy” that is used during models of OCD show excessive self-grooming to
repetitive task performance. The downside of the point where they pull their fur out and paw
habits is that reliance on habitual responding can their skin to the point of injury.
limit behavioral flexibility, and cause a person to Drug addiction is also a striatal disorder.
act in a suboptimal manner, perhaps behaving in Compulsive drug use is often associated with
a way that led to a positive outcome in a previous a series of habitual motor actions that happen
Caudate
Striatum
Putamen
Globus pallidus
Subthalamic nucleus
Substantia nigra
Figure 13.14 Several subcortical brain areas make up the basal ganglia.
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before a person experiences the drug effect.
Hypermnesia
For example, in tobacco use disorder, people
Solomon Shereshevsky was one
will perform an orchestrated series of actions,
of a handful of rare, clinically documented
including opening a pack of cigarettes, flicking
cases of hypermnesia, the capacity to recall
the lighter, withdrawing the cigarette and taking
nearly any memory with perfect precision,
a deep inhalation. Some of these behaviors are
even after several years. Remarkably,
likely stored across striatal circuits (chapter 11).
he could “easily remember any number
of words and digits, equally easily he
Cerebellum
memorizes whole pages from books on
The cerebellum is the phylogenetically
any subject and in any language and for
ancient structure found posterior and ventral to
a quite long time at that. Shereshevsky
the cerebrum, and functions generally to help
can accurately quote anything he was
with motor functions (chapter 10). The cerebellum
told ten or twelve years ago.” He received
is involved in procedural memories, particularly
recognition in 1968 when his psychologist
the performance of motor abilities. Learning new
A. R. Luria published a case study in “The
motor skills likely requires changes in the circuit
Mind of a Mnemonist.”
strength of cerebellar neurons.
Today, we would describe
Shereshevsky as being autistic with strong
This list of brain structures involved in
multimodal synesthesia. Also of note,
memory is certainly not exclusive. For example,
he had significant deficits in executive
the orbitofrontal cortex plays a role in positive
function, difficulty with recognizing faces,
emotional memories, and sensory cortices are
and could not interpret abstract ideas.
important for the memories related to the specific
stimuli that are processed in those areas. A single
memory could likely be stored in several brain
areas, much like a mosaic.
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In the late 1800s, around the time when when we repeat a phone number to ourselves
Golgi and Ramon y Cajal were engaged in intense until we have a chance to write it down. It is also
debate about the organization of the nervous easier to encode novel information that “builds”
system, many neuroscientists came to a strange on previous bits of knowledge, or information
observation: the weight of the brain increases that is closely related to other well-established
dramatically over the first 10 years of life, but not information, which is why analogies are such an
much more after that. Even though we learn lots effective way to learn new facts.
of new facts and make lots of new memories in
adulthood, the brain itself doesn’t grow in size. 2. The process that enables memory
So how is it possible to store new knowledge if storing is called consolidation, which makes
the brain is not making many new neurons? the memory more permanent. In 1949, an early
Most likely, new pieces of information are neuropsychologist, Donald O. Hebb, offered an
held in the connections between cells, not just explanation for how changes in synapses could
in the cells themselves. If our estimate of 150 possibly lead to a phenomenon as complex as
trillion synapses per adult brain is correct, then it learning. His theory, published in his text The
is possible that we could store all the knowledge Organization of Behavior, can be summed up in
and memories that we collect over our lifetime the phrase:
through some combination of activity across
certain connections. “Cells that fire together, wire together.”
The activity at the cellular level is believed
to take place on at least three different levels In Hebb’s framework, repeated activity at
enabling us to build, store, and retrieve memories. a synapse within a circuit of neurons acts as a
reinforcer signal that strengthens this synapse for
1. Encoding refers to the ability for brain future communication, making the next incoming
circuits to store some piece of information. In signal more robust. Hebb also implies the inverse
real life, you are presented with countless stimuli is true: when cells do not fire together, they
simultaneously. Imagine walking down a busy weaken their connection. Through fine tuning of
street, and think of the number of different sights, synaptic connections, some strengthening and
smells, and tactile stimuli you experience. Storing others weakening, a lifetime of memories can be
memories is an energetically costly process, and stored across a wide distribution of neurons. After
we are limited in the fact that all of our sensory a memory has been created, the specific circuit of
inputs cannot possibly get encoded. Instead, neurons that represent that piece of information
evolution has preferred to encode stimuli that is called a memory trace or an engram.
are most salient pieces of information, such A cellular process called reverberation
as perceptual cues associated with predators. is thought to be the mechanism that allows for
Alternatively, information that we pay strong consolidation. Reverberation is the process by
attention to can get encoded more strongly, like which networks of neurons fire repeatedly. Each
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Input have negatively impacted memory consolidation
before the surgery.
Consolidation seems to occur
predominantly during sleep. Specifically,
declarative memory is enhanced during non-REM
sleep, while procedural memory is enhanced
during REM sleep. Studies investigating sleep
consolidation are often done by letting participants
learn or perform behavioral tasks, after which they
are deprived of a specific phase of sleep. To wake
participants at the right moment, researchers
commonly use EEG signatures, which are unique
for different phases of sleep: sleep deprivation
To output early in the night denies non-REM slow wave
sleep, while late-sleep deprivation decreases
time spent in REM sleep. Some speculate that the
Figure 13.15 A reverberating circuit (purple) is a hallucinations we sometimes experience during
series of neurons that are activated repeatedly dreaming are a consequence of consolidation
with the activity of a positive feedback circuit. processes, but it is inconclusive as to what role
dreaming plays in memory formation.
time that circuit is activated, the strength of the
network is increased, meaning that it becomes 3. Finally, for the stored memories to
easier for that circuit to be activated in the future. be recalled, a cellular process called retrieval
Throughout the process of consolidation, happens which brings back the specific engram.
memory traces are thought to become more Retrieval happens for both declarative and
represented in the neocortex and less in the procedural memories.
subcortical structures like hippocampus or The writing of memories can be
amygdala. Recall Patient HM’s temporally graded differentiated from the retrieval of memories using
retrograde amnesia, where he had lost declarative specific priming-related behavioral tests. One
memories in the two years leading up to this example is a vocabulary recall test. Consider if
surgery, and yet his memories from the long past you were given a list of 50 words to memorize,
were maintained. This finding suggests that some words that belong to a handful of different
aspects of declarative memory consolidation conceptual categories (such as cinnamon,
depends at least partially on medial temporal lobe pepper, or curry, which fall under the category
and HPC for a period of time, maybe up to two “food flavors”). When asked to write down as
years, before those memories get stored in the many words as possible from the list using your
cortex more permanently. However, we cannot memory, a test called free-recall, you may be
conclude how long consolidation takes in healthy able to successfully remember about a third of
humans based on findings from HM, who had them. However, if you were prompted with the
pervasive and frequent seizures, which might category titles, a related test called cued-recall,
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you would perform much better at retrieving topographical arrangement of these place cells,
those memories, possibly recalling up to 75% meaning that adjacent areas of an environment
of the words. The fact that cued-recall scores do not necessarily activate adjacent hippocampal
are often higher than free-recall scores indicate place cells. The place cells, when firing at the
that there is a distinction between the encoding right times, help the animal create a spatial map
/ consolidation of memories and the retrieval of of their surroundings.
memories.
Retrieval is not a passive function. When Grid cells
an engram is retrieved, it is reconsolidated, Grid cells are located in the entorhinal
which is an act similar to replaying the activity cortex, the main input structure to the HPC.
of the circuit. During this reconsolidation, it is Closely related to the place cells described
possible that some aspects of the memory are above, grid cells increase their firing properties
emphasized, while others are lost. This is likely
the main reason why we experience false
memories, memories that are not true to reality Neuron 1
- one reason why eyewitness testimonies are
notoriously unreliable. We may imagine our good
memories as better than they actually were,
while simultaneously dampening the negative
aspects of those memories. A dysregulation of Neuron 2
this reconsolidation process could lead to the
symptoms seen in post-traumatic stress disorder,
where the negative emotional components of a
particular memory are exaggerated rather than
being blunted. Neuron 3
Special populations of neurons

An individual memory is likely distributed
widely across several different parts of the brain.
Neuron 4
However, there are a few special populations
of neurons mainly in the MTL that contribute to
highly specific types of memories.
Place cells Figure 13.16 A rat is tracked (left, gray) as they

Place cells are a special population move through an open field. Individual grid
of pyramidal cells of the hippocampus. These neurons spike when the rat passes through
neurons increase their firing activity when the particular areas of the open field (left, red). Heat
animal is in a particular location in an environment, map (right) showing high neuronal activity in
indicating that they contribute strongly to location warm colors (red and yellow) with low activity in
and navigational memory. There is no apparent cool colors (blue).
13-16
periodically when an animal is at an intersection or the Tower of Pisa. These concept cells respond
of a “grid” in a wide-open, previously-explored to much more than just pictures: for example,
environment. The grid itself is roughly hexagonal, a Luke Skywalker neuron that responded to
and spans the whole environment an animal is in. a picture of young Mark Hamill (the actor who
The overlap of multiple grids gives the animal an played Luke Skywalker) will also respond to text
idea of the surroundings. The scientific description that reads “LUKE SKYWALKER” and the sound
of grid cells earned three scientists a Nobel Prize of a person saying “Luke Skywalker”. Although
in Physiology or Medicine in 2014. this particular neuron probably won’t fire in
response to pictures of athlete Manu Ginobili or
Jennifer Aniston neurons actress Marilyn Monroe, the neuron might fire
The “Jennifer Aniston” neurons, also called in response to pictures of Yoda or Darth Vader,
concept cells, are a series of cortical neurons indicating that the neuron may encode an even
in the temporal lobe that increase their firing broader concept, such as “Star Wars characters”
exclusively in response to highly-specific stimuli, or “Jedi”, or is a part of a network that encodes
such as the idea of Jennifer Aniston, Halle Berry, concepts related to the Star Wars franchise.
Figure 13.17 Concept cells change their firing pattern in response to the presentation of highly specific
stimuli, such as the character Luke Skywalker (portrayed by actor Mark Hamill; images 1, 3, and 5).
Visually similar but conceptually different stimuli (male brunette actors appearing in film), like pictures
of Leonardo diCaprio (image 2) or Keanu Reeves (image 4), fail to induce changes in firing. However,
visually distinct but conceptually-related stimuli, like the picture of Yoda (a related character from the
same series of films; image 6) may also drive the concept cells to fire.
13-17
Zooming in beyond the level of anatomy, Instead of simply giving a single electrical
the substrates of learning can be found at the level stimulation, however, Bliss and Lomo were
of synapses. Synapses change in a phenomenon interested in testing Hebb’s theory about
called plasticity. The word “plasticity” refers to plasticity. If “cells that fire together, wire together,”
a change in synaptic strength, which may be an then perhaps they could experimentally drive
increase or a decrease. This change may persist those cells to fire in a pattern that would
for minutes, hours, days, or in some cases, induce a rewiring of the connections, resulting
even a whole lifetime. When synaptic strength is in LTP. The duo delivered a very intense
increased and remains elevated, we call this long- electrical stimulation, zapping the axons at 100
term potentiation (LTP). A prolonged weakness stimulations a second (100 Hz) for 3 seconds.
of a synapse is called long-term depression This high frequency stimulation (HFS) led to
(LTD). In our current limited understanding of an enhancement of the amplitude of the fEPSP in
plasticity, both phenomena are important for a response to a single stimulus - this demonstrated
healthy brain, and neither one is always good or that LTP was a measurable phenomenon. In a
always bad. different experimental setup, this LTP was shown
It is also important to clarify that both to persist up to one year later! In humans, we
excitatory synapses and inhibitory synapses can theorize that some synaptic connections may
be subject to either LTP or LTD. remain potentiated for our entire lifetime, however
investigating this is in humans is ethically
Long-term potentiation constrained.
In 1973, Bliss and Lomo were the Long-lasting changes in synaptic
first to publish evidence of plasticity using strength, such as the LTP that Bliss and Lomo
electrophysiology. The experiment began at the demonstrated, are made possible through a
hippocampal connections of an anesthetized series of molecular and cellular level changes.
rabbit. They put a stimulating electrode among the One form of LTP results from a change in the
axons of the perforant pathway, at the entrance to types of glutamatergic receptors. Of the three
the hippocampus. A second electrode, capable of classes of ionotropic glutamate receptors, two are
detecting electrical charges in brain tissue, was important for this form of LTP: the AMPA and the
placed among the cells of the dentate gyrus, the NMDA receptors. The AMPA receptors are the
area where those axons release neurotransmitter. glutamate receptors that we generally imagine
By stimulating the perforant pathway, Bliss and as contributing to excitation (more information
Lomo could record how neurons of the dentate in section 5.4). When a molecule of glutamate
gyrus respond. A single pulse caused the neurons binds to the active site of this receptor, the ligand-
to depolarize, a measurable observation called gated ion channel changes and allows cations,
a field excitatory post-synaptic potential mostly Na+, to cross the cell membrane, leading
(fEPSP). The more neurons that depolarize, the to depolarization.
larger the fEPSP would be.
13-18
Recording electrode High frequency stimulus
Stimulator
EPSP amplitude
Long term potentiation
Baseline
Hippocampal slice
-15 0 30 60
Time (minutes)
Figure 13.18 Schematic of the recording configuration of Bliss and Lomo’s experiments (left)
demonstrating that high frequency activation of the Schaffer collaterals while recording the field EPSP
in the CA1 region leads to long term potentiation (right).
The NMDA receptors are somewhat more is the crucial trigger that leads to the cellular
complex. NMDA receptors are like the ionotropic expression of LTP. Ca2+ ions activate an enzyme
AMPA receptors because they are permeable to called calcium / calmodulin-dependent protein
cations and therefore excitatory, but they have kinase II (CaMKII). CaMKII itself has many
a few specific functional differences. For one, molecular targets. As a kinase, it’s main molecular
their molecular pore has space for a magnesium action is to phosphorylate proteins. When
ion (Mg2+) to sit in the middle of the ion channel. CaMKII becomes activated, it phosphorylates
Mg2+, like the other ions that we have discussed amino acid residues on the AMPA receptor,
(chapter 4.2), responds similarly to the forces of which enhances their current passing properties,
the electrochemical gradient. Mg2+ is more highly thereby increasing their response with glutamate
concentrated outside the cell compared to the present. Secondly, CaMKII also contributes to
inside, and it has two positive charges, so these cellular mechanisms which result in increased
ions are drawn to the interior of the cell. But, the trafficking of AMPA receptors to the cell surface.
pore of the NMDA receptor is not large enough to Thirdly, CaMKII interacts with the transcription
allow the bulky Mg2+ ion to actually cross into or factor cAMP response element-binding protein
out of the cell membrane. Instead, it stays stuck (CREB), which can then move into the nucleus
inside the ion channel. Mg2+ physically takes up and instruct the nucleus to synthesize more of
so much space that it occludes the movement of the mRNA that leads to increased synthesis of
other ions across the cell membrane, basically the AMPA receptors. Taken together, increases
blocking passage of ions through the NMDA in intracellular Ca2+ postsynaptically leads to an
receptor. enhancement of a signal that persists over the
The other relevant feature of the NMDA time course of hours: The definition of LTP.
receptor is that it is permeable to the Ca2+ ion. But, these NMDA receptors are not
Increases in intracellular Ca2+ postsynaptically activated by glutamate alone. Because of the
13-19
No stimulation Low stimulation High frequency stimulation
Mg2+
Na+ Na ,Ca
+ 2+
Na+,Ca2+
P
Na + Ca2+
Na+
CREB CaMKII
Figure 13.19 Molecular mechanisms explaining postsynaptic LTP. At no stimulation, glutamate (pink)
does not strongly activate the AMPA receptors (purple; left). A single presynaptic depolarization causes
some glutamate to be released, which activates AMPA receptors, causing postsynaptic depolarization
(middle). At high frequency stimulation, significant glutamate release activates AMPA receptors,
strongly depolarizing the postsynaptic cell, which causes the Mg2+ ion to leave from the NMDA receptor
(green). Ca2+ enters through the NMDA receptor, and can trigger long term changes in the molecular
components of the neuron (right).
molecular properties of the NMDA receptors, they movement of cations across the cell membrane.
need two conditions to be fulfilled before these Because both conditions must be met
receptors get activated and Ca2+ moves into the before Ca2+ can trigger plasticity through CaMKII
cell membrane: activation, the NMDA receptor can be described
1. A ligand like glutamate must activate as a coincidence detector. These properties
the receptor. As with other receptors, there is no can help explain why LTP was only observed
activation in the absence of an agonist. after Bliss and Lomo activated the hippocampal
2. The postsynaptic cell must also be slices robustly with their high frequency stimulus
depolarized. When the cell is at positive potentials, paradigm. Strong activation depolarized the
the electrical gradient causes the bulky Mg2+ ion axonal fibers, which caused a significant amount
that is stuck in the pore to be repelled by the of glutamate to be released, activating many of
cell’s interior, which then frees the ion channel for the postsynaptic AMPA receptors. This strong
13-20
activation caused the postsynaptic neurons to
depolarize, which expels the Mg2+ ion out of the
NMDA receptor. At this stage, both conditions are
fulfilled, and Ca2+ enters into the postsynaptic
cell, which activates CaMKII, triggering LTP.
Some glutamatergic connections between
neurons contain only NMDA receptors but no
AMPA receptors. Because these postsynaptic
cells do not depolarize in response to glutamate
release, and no current passes through the
NMDA receptor due to the Mg2+ block, these
synapses do not change their activity even with Figure 13.20 Aplysia californica was the model
glutamate release. These synapses are called organism first used to demonstrate the neuronal
silent synapses. As we grow, the number of level changes that underlie the habituation
silent synapses decreases, another aspect of behavior.
brain development.
such as a hungry predator (or an experimenter’s
Long-term depression paintbrush), grazed the siphon, the Aplysia would
Around the same time LTP was being reflexively withdraw their gill, as if to protect this
characterized in the rabbit hippocampus, its vital organ by shrinking away from the threat.
cellular opposite, long-term depression (LTD), However, after repeated brush strokes to the
was also being demonstrated in a different siphon, the sea slugs figured out that the stimulus
experimental preparation. Through the 60s, was completely innocuous, and decreased the
psychiatrist Eric Kandel and his colleagues worked strength of gill withdrawal. Kandel and team
with the marine mollusk Aplysia californica. With suggested that this change in behavior was a
a nervous system of only 20,000 cells, Aplysia is form of learning.
orders of magnitude simpler than the other model Kandel discovered evidence of habituation,
organisms used at the time. Additionally, some the suppression of a normal reflex behavior that is
Aplysia neurons are huge, up to a millimeter in dependent on LTD. To further explore the cellular
diameter, which took away the need for highly and molecular level changes behind this LTD,
precise equipment. they conducted electrophysiological experiments
Aplysia also has a relatively simple on Aplysia. The gill-withdrawal reflex circuit relies
anatomy. It breathes using a half-circle of heavily on two different populations of neurons:
delicate tissue called the gill, which is guarded the sensory neurons that receive somatosensory
by the mantle shelf. They also have an organ information from the skin of the siphon, and the
called the siphon, a small tube that is used for motor neurons that control the muscles of the
moving water through the animal. Kandel and his gill. By using two different tiny glass pipettes,
colleagues began their exploration of memory by they could impale these neurons, inducing action
studying the gill-withdrawal reflex, a defensive potential firing in the sensory neuron, and observe
motor response behavior. When a stimulus, changes in membrane potential of the motor
13-21
neurons (a depolarization of the membrane of Repeated brush
a single neuron is called an excitatory post- strokes
synaptic potential, or EPSP). When the Control Habituated
sensory neuron was activated, they observed
an EPSP in response, since an action potential Siphon
caused release of glutamate that activates Sensory
post-synaptic receptors on the motor neuron. neuron
However, after the reflex had been habituated,
the same sensory neuron activation caused a
much smaller EPSP in the motor neuron. Large EPSP Small EPSP
The group went about seeing if they
could modify this habituated response, curious
if a stored memory can be modified by stimuli Motor
from the outside world. When they paired the neuron
mild siphon touch with a painful electric shock Action Fewer
potentials action
to the tail, the Aplysia began responding with a
Gill potentials
strong motor reaction, withdrawing the gill very
intensely, indicating that the inhibited response
disappeared. They called this observation
sensitization. In electrophysiological studies,
they observed that the EPSP at the motor
Strong withdrawal Weak withdrawal
neuron was much larger following the tail
shock.
On a molecular level, presentation of Figure 13.21 Habituation of the gill withdrawal reflex
sensitization is downstream of the action of was modeled by Kandel using Aplysia. Repeated
a third population of neurons, interneurons brush strokes to the siphon caused cellular level
that synapse onto the motor neurons. The changes that led to decreased gill withdrawal.
noxious stimulus triggers these interneurons
to release the neurotransmitter serotonin, which One important form of plasticity is
activates the excitatory signaling molecule cAMP dependent on the activity of the endocannabinoid
found at the terminals of the motor neurons, thus signaling pathway. During robust post-synaptic
increasing release probability and strengthening depolarization, enzymes such as phospholipase
the gill withdrawal reflex. C or DAG lipase create signaling molecules
called endocannabinoids (eCBs), which are
Other forms of plasticity chemically similar to the primary psychoactive
There are many possible mechanisms ingredient of Cannabis (chapter 11). These eCBs
that can lead to plasticity. Some activity patterns are neurotransmitters that act in a retrograde
may induce a short-term plasticity that does not manner, meaning they are produced at dendrites
last on the scale of hours or years, but rather on and signal to the axons. Expressed at some
the order of minutes or seconds. populations of axons are inhibitory Gi/o coupled
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receptors that respond to the presence of eCBs,
called cannabinoid receptors (CB1 is the main
form that exists in the brain). These receptors
inhibit cAMP signaling, which decreases release
probability. This specific mechanism of plasticity Decreased
release
is called endocannabinoid-mediated LTD. CB1R
probability
Another atypical neurotransmitter, the gas
nitric oxide (NO), also contributes to a similar
form of LTD. The enzyme nNOS synthesizes NO,
which diffuses across cell membranes and can
activate an intracellular receptor called soluble eCB
production
guanylate cyclase (sGC). SGC changes the
activity of the signaling molecule cGMP, which Elevated
can either lead to enhancement or depression of [Ca2+]i
synaptic strength.
There are also two directionally-opposite
forms of plasticity that function at the millisecond
timescale, called paired-pulse facilitation (PPF)
and paired-pulse depression (PPD). These
forms of plasticity can be observed by stimulating Figure 13.22 Endocannabinoid-mediated LTD
a presynaptic area while recording simultaneously is a result of a retrograde signal that decreases
from the post-synaptic site. However, instead release probability.
of delivering a single depolarizing pulse pre-
synaptically, these forms of plasticity can only at the same synapse by varying the duration of
be observed by giving two pulses right after the IEI.
each other, usually separated in time by 10 By understanding the molecular
milliseconds up to a second. In response to mechanisms of synaptic release, we can explain
these depolarizations, you can also observe two how PPF and PPD can occur at the same synapse.
EPSPs. Depending on the time between the Recall that increased Ca2+ concentration is an
pulses (called the interevent interval, or IEI) important pre-synaptic intracellular signal that
you may see that the second pulse is a different allows for vesicular fusion and neurotransmitter
amplitude than the first. Dividing the amplitude release (see section 5.2 for more details).
of the second EPSP by the amplitude of the first Generally, pre-synaptic Ca2+ enters through
EPSP gives us a value called the paired pulse voltage-gated calcium channels (VGCCs) that
ratio (PPR). If the amplitude of the second pulse open during depolarization. Delivering a single
is increased relative to the first pulse (PPR > pulse causes some Ca2+ entry, but giving two
1), this is described as a PPF, whereas if the pulses, one right after another, allows for more
amplitude in response to the second pulse is robust activation of the VGCCs thus increasing
smaller than the first (PPR < 1), this is PPD. Both the intracellular Ca2+ greatly, leading to more
of these plasticity phenomena can be observed neurotransmitter release.
13-23
Paired pulse ratio
20
1.5
1.25 40
1
.75
100
20 40 60 80 100
Interevent interval (ms)
Figure 13.22 Paired pulse ratio an electrophysiological

measure of short term plasticity.
PPD can also be accounted for by looking

at the localization of vesicles in the axon terminal.
The readily-releasable pool are the vesicles that are
close to the inside of the cell membrane. During a
depolarization of the terminal, these vesicles are the
first ones to fuse. However, the readily-releasable pool
of vesicles can get depleted. On the second pulse,
there may be a small number of vesicles remaining
because vesicles need to be refilled before they
can be released, which makes the amplitude of the
second pulse small compared to the first. This is an
explanation for paired-pulse depression.
13-24
13.5 Disorders of memory
Alzheimer’s disease older than 65 and nearly a third older of people
In 1907, Dr. Alois Alzheimer described older than 85 has AD.
one of his patients, a 50-year old woman named AD is divided into two categories, familial
Auguste Deter, whose symptoms included and sporadic. Familial AD is diagnosed when
profound cognitive impairment, memory deficits, a person is in their 50s or 60s, and is strongly
and delusions. After Deter’s death, post-mortem influenced by genetic risk factors. This form of AD
analysis of her brain revealed anomalies: only makes up about 10% of cases. Sporadic
degenerating neurons that contained atypical AD is by far more common than familial AD, and
tangles and deposits scattered between cells. is believed to be caused by a combination of
These reports were the first of a disease we now old age and environmental factors in addition to
call Alzheimer’s disease (AD). It is an irreversible, genetic risk factors.
slowly progressing neurodegenerative condition Several genetic risk factors are linked
that leads to deficits in thinking, behavior, and to AD risk. Apolipoprotein epsilon4 (ApoE4)
memory loss. Specifically, declarative memory is the greatest genetic risk factor identified,
is the first form of memory loss observed in AD where individuals who are homozygous for the
patients. As the disease progresses, procedural e4 polymorphism have a 12-times higher risk
memory loss becomes more apparent. of developing AD than people with the more
AD is a devastating disease that accounts common e3 variant. Additionally, mutations in
for 60-80% of all cases of dementia and is the genes like amyloid-precursor protein (APP),
sixth leading cause of death in the United States. presenilin-1 (PSEN1) presenilin-2 (PSEN2), and
As for prevalence, approximately 10% of people triggering receptors expressed on myeloid cells
Healthy Alzheimer’s disease
Cortex Cortical
atrophy Ventricular
enlargement
Hippocampal
shrinkage
Hippocampus Entorhinal
cortex
Figure 13.23 Gross anatomical changes observed in the brain of a patient with Alzheimer’s disease.
13-25
2 (TREM2) are all associated with higher risk of levels of acetylcholine. Unfortunately, these
developing AD. compounds show only short-term benefits for
To this day, only post-mortem analysis cognitive function, and these therapeutic effects
can conclusively diagnose someone with AD. subside over time.
As expected, this raises many issues in terms Pathologically, AD is characterized by
of treating these patients. Currently, physicians the extracellular accumulation of amyloid-
diagnose a patient with AD based on the beta plaques (Aβ) and intracellular
symptoms they presented with. However, new hyperphosphorylated neurofibrillary tau-
techniques to make more accurate diagnoses tangles (NFT).
are emerging, including identifying the presence The amyloid cascade hypothesis,
of biomarkers from blood samples, certain originally proposed in 1992, has become the
functional characteristics as observed in PET leading theory in the field describing how AD
or fMRI imaging, and possibly even through eye develops. The hypothesis suggests that the main
exams! driving factor of AD is the deposition of Aβ in the
An early hypothesis proposed to explain brain, and this in turn leads to neurodegeneration
the neuronal loss and memory deficits observed via cell death, abnormal protein buildup, and
in AD is centered around changes in the signaling neuroinflammation. Aβ is produced from the
of acetylcholine. Early post-mortem analyses cleavage of amyloid-precursor protein (APP),
discovered that people with AD have profound an integral membrane protein expressed by
atrophy of the basal forebrain, an area which neurons. A class of secretase enzymes are
contains a large density of cholinergic neurons. responsible for the degradation of APP. When
The cholinergic hypothesis suggests that the alpha and gamma secretases degrade APP,
it is this loss of cholinergic neurons and the the resulting Aβ protein is likely to clump together
loss of acetylcholine signaling that is the main in unpredictable ways, leading to the formation
pathological driver of AD. The theory is supported of Aβ plaques (pronounced “A beta”). These
by the idea that acetylcholine plays an important plaques can cause neuronal death and lead to
role in learning and memory. Three of the four FDA the cognitive deficits observed in AD patients.
approved drugs for AD are acetylcholinesterase Two major genetic risk factors for AD, presenilin
(AChE) inhibitors, drugs that act to increase 1 and 2, are mutations of the gamma secretase
Beta-amyloid
Beta-amyloid plaque
APP
Secretase
Figure 13.24 Amyloid precursor protein is processed by a secretase enzyme, resulting in beta amyoid,
which may accumulate and form plaques in the extracellular space.
13-26
that leads to increased APP cleavage. hyperphosphorylated tau and neurofibrillary
Therapies are being developed to target tangles (NFTs) are also potential culprits in
and control the Aβ protein to mitigate AD disease progression. NFTs are an intracellular
symptoms. Recently an antibody-based drug has pathological marker of AD and correlate strongly
been approved by the FDA. This groundbreaking with cognitive deficits in AD. Tau protein is the
drug is unique from those traditionally prescribed major microtubule-associate protein (MAP) of
because it directly targets Aβ. mature neurons, and helps to function to maintain
However, the amyloid-cascade hypothesis cellular morphology. Excess phosphorylation
does not tell the whole story. For one, there are of this protein causes tau to accumulate inside
patients who carry a heavy Aβ load but present no the cell, leading to neuronal dysfunction and cell
clinical symptoms of AD. More so, in mouse models death. The presence of Aβ increases the levels of
with APP mutations, they develop significant Aβ the tau, and vice versa, adding to the complexity
plaques, but have no accumulation of tau (see and difficulty of treating AD. Tau pathology is also
below) and no significant neurodegeneration. observed in other neurodegenerative diseases
Additionally, there have been several drugs such as frontotemporal lobe dementia and
targeting Aβ that have failed in human trials. Parkinson’s disease.
While these amyloid plaques seem Although most discussion of AD revolves
to be the primary driving factor of AD, around plaques and tangles, it is well known that a
Stabilized
Healthy neuron
Microtubules
Destabilized
Tau tangles
Destabilized
Alzheimer’s neuron
Microtubules
Tau tangles
Figure 13.25 Tau protein is used in stabilization of microtubules.
13-27
cacophony of pathological markers are also seen confabulate as a compensatory mechanism to
in AD, including neuroinflammation, oxidative make up for their retrograde amnesia.
stress, blood-brain barrier dysfunction, heavy Destruction of both neurons and glia are
metal dysregulation, mitochondrial impairment, seen in the brains of people with Korsakoff’s
and many more. syndrome. As a result of this cell loss, there is
often shrinkage of the cortex, thalamus, the
Korsakoff’s syndrome hippocampus, cerebellum, and the mammillary
Korsakoff’s syndrome is a disorder bodies, paired structures located at the ventral
resulting from a severe deficiency of thiamine, surface of the brain close to the brain stem,
an essential vitamin that functions in metabolic themselves part of the limbic system.
processes. Dietary thiamine is found in whole Korsakoff’s syndrome can be treated by
grains, legumes such as beans and peas, as giving thiamine supplements and eliminating
well as some meats and fishes. Healthy people alcohol consumption. If treated within days after
with a well-balanced diet get sufficient thiamine, the onset of brain damage, people are expected
however gastrointestinal illnesses can cause to make a complete recovery. However, one of the
an inability to absorb thiamine properly. Chronic major challenges is making a proper diagnosis,
alcohol misuse also impairs the body’s ability since the symptoms of Korsakoff’s syndrome
to take up thiamine, and is often the cause of present similarly to other disorders.
Korsakoff’s syndrome.
People with Korsakoff’s syndrome Traumatic brain injury
experience both retrograde and anterograde A sudden blow to the head is likely to produce
amnesia, as well as severely impaired short- a traumatic brain injury (TBI). TBIs are the
term memory. The patients may experience a most common form of brain damage, with about
very strange behavior called confabulation, 2.88 million Americans in 2014 with a TBI-related
which is the fabrication of false memories emergency department visit, hospitalization,
ranging from subtle to wildly fantastical. People or death. People are exposed to these injuries
who confabulate do not
consciously recognize that Visual task Auditory task
their statements are untrue,
100
and are not intentionally trying
Control
% correct responses
to deceive others, which is why Alcoholic

it is sometimes called “honest Korsakoff’s
lying”. Generally, confabulation
only happens as a person
90
is trying to recall recent Increasing stimulus Increasing stimulus
autobiographical memories, duration duration
while their semantic and
procedural memories are less Figure 13.26 On a delayed-response task, a measure of short term
susceptible to confabulation. memory, patients with Korsakoff’s perform significantly worse than
Scientists suggest that people either a control population or a similar group of alcoholics.
13-28
regularly, such as in automobile accidents, falls, as microglial activation, axonal stretching, and
high-contact sports, occupational hazards such elevated levels of immune signaling molecules.
as in construction or military deployment, among People with repeat head injuries may also
many others. A concussion is a mild form of experience some memory loss. It is suggested
a TBI. Some of the common symptoms that that the damage to the brain creates an abnormal
people experience shortly after experiencing a cellular environment that interferes with the
TBI include double-vision, headache, dizziness, reverberation processes that are normally
nausea and vomiting, and loss of consciousness, important for solidifying memories. Additionally,
which are common symptoms in concussions as TBI decreases hippocampal neurogenesis, which
well. is likely to impair the formation of declarative
Usually in a traumatic brain injury, there memories.
are two simultaneous insults: the coup, which is
the injury when the brain hits the inside of the
Savant syndrome
skull closest to the external force. Shortly after,
Savants are people with “islands
the contrecoup happens, which is the injury
of genius,” knowledge in extreme
when the brain recoils backwards and hits the
specializations, such as ability to calculate
interior surface of the skull opposite of the cause
large prime numbers, identify the specific
of the insult. Following these injuries, there is a
day of the week for any date, or recall
widespread inflammatory response that changes
sports trivia. Many savants have a passion
cellular activity in numerous complex ways, such
for creative endeavors, such as in the
visual arts or musical performance. About
Coup injury Contrecoup
injury 20% of savants demonstrate extraordinary
memory. The prevalence of savants in the
general population is exceedingly low, but
about 1 in 10 autistic people demonstrate
some expression of savant skills.
While most savants are born with these
skills, some acquire them as a result of a
head injury. Orlando Serrell, after losing
consciousness in a baseball accident,
developed a complete autobiographical
memory, able to remember where he was
and exactly what he was doing on any
given date after his injury. Following a
diving accident, Derek Amato developed
prodigious musical talents despite never
Fixed object having taken lessons, improvising on the
piano as if playing through procedural
Figure 13.27 TBI is often characterized by a pair memory.
of injuries, the coup and the contrecoup injury.
13-29
One of the biggest difficulties is that
TBI is very different from case to case, making
development of new therapeutic strategies
challenging. Currently, the best treatment for TBI
is rest. There is still debate about the types of
medications that can help best improve outcomes,
psychostimulants and antidepressants being the
most common classes of drugs used in TBI.
DePaul University.
13-30
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13-31
14-1
Editor: Sandra Virtue, PhD (DePaul University)
A common misconception among non- than the other. We describe these features as
scientists, popularized by the media and online being lateralized. Many different functions have
quizzes, is that analytic people are “left brained” a slight preference in lateralization: for example,
while the creatives among us are “right brained” the right hemisphere seems slightly better at
(Chapter 1). Modern studies have concluded making judgments about the duration of visible
repeatedly that correlating brain function with stimuli or processing of low-frequency musical
behavior on this broad level is not this simple. stimuli. Keep in mind, the left hemisphere can
Both hemispheres of the brain are capable also perform these functions, just not quite as
of carrying out the same essential functions: well as the right can.
processing sensory and perception information, One heavily-lateralized function is
motor communication to the body, and the storage language: for most people, the production and
and retrieval of memory. comprehension of language is dominated by
However, there are some features that structures in the left hemisphere of the brain. This
are slightly more focused in one hemisphere chapter deals with these particular functions.
Chapter 14 outline
14.1 Lateralization
14.2 Language
14.1 Lateralization
Almost all mammals are bilaterally The brain’s two hemispheres are connected
symmetrical, with a left half that is more or less by white matter tracts which allow the two halves
a mirror image of the right half. The internal to communicate. The largest interhemispheric
organs, however, often tell a different story. We white matter tract is the corpus callosum, which
have a single stomach, liver, and heart, none of is made up of 200-250 million axons. If you held a
which are symmetrical. Even paired organs like human brain and separated the two hemispheres
the lungs or kidneys, are slightly asymmetrical. dorsally along the longitudinal fissure, you would
The brain can most accurately be thought of as be able to see the fibers of the corpus callosum
a pair of intimately-connected organs with subtle holding the two halves together. The corpus
differences in function. callosum is about 10 cm (~4 inches) long from
14-2
anterior to posterior, and the middle part of the One of their early experiments presented healthy
structure forms the dorsal-most roof of the lateral cats with two different boxes, only one of which
ventricles. contained food. An eyepatch was placed over
In addition to the corpus callosum, there one of the cat’s eyes, and the cat was free to paw
are a handful of other white matter tracts that at one of the boxes, which if chosen correctly,
allow the hemispheres to communicate. The would yield the food reward. At first, as expected,
much-smaller anterior commissure is a tenth of the cat would choose from the boxes at random,
the thickness of the corpus callosum, connects obtaining the food reward 50% of the time. Over
the two temporal lobes, and conveys important multiple trials, as the cat began to learn which box
limbic information such as memory and emotion. held the food, the success rate rose to picking
The hippocampal commissure is one of the the rewarded box 100% of the time. When the
outputs of the hippocampus that connects the eyepatch was then moved to the other eye, the
structures in the left and right hemispheres. cat performed the task correctly 100% of the time,
These small white matter tracts are often used as reliably picking the box associated with food.
points of reference in imaging studies or surgical Then, Myers and Sperry performed a
dissection. two different surgical procedures on the cats.
A pair of researchers, Drs. Ronald Myers One severed the optic chiasm, which kept
and Roger Sperry, were very curious about visual information in the ipsilateral hemisphere.
these pathways of communication between the This ensured that when wearing the eye patch,
two hemispheres. In the 1950’s, they wanted to visual information does not cross into both
understand how information from one visual field hemispheres. The other procedure to severed
gets conveyed into the opposite hemisphere of the their corpus callosum, a process called a
brain. To answer the question of interhemispheric corpus callosotomy (or commissurotomy),
transfer, they conducted experiments in cats. which limited interhemispheric transfer after
visual cortex processing. Between these two
interventions, there were four groups
of cats: Fully intact, optic chiasm
cut, corpus callosum cut, and the
experimental group with both optic
chiasm and corpus callosum cut..
The box-selection behavioral
experiment was then repeated. As with
the intact cats, when the eyepatch was
placed over one eye, the experimental
cats (both chiasm and corpus callosum
severed) initially guessed at the
boxes, getting the reward 50% of the
Figure 14.1 The corpus callosum, indicated in yellow with time. Again, as before, these animals
red arrow, in a coronal slice (left) and seen from the top improved their performance over
when both hemispheres are gently pulled apart (right). repeated trials, eventually getting the
14-3
the optic chiasm intact, the visual
information made their way into both
hemispheres through the optic nerve.
Myers and Sperry then
extended their research to humans.
100% 100%
Success rate
Sometimes, commissurotomy is
Controls suggested for younger patients with
50% 50%
drug-resistant epilepsy. Grand mal
0% 0%
seizures are often characterized by
Trials
uncontrolled electrical activity in one
hemisphere, which then crosses
Success rate
100% 100%
the corpus callosum to the other
Experimental 50% 50% hemisphere before “bouncing back”
0% 0% to the original hemisphere. During
the procedure, the surgeon cuts the
Figure 14.2 Myers and Sperry demonstrated that each corpus callosum, and in doing so,
hemisphere is capable of learning and storing memories keeps the atypical electrical activity
independently. isolated in one hemisphere. Patients
have significantly fewer and less
reward every time. However, after the eyepatch severe seizures following recovery
was switched from one eye to the other, these from the operation.
cats essentially had to “start over” with their People who have had this surgery
learning: they picked the rewarded box only 50% are sometimes called split-brain patients, a
of the time, improving to 100% over trials. population of patients who were extensively
Because of the surgical procedures, the visual
Clinical connection: Agenesis of the corpus
information and associated reward memory
callosum
in one hemisphere never made it to the other
In a handful of rare cases, people can be
half of the brain - a failure of interhemispheric
born without a corpus callosum, a condition called
transfer.
agenesis of the corpus callosum (ACC). Some
The two other control groups
people with ACC develop atypically, experiencing
immediately performed at 100% after the
seizures and poor motor control or coordination.
eyepatch was switched over, just as well as
An estimated one-fourth of people diagnosed with
the fully intact cats. When the optic chiasm
ACC after birth have some intellectual disability,
was severed with the corpus callosum
but most have typical levels of intelligence. They
intact, the visual information remained in the
may have subtle abnormal developmental traits,
ipsilateral hemisphere, but after processing in
such as a difficulty with processing common
V1, that information passed over the corpus
social cues (as seen in autism). Notably, the real-
callosum to the contralateral hemisphere.
life savant who served as the inspiration for the
When the corpus callosum was severed with
movie Rain Man was born with ACC.
14-4
studied by Dr. Michael Gazzaniga.. is then placed in their right hand. As the patient
Overwhelmingly, split-brain patients are healthy feels that object, tactile information such as its
with no significant changes in intelligence and no hardness, diameter, and temperature, ascends
dramatic changes in personality. However, some contralaterally into the left somatosensory cortex
of them do experience deficits in memory and (chapter 8). After the object is removed from their
concentration. hand, the patient is asked to feel blindly through a
Among split-brain patients, very unique collection of objects, all hidden behind the screen,
behavioral and cognitive deficits can be observed and find a matching object. When doing this task
under specific experimental circumstances. with the right hand, they would be successful in
The baseline test begins by briefly showing the selecting an apple (because the motor system
patient some visual stimulus, such as a picture is crossed). However, when the left hand was
of a donut, only in their right visual field, which now tasked with reaching behind the screen
gets represented in the left visual cortex (refer to select a matching object, they would not be
back to chapter 7.2 for a reminder of the circuitry able to know which object to pick up because
of the visual system). When asked what the this information goes to the right somatosensory
patient had seen, they would report “a donut,” cortex (which has no knowledge of the apple).
just as any typical person would (because the left From these data, the researchers concluded that
hemisphere is highly involved in language and each hemisphere is independently capable of
enables the person to report the object verbally). receiving their own sets of somatosensory inputs
In a second experiment, both of the
patient’s hands are placed on a table hidden Left Right
behind a screen. An object, such as an apple, hemisphere hemisphere
Se
or
ns
ot
or
M
Figure 14.3 Experimental setup for studying

interhemispheric transfer of visual information
in humans (left). After fixation on the dot in the
Left hand Right hand
center of the visual field, the stimuli (right) are
flashed briefly, and the patient is asked the either Figure 14.4 In split-brain patients, when an apple is
name the item observed, or reach behind the placed in the right hand, that information ascends
screen and select a matching object. contralaterally but cannot cross hemispheres.
14-5
and storing their own memories. Without an For most people, who have their corpus
intact corpus callosum, the two hemispheres are callosum intact, information is transferred rapidly
unable to share that knowledge, so the sensory between hemispheres. So, when a spoon is
and memory information that reaches the left shown to our right brain, the left brain learns that
hemisphere isn’t capable of reaching the right information as well, which is why we would be
hemisphere, which controls the left hand - so the able to select a matching object with our right
left hand is clueless to the object placed in the hand.
right hand. Myers and Sperry’s human studies
In the next step of the experiment, a noted an interesting difference in the ability of
different visual stimulus, like a picture of a spoon, split-brain patients to respond verbally. When
is presented to the left visual field, which is the stimulus was sent into the left hemisphere,
initially sent to the right half of the brain. When either a visual stimulus in the right visual field or
asked what they saw, they might say “nothing” an object placed in the right hand, the patients
or “I don’t know.” (because the right hemisphere were able to verbalize what they either saw or
is not specialized for language and the person is felt. But, when the stimulus was represented
not able to report the object verbally). But, when in the right hemisphere, they couldn’t. Their
the patient is asked to reach behind the screen conclusion was that the left hemisphere is much
with their left hand, they could successfully better equipped for language-related functions
select a spoon! (Left hand is controlled by the compared to the right hemisphere. As it turns
right brain, which has knowledge of the spoon.) out, language comprehension and production is
Their right hand, however, couldn’t correctly pick heavily lateralized to the left hemisphere. For his
a matching object (since the left brain does not work regarding the “effects of disconnecting the
have the information about the spoon). Again, cerebral hemispheres”, Dr. Sperry earned the
these results demonstrate that each hemisphere 1981 Nobel Prize.
is capable of receiving their own contralateral
sensory information and storing their own sets of
memory.
14-6
14.2 Language
Language is one of Homo sapiens’ greatest inappropriate deviation from these rules can
intellectual evolutionary accomplishments. Using change the meaning of the sentence dramatically.
language, we are able to communicate very Semantics refers to the understanding
complex concepts, such as survival instructions of meaning, especially the meaning of words in
(Don’t eat those berries because they taste relationship to one another in a phrase, sentence,
weird and you’ll get sick) or a shared belief in the or paragraph. Extracting meaning from statements
existence of complex stories (Hang stockings by not meant to be taken literally (such as a hungry
the chimney and you’ll get presents if you were person exclaiming “I’m so hungry, I could eat a
good). Language, when used in these ways, has horse!”) and identification of the meaning of a
a powerful influence on behavior, and modern word under two different contexts (such as in the
humans rely heavily on language in every aspect sentence “I held a nail between my fingers, but
of society. when I swung the hammer, I hit my nail instead.”)
fall under the category of semantics.
Components of language
Speech pathology experts have identified Brain structures involved with language
at least four distinct components for describing Whereas the left and right hemispheres
different aspects of language. The most granular of the brain are mostly symmetrical, one of the
unit is the phoneme, which is an individual sound biggest asymmetries is related to the structures
that generally has no meaning on its own. For responsible for language. Myers and Sperry
example, the word map can be split into three observed that split-brain people can verbally
phonemes, “mm”, the short “/ă/”, and “p” sound. report observations made with the left brain,
The next larger unit of language is the while having difficulty when information is stored
morpheme, which is a combination of phonemes. by their right brain. This suggests that the left
Morphemes are capable of conveying an idea, hemisphere is dominant for language functions.
such as “cat”. Suffixes such as “-s” and “-ing” It is estimated that about 90% of right hand-
also convey ideas (plural and verbs in action, dominant people and about 50% of left hand-
respectively) are also considered morphemes. dominant people use their left hemisphere for
The syntax represents the next higher language related functions.
level of language, which is the information However, this does not mean that the other
conveyed when words are combined in order hemisphere does not contribute to language. The
to produce meaning at the level of phrases and right hemisphere, for example, shows activation
sentences. For example, a statement such as during the use of nonliteral language, such as in
“He gave a gift to his brother” contains syntactic metaphor production or irony comprehension.
information identical to “He gave his brother a In addition to the split-brain patient case
gift”, even though the organization is different. studies, there are several other significant pieces
The grammatical rules of many languages tell of evidence to support left hemispheric dominance
us the order of nouns, verbs, and objects, and for language.
14-7
into the internal carotid artery, the drug
gets delivered into just one hemisphere
of the brain with little leakage into the
other. When the anesthesia perfuses
through the left brain, their right hand
loses muscle tone and their fingers will
ACA stop moving (remember the contralateral
MCA organization of the motor control system,
PCA
chapter 10.) And, if language is lateralized
Figure 14.5 Areas of the cortex that receive blood in this hemisphere as it is for most people,
flow from specific arteries (left). The middle cerebral they will also be unable to count during
artery (MCA) provides perfusion to frontal, parietal, and this time. Within seconds, the anesthesia
temporal areas that are important for language. CT scan is cleared from the brain, and the wiggling
of a patient after a stroke of the MCA, showing loss of and counting resume. If the patient is right
brain tissue (red arrow, right). hemisphere dominant for language, then
they will be able to count, even though
People with left hemisphere lesions may the fingers stop moving. The procedure is then
lose their language capacities. A stroke of the left repeated while the anesthetic is perfused into the
middle cerebral artery often leads to a variety of other hemisphere.
language related deficits. Unfortunately, similar The Wada test, because of its invasive
injuries sometimes happen after brain surgery, nature and occasional side effects (pain,
traumatic brain injury, or brain infections, also infection, and seizure or stroke in very rare
resulting in language deficits when localized to cases), is used less frequently as functional
the left hemisphere. brain imaging methods have become cheaper
Experimental methods have allowed and more available through the 2000s. The fMRI
researchers to study the lateralization of language is a preferred test of hemispheric dominance.
without causing any permanent damage. The To conduct these tests, a person is put into the
Wada test is the most reliable method by which imaging machine, then asked to perform a series
hemispheric lateralization of language can be of language tests, such as listing several items
determined. Named for the Japanese-born of a given category, or listening to a conversation
neurosurgeon Jun Wada, the test is a presurgical in preparation for follow-up questions. During this
assessment to minimize the risk of a person losing process, the fMRI informs the medical team about
their language capacity in the process of brain which half of the brain shows greater activity
surgery. The protocol begins with the surgical during the language tests. These behavioral tests
team asking the patient to hold up both hands, have been found to be as accurate as the Wada
wiggling their fingers, while counting. The patient test in determining lateralization of language
then receives an intravenous infusion of sodium functions.
amytal, a GABA receptor positive allosteric Across the language dominant
modulator that acts as an anesthetic. When infused hemisphere, there are a few brain regions that
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Figure 14.6 Non-invasive fMRI scans demonstrate that left hemisphere (negative x) brain areas
increase in blood flow compared to right hemisphere (positive x) during the performance of language
tasks. Warmer colors indicate increases in blood flow, while cooler colors represent decreases.
contribute significantly to language functions. secrets. Because of this, the staff at the hospital
When something goes wrong with these areas, called him Patient Tan.
a person may develop aphasia, a language When Patient Tan died, the French
disorder. It is estimated that about 180,000 new physician Paul Broca performed an autopsy on
cases of aphasia are diagnosed in the United the brain. Broca discovered a huge lesion about
States annually. Stroke is a common cause of the size of a “chicken’s egg” in the left hemisphere,
aphasia, but other neurological insults such as just dorsal of the lateral fissure in the frontal
head trauma, traumatic brain injury, or subdural lobe. Soon after, Broca performed autopsies on
hematoma can induce aphasia. Just like nearly the brains of seven other patients with similar
everything in biology, there is a wide range of language difficulties, all with the same prominent
severity, with some cases being very minor and injury to this portion of their frontal lobe. Because
other cases being much more severe. Speech of the work that Broca did in correlating structure
therapy can help a patient recover from aphasia, with function, the posterior IFG came to be called
and this progressive restoration of function is a Broca’s area.
demonstration of the brain’s capacity for plasticity
and remodeling.
Expressive (or non-fluent; or Broca’s)

aphasia
One of the first language-related cortical
Anterior
structures identified is the posterior inferior

frontal gyrus (IFG). Deficits in this area lead to a
difficulty with the production of language.
In the 1860’s, a patient named Louis
Victor Lebourgne had a very unusual condition:
he could only speak one syllable. For Lebourgne,
the syllable “tan” meant everything, from “yes” to
“no” to “hat” to “thirty-four”. Lebourgne would say Figure 14.7 The posterior IFG, or Broca’s
“tan” while gesturing emphatically, scream “TAN area (labeled as 45 and 44; purple and yellow)
TAN!!” when angry, and whisper “tan” when telling contribute to language production.
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Today, we understand that a localized
injury to the IFG produces a form of aphasia
called expressive aphasia (also called non-
fluent aphasia or Broca’s aphasia). These
patients have difficulty expressing themselves,
only speaking in short, effortful phrases, using
just nouns and verbs while omitting tenses,
conjunctions, and prepositions. They speak
haltingly, sometimes filling the silences in their
sentences with filler phrases. The patients are
profoundly aware of their deficit, leading to Figure 14.8 The superior temporal gyrus, or
overwhelming frustration with their inability to Wernicke’s area (red), contributes to language
communicate. They know what they want to comprehension.
say, but often can’t get it out. Interestingly, these
patients do not have any significant impairment dramatic impairments in comprehension. This
of comprehension. language disorder is receptive aphasia (or
Patients with IFG injury show similar fluent aphasia, or Wernicke’s aphasia.)
expressive deficits regardless of the modality While talking, people with receptive
of their language. For example, when asked to aphasia may create new meaningless words they
write, they write slowly, using mostly nouns and are unaware of, a symptom called paraphasia.
verbs. Alternatively, patients who use American These words could be a mispronunciation of a
Sign Language also lose grammatical syntax and word, perhaps sounding like the jumbling of
communicate slowly when signing! syllables. They can happen at the level of the
phoneme or morpheme, such as in nonwords
Receptive ( or fluent; or Wernicke’s) such as “emchurch” or “plehzd”. They also appear
aphasia at the level of syntax, when a person substitutes
A different brain structure, called the a word incorrectly for another, as in the sentence
superior temporal gyrus is linked to language “But I seem to be table you correctly, sir.”
comprehension. This area is sometimes also Sometimes, they experience a difficulty
called Wernicke’s area, named for the German with recalling words, a symptom called anomia.
physician named Carl Wernicke, who studied a This happens in the middle of a sentence, and
group of patients with a different form of aphasia may be difficult to catch in casual conversation,
than Broca’s. These patients had no deficits in since they will often use vague language (“stuff”
the production of speech, but the words they or “things”) or use several words in a roundabout
used were very disorganized. They could speak fashion to describe what they are trying to say, a
complete sentences fluently, but their speech behavior called circumlocution (“red, it’s green,
contained almost no substantial semantic content. and yellow means be cautious, to keep people
Unlike Broca’s patients, Wernicke’s patients had safe” instead of “traffic light.”)
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Conduction aphasia deficits, usually only being able to communicate
Early theories suggested that using only single words or grunts. They also
communication between the STG and the IFG struggle with repeating words spoken to them.
is important for healthy language production and Following a major stroke to the left middle cerebral
comprehension. Anatomically, a band of white artery, global aphasia may first present, possibly
matter called the arcuate fasciculus spans lessening in severity as the brain heals.
these areas, originating in STG and terminating If their other hemisphere is spared, patients
in the IFG. When this structure is injured, people with global aphasia can learn to communicate
develop some difficulty with repeating language using pantomime or facial expressions.
they hear, a disorder called conduction aphasia.
Generally, these patients display paraphasias The Wernicke-Geschwind model
when asked to repeat multisyllabic words, often From case studies of injuries leading to
switching phonemes around in a single word. aphasia, a few cortical structures emerge as being
These patients have no significant deficits major contributors to language: the IFG, STG, and
in language production or comprehension, the arcuate fasciculus that connects the two. Two
presumably because their IFG and STG are still neurologists, Carl Wernicke and later Norman
intact and healthy. Conduction aphasia is less Geschwind, proposed the Wernicke-Geschwind
severe than expressive or receptive aphasia. model, which suggests that information is passed
along through language structures in a linear
pathway, and each section is responsible for a
different aspect of language.
The model begins with the simple scenario:
An interviewer is asking you a question, and you
answer. First, the sound information arrives into
A1, the primary auditor y cortex (see chapter 8
for more details). From there, that information
is processed by the STG (Wernicke’s area),
which then takes meaning out of those sounds.
Then, that information travels across the arcuate
fasciculus. Then, that information arrives at
the IFG (Broca’s area), where neurons carry
Figure 14.9 The arcuate fasciculus (colored) is
information related to the planning of language,
a large white matter band that connects the two
such as coordinating the muscle movements
major language-related cortical structures.
that create the verbal response. Finally, those
signals arrive at the motor cortex, which is then
Global aphasia responsible for sending the descending signals to
Extensive brain damage to the left IFG, control the muscles required for speech (chapter
STG, and arcuate fasciculus may cause the most 10).
severe form of aphasia, global aphasia. Patients Another component of the model proposes
experience both expressive and receptive an explanation for the following situation: You read
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M1 M1
Arcuate Arcuate
fasciculus fasciculus
IFG STG IFG V1
Angular gyrus
A1 STG
Figure 14.10 The Wernicke-Geschwind model in auditory processing and responding suggests that
information signaling arrives into cortex through A1, travels through STG, IFG, then M1 (left). In a
reading and responding task, the model suggests that information signaling arrives into cortex through
V1, passes through circuits in the angular gyrus, then through STG, IFG, then M1 (right).
a question on a piece of paper, and answer the

question verbally. Visual information arrives into Clinical connection: Dyslexia
the V1, the primary visual cortex. The output of Affecting an estimated 7-20% of the
the visual cortices arrives at the angular gyrus, population, developmental dyslexia is a
a parietal lobe structure just posterior to the pronounced difficulty with identification of
STG. From here, the signal travels through phonemes in printed words and a related difficulty
STG and continues through motor cortex, with reading unfamiliar words. Challenges appear
following the same pathway described above. in preschool, when learning to decode phonemes
This Wernicke-Geschwind model was is an expected developmental milestone. These
initially helpful for providing a framework for difficulties are not a result of intellectual disability.
understanding language. But in modern times, However, dyslexia is not explicitly a language
we regard it as an oversimplified and outdated disorder, since patients generally have no
explanation of a complex behavior. Sometimes difficulties with comprehension of spoken word.
the model fails to accurately predict the nature Genetic factors contribute to risk, but a
of a patient’s aphasia even if the locus of a lesion definitive neural mechanism behind dyslexia is still
has been precisely identified. Furthermore, unknown. There are differences in the anatomy
some injuries to brain areas outside of those and activity of the cerebellum and some atypical
structures identified in the model produce lateralization in temporal, parietal, and occipital
aphasia. lobes, suggesting that perhaps some atypical
Modern research indicates that language communication from V1 to the language areas of
functions are not strictly localized as described the brain or memory of previously-learned words
by the Wernicke-Geschwind model. Instead, contribute to symptoms.
language is such a complex behavior, that the
interactions between these areas and more are
used in language.
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Cover art: https://pixabay.com/photos/call-calling-cell-cellphone-15828/
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Lim
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14.6 Wegrzyn M, Mertens M, Bien CG, Woermann FG and Labudda K (2019) Quantifying the Confidence in fMRI-Based
Language Lateralisation Through Laterality Index Deconstruction. Front. Neurol. 10:655. doi: 10.3389/fneur.2019.00655
14.7 https://upload.wikimedia.org/wikipedia/commons/c/ca/Broca%E2%80%99s_area_-_BA44_and_BA45.png
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DePaul University.
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15-1
Editor: Helena Ledmyr, PhD, INCF (Karolinska Institutet)
At the airport, you can observe people (surprise) while others may persist over years
experiencing a wide range of emotions: Sadness (vengefulness).
at seeing family members off, fear and anxiety for However, beyond this statement, it
those about to fly for the first time, love when a becomes very difficult to put a clear-cut definition
long-distance relationship is reunited, and anger on “emotion”. The difficulty with defining emotion
over unpredictable cancellations. arises because of the fluid nature of emotions:
Emotions are complex neurophysiological they exist on a spectrum, multiple emotions are
states that contribute to an internal feeling and experienced simultaneously, each emotion is
guide behavior. Some emotions are pleasant perceived by different people in unique ways, and
(joy), some are negative (disgust), and some are everyone has a slightly different interpretation
a mix of both (nostalgia). Some are short-lasting and understanding of an emotion.
The field of affective
neuroscience seeks to understand
the neural mechanisms that underlie
emotion. The field has expanded
with the help of functional
imaging methods like EEG
and fMRI, where changes
in brain activity can
be measured and
quantified as a person
experiences different
emotion-provoking
stimuli. Affective
neuroscientists work
to develop biology-
supported therapies
for disorders such
as depression, PTSD,
and addiction, which are
dysregulations of the emotions
of sadness, fear, and desire,
respectively.
Figure 15.1 An emotion wheel listing several related subtly different feelings.
15-2
Chapter 15 outline

Origins of emotion
One of the older theories about the origin emotion. According to the James-Lange theory
of emotion is based on the most common sense of emotion, and contrary to a common sense
interpretation of cause and effect. For example, understanding of the origin of emotion, the
imagine some noticeable emotional stimulus, such body’s physiological changes precede the onset
as encountering a hungry lion on the sidewalk. of an emotional response. For example, imagine
The logical cause and effect explanation suggests encountering that same hungry lion on the
that seeing the lion prompts the emotion of fear, sidewalk. The James-Lange theory tells us that
which then causes the sympathetic nervous the perception of the threat of being eaten causes
system “fight-or-flight” response (elevated heart the sympathetic nervous system response, and
rate and blood pressure, increased respiration, that these physiological changes trigger the onset
and cellular mobilization of energy). of fear.
In the 1880s, psychologist William Soon after, in the 1920s and 30s, two
James and physician Carl Lange independently physiologists named Walter Cannon and his
developed a new theory about the origin of doctoral student Philip Bard criticized the James-
Common sense James-Lange Cannon-Bard

interpretation interpretation interpretation
Stimulus Stimulus Stimulus
Emotional Physiological Physiological Emotional

response response response response
Physiological Emotional
response response
Figure 15.2 Three different theories about how an organism responds to some stimulus.
15-3
Lange theory. In one experiment, they surgically of epinephrine, onset of fever, or being in cold
removed the entire sympathetic nervous system temperatures may also trigger some physiological
from cats, destroying the nerves that regulate changes without causing a strong emotional
vascular dilation, the activity of liver enzymes, response.
and the reaction that causes the hair standing Based on their evidence opposing
on end. These cats were then put before a the James-Lange theory, Cannon and Bard
threatening aggressor. If the James-Lange theory developed an alternative explanation for the
was true, then the physiological changes should origin of emotions. According to the Cannon-Bard
precede the emotive response. However, the cats theory of emotion, the perception of an emotionally
exhibited the fear / aggression response (such as charged stimulus prompts simultaneous but
posturing, hissing, and clawing) even without an independent activation of both the autonomic
intact sympathetic nervous system. Relatedly, nervous system and the emotional response.
patients with spinal cord injuries have a similar The Cannon-Bard theory also draws
lack of autonomic inputs to the brain, but their attention to the neuroanatomical structures that
capacity for emotional responding is still intact. trigger the autonomic and emotional responses,
In a second criticism, Cannon and Bard with a particular focus on diencephalon structures
proposed that the physiological changes seen such as hypothalamus and thalamus. To
in sympathetic nervous system activity may localize the anatomy behind emotional signaling,
arise for a variety of reasons, not always for researchers performed a series of lesion
emotionally salient reasons. For example, experiments, systematically injuring different
intense exercise causes strong cardiorespiratory parts of the brain. To their surprise, when the
changes; however, we do not necessarily feel cortex of the cat was surgically separated from
a strong emotional state after this physiological the rest of the nervous system, a procedure
perturbation. Likewise, exogenous administration
Figure 15.3 Contrary to the James-Lange theory

of emotion, physical exercise produces a high Figure 15.4 Decorticated cats express sham rage
physiological state without always inducing an in response to harmless stimuli, suggesting that
emotional response. anger is kept under control by cortical inhibition.
15-4
called the decorticate preparation, the cats In 1939, two researchers named Heinrich
would exhibit a hyper-aggressive response to Kluver and Paul Bucy described a unique set
stimuli. For example, an innocuous touch of of emotional deficits in monkeys with bilateral
the tail would trigger violent clawing, biting, and temporal lobe removal, further providing evidence
hissing, behaviors which were described as of the neuroanatomy of emotion. These animals
sham rage. However, when they lesioned the fail to display fear or anger, even in the face of
thalamus, sham rage was no longer observed. life-threatening stimuli such as a large snake.
They concluded that rage (and other powerful They also display visual agnosia (the inability
emotions) is normally under inhibitory control by to recognize faces or objects visually), psychic
the cortex. blindness, hypersexuality, and hyperorality (an
Just years later, in 1937, American inappropriate fixation with using the mouth to
neuroanatomist James Papez (pronounced interact with surroundings, such as licking or eating
payps) ascribed emotional behavior to a particular nonfoods). Collectively, these sets of symptoms
series of brain structures. These structures, are called Kluver-Bucy syndrome. Although it is
collectively called the Papez circuit, consist of primarily an experimental manipulation observed
the hypothalamus, cingulate gyrus, thalamus, in monkeys, some human patients may develop
hippocampus, and more. Papez observed the condition, such in after brain surgery, stroke,
unusual aggression among animals with injury viral encephalitis, traumatic brain injury, and
to these structures, suggesting that emotional many others.
responding is distributed across many areas, A new angle to the origin of emotion was
rather than localized. (Notably missing from the proposed by Stanley Schachter and Jerome E.
Papez circuit structures is the amygdala, which Singer in 1962. They were interested in how the
was later added in a future revision in the 1950’s.) same physiological response can be attached to
Stimulus Thalamus Sensory cortex
Hippocampus Cingulate cortex Feeling
Anterior
Hypothalamus
thalamus
Physiological
response
Figure 15.5 The Papez circuit was an early neuroanatomical description of some structures (green)
involved in emotional processing and responding (purple).
15-5
Singer-Schachter two-
factor interpretation
Stimulus
Physiological Cognitive
response label
Emotional
response
Figure 15.6 In addition to a loss of fear, a Figure 15.7 The Singer-Schachter two-factor
macaque monkey with Kluver-Bucy syndrome theory of emotion suggests that both the
would display hyperorality. physiological response and a cognitive label
contributes to the emotional response.
two wildly different emotions - consider the rise
in heart rate and respiration that are associated research team (the confederate). For one set of
with encountering that lion (fear), or when you patients, the confederate would act “euphorically,”
receive wonderful news (elation), or when you jokingly playing trash-can basketball, making
make eye contact with your romantic partner paper airplanes, and hula-hooping, all the while
(love). According to their two-factor theory exclaiming how much fun they are having,
of emotion, people use a combination of the inviting the patient to play along. For another set
physiological response and a cognitive label to of patients, the confederate would act in anger,
determine the emotion that is most appropriate expressing irritation before eventually ripping up
for a given circumstance. The cognitive label the survey and storming out of the study.
comes from two parts. One is prior knowledge, When the patients were not told what
such as the thought processes “lions eat meat to expect from the epinephrine, they were
if they are hungry, so I should be afraid.” The more sensitive to the emotional responses
other part is observing environmental cues, such of the confederate. This demonstrated that
as “everyone around me is running away and environmental cues play a significant role in
screaming, so I should also be afraid.” determining emotion regardless of physiological
To test their theory, Schachter and state.
Singer administered epinephrine to patients.
Epinephrine is a hormone that produces the Faces in Emotion
physiological signs very similar to those observed Although best known for his theory on
in a sympathetic nervous system response: evolution, naturalist Charles Darwin published
elevation of heart rate, respiration, blood flow to prolifically about other topics in biology, ranging
muscles, and energy utilization. Then, the patient from botany, coral reefs, and even a treatise
is put into a waiting room with another “patient” on psychology. In this 1872 text, called The
- in actuality an undercover member of the Expression of Emotions in Man and Animals,
15-6
Moving forward into more modern times,
the American psychologist Paul Ekman expanded
on Darwin’s theory, distilling down the range of
human emotions to belonging in one of seven
basic categories of emotions: Anger, contempt,
disgust, fear, happiness, sadness, and surprise.
If the purpose of emotion was to communicate
pro-survival cues, then Ekman theorized that all
humans, regardless of culture, would use similar
facial expressions. To test this hypothesis, Ekman
visited a remote village in Papua New Guinea,
where he studied a population that is isolated
from any other known cultures. As predicted,
these people made the same facial responses in
reaction to various emotional circumstances. In
1972, Ekman published his theory of universal
facial expressions.
Part of Ekman’s research led their team
to develop a series of photographs of actors
portraying six major emotions. This Ekman 60
Figure 15.8 Charles Darwin suggested that faces (EK-60F) test has since been used to
emotional facial expressions are useful for assess facial emotional with fascinating results:
conveying survival cues, such as evoking People with major depressive disorder or
prosocial behaviors towards sad people (top) or borderline personality disorder have a lessened
avoiding angry animals (bottom). ability to detect happiness in others, seeing
emotional faces results in a similar emotion in the
Darwin suggested that similar emotional viewer, and people with dementia or Parkinson’s
responding is found across different cultures, and disease identify emotions as being less intense.
to some extent, even in nonhumans. In his view, Ekman’s research led them to develop
the main purpose of emotive expression is to the Facial Action Coding System (FACS), a
communicate survival cues between individuals: system that uses facial anatomy to differentiate
a relaxed expression conveys safety, while a the features that are characteristic of different
fearful expression promotes alertness, since expressions. For example, a feature of a happy
danger may be nearby. Darwin also suggested face is the flexing of the zygomaticus major and
that we gain survival information from non-human orbicularis oculi muscles, which produces an
behaviors, for example, a hissing snake or a upward turn of the corners of the mouth and a rising
snarling lion is an immediate threat that should of the cheeks. Other facial features, such as head
cause fear or other avoidance behaviors. movement, eye movement, and larger physical
15-7
Figure 15.9 Paul Ekman’s research in Papua New Guinea suggests that across cultures, humans use
similar facial muscle activity patterns to convey a universal set of emotions. Ekman also developed
anatomical definitions for describing specific emotions.
movements are also scored, and are also used

to help identify emotions. The FACS can be used
to formally describe why some smiles appear as
genuine (a Duchenne smile, with simultaneous
muscle action) while others look fake or forced (a
non-Duchenne smile, characterized by the turn of
the corners of the mouth without much change to
the top part of the face).
15-8
Emotions are one of the most holistic Of the forms of declarative memory (chapter
functions of the brain, incorporating neural 13), autobiographical memories more often
circuitry from across several different structures, have emotional content compared to semantic
ranging from the phylogenetically older to the most memories.
advanced frontal cortical areas. The structures of Amygdala lesions have been used as a
the Papez circuit are not a comprehensive list of last resort treatment for patients with temporal
brain structures involved in emotional processing lobe epilepsy or psychiatric conditions with
but offer a good starting place for describing the pathological and dangerous aggressiveness.
anatomy of emotion. These psychosurgery strategies have been
variably successful, but they often have high
Amygdala complication rates and upwards of a 4% mortality
A limbic structure called the amygdala rate. These treatments are rarely used today.
contributes heavily to processing the valence Deep brain stimulation may offer a less intrusive
of emotional experiences. Roughly the shape and therefore less risky therapeutic approach.
and size of an almond, the amygdala is part of Monkeys with amygdala lesions made
the temporal lobe. Generally, the amygdala is up the earliest descriptions of the emotional
subdivided into several nuclei, including the disruption condition later described as Kluver-
basolateral amygdala, central nucleus, and Bucy syndrome. These monkeys did not exhibit
cortical nucleus. the traditional fear response when presented with
As a temporal lobe structure, amygdala the hissing of a large snake. They also showed
is strongly implicated in emotional memory an absence of anger, such as when the animal is
formation. Emotional memories can be either exposed to provocative novel stimuli.
positive valence (such as the happiness you A useful nonhuman model for studying
may have experienced at a birthday party emotional learning is the fear conditioning
when younger) or negative valence (such as paradigm. In this test, a rodent is put into a cage.
childhood trauma or being teased as a child). Occasionally, an innocuous tone and light would
activate. Shortly after, an unpleasant foot-shock
would be delivered to the animal. Over time,
the healthy animal learns that the tone and light
precede the shock to the foot, and upon future
presentation of these stimuli, they will freeze. If
the amygdala is lesioned, however, they freeze
less, meaning they do not acquire the emotional
memory associated with the stimuli. This
paradigm is used as a model for post-traumatic
Figure 15.10 The amygdala (red) contribute to stress disorder (PTSD), a psychiatric condition
emotional processing. associated with the recurring recall of negative
memories.
15-9
Hypothalamus neurohormones. Instead, the axonal projections
One of the major output signaling of the magnocellular neurosecretory cells of the
pathways of the amygdala is the hypothalamus, hypothalamus run through the posterior pituitary,
an almond-shaped nervous system structure where the hormones are secreted into a special
found at the base of the brain. The hypothalamus anatomical feature called the hypophyseal
is often seen as the neural structure that initiates portal system, a series of leaky capillaries
endocrine responses in the rest of the body, densely wrapped around the area, allowing for the
such as hormone production. Several different hormones to easily diffuse into the bloodstream.
behaviors, ranging from homeostasis, hunger, There are predominantly two main hormones
and circadian regulation are modulated by released at the posterior pituitary.
hypothalamic signals. Oxytocin (OT) plays a significant role in
the development and maintenance of prosocial
behaviors, acts such as trust, compassion, and
empathy, all actions that enhance interpersonal
relationships. For example, increased blood levels
of OT is seen in new couples compared
Thalamus to unattached singles, and OT release
Hypothalamus
Infundibulum happens during orgasm, which may
Anterior pituitary
Posterior contribute to romantic attachment. OT
pituitary signaling increases dramatically during
childbirth and triggers milk letdown in
Figure 15.11 The hypothalamus is a brain structure lactation, which strengthens the mother-
that initiates hormonal changes through influencing the child relationship. Interestingly, while
pituitary gland. OT generally strengthens the social
bonds between people, it promotes
Pituitary gland antisocial behaviors against those not
Downstream from the hypothalamus perceived to be within one’s own social group.
is the pituitary gland, a pea-sized endocrine Disorders of the OT system are believed
organ that protrudes from the base of the brain. to contribute to autism spectrum disorder
It is strongly involved in the production and and psychopathy, two complex conditions
release of neurohormones, signaling molecules characterized partly by social impairment. Some
produced by nerve cells that travel throughout the studies have examined the therapeutic use of
bloodstream to influence the activity of several nasal OT for a variety of psychiatric conditions,
organs throughout the entire body. The pituitary but the studies have been unable to demonstrate
gland is subdivided into two regions with distinct strong clinical effects despite success in non-
anatomical and functional differences. human animal models.
Vasopressin (AVP; or antidiuretic
Posterior pituitary gland hormone, ADH) like OT, also contributes to social
The posterior pituitary gland (also called behaviors. Biochemically, AVP is very similar to
the neurohypophesis) does not synthesize any OT, as they are both nine amino acid peptides
15-10
differing by only two residues. AVP additionally Anterior pituitary
regulates osmolarity, increasing water retention The anterior pituitary (or the
by the kidneys, which returns the body from adenohypophesis) is capable of both
a hypertonic state back to homeostasis. AVP synthesizing and secreting a variety of
also constricts blood vessels, raising blood neurohormones, which contribute to several
pressure. AVP is also used therapeutically to functions such as the stress response, growth,
raise blood pressure for patients in shock and to sexual development, circadian rhythms, and
treat diabetes insipidus, a fluid dysregulation more. These hormones are collectively called the
disorder (unrelated to diabetes mellitus, the much trophic hormones. The neurosecretory cells of
more common blood glucose disease). the anterior pituitary are sensitive to signals from
the hypothalamus.
Posterior pituitary hormones
Releasing hormone Pituitary Target Effect

(from hypothalamus) hormone
Breasts Milk letdown

OT
Uterus Contractions
Kidneys Increased water retention

ADH
Circulatory system Constricts blood vessels
Anterior pituitary hormones
GHRH GH Somatic tissue Promotes

anabolism
CRH ACTH Adrenal glands Glucocorticoid production

(stress response)
LH Reproductive Sex hormone production

system
GnRH
FSH Reproductive Production of sperm and
system eggs
Thyroid Thyroid gland Promotes metabolism

Thyroid releasing stimulating
hormone hormone
Prolactin Mammary glands Milk production
Figure 15.12 The hypothalamus sends a variety of hormonal signals, which influence several different
physiological features.
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Within the anterior pituitary are cells Insula
called somatotrophs, which produce and The insula (or insular cortex) is the lobe
secrete growth hormone (GH). GH is a signal of the cortex buried deep within the lateral fissure.
that promotes anabolism, the buildup of larger Although not visible from a side view, the insula
molecules through biochemical reactions. is often considered to be the fifth lobe of the
Anabolic processes increase cellular repair and telencephalon. Early studies by Wilder Penfield
protein synthesis, which promote growth. Most of where he directly stimulated the brain during open
the time in the day, GH production is at a steady brain surgery led researchers to suggest that the
low level, but it increases at specific events, such insula contributes to interoception, detecting
as after meals or during slow wave sleep. The the internal state of the body and conveying that
biochemical signal from the hypothalamus is information for processing.
growth-hormone-releasing hormone (GHRH).
The anterior pituitary releases
adrenocorticotropic hormone (or ACTH). Once
ACTH is released into the bloodstream, it travels
to the adrenal cortices, a pair of organs that
sit on the anterior surface of the kidneys. Once
there, ACTH triggers production of cortisol, a
glucocorticoid hormone. Cortisol is best known
for its initiation of the stress response, which
is characterized by mild sympathetic nervous
system activity. ACTH is synthesized downstream Figure 15.13 The insular cortex is only visible in
from the hypothalamic signal corticotropin a cut-away view of the brain.
releasing hormone (CRH). The series of organs
that result in the stress response is called the In functional imaging studies, the insula is
hypothalamic-pituitary-adrenal axis, or the involved in the recall or many different emotional
HPA axis for short. stimuli, especially those emotions that have a
The anterior pituitary also synthesizes sensory component.
and releases the gonadotropins, hormones that Notably, the insula is strongly implicated
are important for regulation of puberty, sperm / in the emotion disgust. For example, a patient
egg production, the release of sex hormones by is placed in an fMRI scanner while breathing
the testes / ovaries, and menopause. The two through a mask, which allows the experimenters
main gonadotropins in humans are luteinizing to change the smells that are perceived. Patients
hormone (LH) and follicle-stimulating hormone are then given pleasant smells (such as passion
(FSH). These are produced in response to the fruit, pear, or mint), a neutral smell, or unpleasant
hypothalamic signal gonadotropin-releasing smells (like ethyl-mercaptan or isovaleric acid,
hormone. This signaling cascade is called the which smells like skunk or body odor, respectively).
hypothalamic-pituitary-gonadal axis, or the There is increased activity of the anterior insula
HPG axis. in response to the unpleasant smells but not the
pleasant smells.
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The insula also responds to social cues
related to disgust as well. When a patient in an
fMRI sees a video of a person smelling something
unpleasant and reacting with a “repulsed” face
(the closing of the nostrils and curling of the upper
lip), their anterior insula likewise increases in
activity just as if they had smelled it themselves.
In addition to sensory stimuli, feelings
of social repugnance (unwarranted violence,
murder) or moral disgust (incest) also increase
insula activity.
Atypical insula activity is implicated in
behavioral disorders. For example, insensitivity
to disgust can lead to squalor-dwelling conditions
(sometimes seen in excessive hoarding or late
cognitive decline), which puts those people at
heightened health risks due to regular exposure
to unsanitary conditions. Substance use
disorders, PTSD, and suicide attempts have all
been associated with atypical insula activity.
15-13
Fear / Anger threat is nearby, which helps initiate heightened

Nearly everyone has experienced the alertness and the appropriate fight-or-flight
prototypical fear response: Imagine reading a response.
book when you see a spider skittering along the
wall. Suddenly, you’ll feel your heart racing, your
breathing increase, dryness of your mouth, and
your palms sweating. You probably won’t notice
the dilation of your pupils or the change in liver
activity and digestion. This sympathetic nervous
system activity is downstream of being presented
with a fearful stimulus.
But upon closer inspection, it was no
spider at all - just an errant piece of brown fuzz
picked up by a draft. Within minutes, your body’s
physiology returns back to normal.
This anecdote points out a few important
features about the fear response. First, the
onset of the fear response is quick, and so is
the dissipation of the fear. Second, it is triggered Figure 15.14 The fear response is likely an
by exposure to a perceived threat, regardless of evolutionarily protective behavior, since it
whether the stimulus is a genuine threat or not (the provides social cues about dangers.
overwhelming majority of spiders are clinically
harmless to humans!). Third, the fear response is Patient SM
greatly modified by knowledge and experience - Patient SM is a notable case study of
an entomologist would recognize that the spider a person who does not experience the fear
is a harmless house spider and would, instead of response. Born with an extremely rare genetic
fear, display curiosity, interest, boredom, or other
condition called Urbach-Wiethe disease, Patient
emotions. On the other hand, someone who has SM progressively developed calcification in her
been bitten by a dangerous spider and sent to amygdala bilaterally, causing destruction and
the hospital when younger would have a much cell death. Like other people with Urbach-Wiethe
stronger physiological response. disease, she had no severe significant cognitive
Fear is likely the most evolutionarily deficits, except for the inability to experience fear.
ancient emotion, and is highly protective. When In one test, she was shown a variety of
encountering a hungry mountain lion, faces emotionally charged videos, then asked to rate
displaying the traits of fear (enlarged eyes, flared
the intensity of each clip with respect to different
nostrils, and a slightly open mouth accompanying emotions. SM found clips from America’s
a gasp) would signal to others nearby that a Funniest Home Videos to be just as funny as
15-14
the control patients, and she found the clips of
disgusting toilets to be just as repulsive. But, when
presented with clips depicting ghost hauntings or
suspenseful serial killers on the loose, SM rated
these stimuli as being non fearful.
Other studies challenged Patient SM with
more concrete threats. Researchers brought
SM to a pet store, where she asked to handle
the snakes. She was stopped by an employee Figure 15.15 Patient SM exhibit no physiological
before she put her hand into a tarantula cage fear response following presentation of typically
out of curiosity. The researchers also took her scary stimuli, such as snakes or a haunted house.
to the Waverly Hills Sanatorium haunted house,
Clinical connection: Plasmatoxmosis

Plasmatoxmosis is a disease caused
by infection of the parasite Toxoplasma gondii.
Plasmatoxmosis may cause symptoms
characteristic of a generic immune response,
such as fatigue, body aches, and fever. Some
people may be completely asymptomatic;
however, others experience severe side
effects like seizures or birth defects when an
infection happens during pregnancy.
T. gondii is only capable of reproducing
within cats, but the parasite has developed
a very unusual evolutionary adaptation that
permits propagation of the species, called the
manipulation hypothesis. Cats excrete T. Figure 15.16 A toxoplasma infection changes
gondii via feces, which is eaten by rats and the rodent fear response, causing them to
mice, where the parasites take up residence be less afraid of predators. At either point,
in their temporary host. T. gondii causes plasmatoxmosis can infect humans with
modifications in amygdala neurons, changing potentially severe outcomes during pregnancy.
the rodent fear response, in turn making
them attracted to cat-related odors rather Some research suggests that a T.
than fearful of them. The fearless rodents are gondii infection subtly affects human behavior
therefore less likely to avoid a hungry cat, in cat owners, hinting that T. gondii infection
increasing their risk of being eaten, which is associated in suicides and the onset of
begins the cycle again. schizophrenia.
15-15
where she bravely led a group of strangers Since anger may precede violence, angry
through the house populated by actors dressed faces function as a warning during evolutionary
as monsters and ghosts. Although she did not survival situations or during interpersonal
display any fearful behaviors, such as hesitation conflict. Seeing angry faces may prompt
to walk through the darkened corridors, patient awareness, initiating the sympathetic nervous
SM reported the sensation of exhilaration and system response in case “fight or flight” becomes
enthusiasm, akin to riding a roller coaster. necessary. As with fear, the emotional response
She also was asked to recall some of to angry faces or body postures is partially guided
her past real-life, fear-provoking experiences, by the amygdala, resulting in communication
such as when she was attacked in a domestic with the rest of the body through cortisol release
violence incident or was held up by a stranger downstream of the HPA axis.
at knife point in a public park. In none of these Environmental factors such as childhood
cases did she ever report feeling fear, although maltreatment or expectations are partially
she was upset and angered at the situation. The responsible for how a person responds to a
destruction of her amygdala seemed to make particular anger-provoking stimulus. Internal
her resilient against PTSD: the day after being homeostatic conditions also influence the anger
threatened with a knife to her throat, she walked response, just as how low blood sugar increases
past the very same park bench. aggression and drives negative or hateful feelings
Fear and anger are two very closely related in the face of a challenge (the portmanteau
emotions. As with many other emotions, anger “hangry” was added to the Oxford Dictionary in
manifests in complex ways. The anger spectrum 2018).
runs from low (irritation) to high (rage), and from Neurobiological factors also contribute
quick (lashing out) to persistent (vengeful). Strong to the anger response. In addition to amygdala
anger can provoke anti-social behavior such as circuits, regions in the frontal cortex decrease
violence. activity during acts of aggression, suggesting that
Clinical connection: Borderline Personality Disorder (BPD)

Borderline Personality Disorder It is estimated that 1.4% of people have
(BPD) is an emotional dysregulation disorder BPD. It is often comorbid with other psychiatric
characterized by disproportionately intense disorders, such as anxiety, depression, or
emotional reactivity to environmental triggers. substance use disorders. The main treatment
For instance, they may experience anger or approach is psychotherapy; medications are
hostility in response to minor inconveniences. not always effective at reversing the symptoms.
These emotional changes may persist for Celebrities such as Saturday Night
unusually long durations, up to hours or Live actor Pete Davidson, musician Amy
days, which often puts strain on interpersonal Winehouse, and Princess Diana likely had
relationships. They also experience a fear BPD. Arguably, the fictional character Anakin
of abandonment, an unstable sense of self, Skywalker from the Star Wars prequel films
suicidal ideation or attempts, and dissociation also displays many diagnostic traits of BPD.
(an emotional detachment from events).
15-16
Stress can either result from
Cortex: purely physical stimuli (exposure to
Cortisol (humans)
Corticosterone constant cold; chronic dehydration), a
(rodents) purely psychological threat (resentment;
religious guilt), or a combination of both
Hypothalamus
(living paycheck to paycheck).
CRF Pituitary Sympathetic The human stress hormone cortisol
branch
triggers the physiological response to
stress. Cortisol is a signaling molecule
ACTH Adrenal Adrenal
cortex medulla synthesized from cholesterol which
readily passes through cell membranes
where it can activate intracellular
Medulla: glucocorticoid receptors (GRs). Once
Norepinephrine
Kidney
Epinephrine the ligand-receptor complex is formed,

it translocates into the nucleus, where it
functions as a transcriptional regulator.
Nearly every cell contains GRs, meaning
that an elevation of systemic cortisol can
Circulatory system
influence several organs to change their
activity.
Figure 15.17 The HPA axis regulates both sympathetic A small amount of stress,
nervous system activity and the stress response. sometimes called eustress, is beneficial
and generally performance-enhancing,
frontal circuits actively inhibit the limbic system, such as in the moments leading up to the beginning
which drive our more “primitive” responses. of an athletic competition. The opposite, distress,
Altered frontal cortical action may therefore is characterized by the inability to cope with rising
account for one reason why two different people demands, leading to increased anxiety and other
would react to the same anger-provoking stimulus maladaptive responses. Distress is the kind of
in different ways. stress that people experience when they are
facing multiple rapidly-approaching deadlines,
Stress difficulties in paying rent, or relationship issues.
Stress is a natural and healthy bodily Biochemically and physiologically,
response that is similar to the prototypical “fight- eustress is the same as distress. The major
or-flight” response: elevated heart rate and blood difference is the psychological interpretation or
pressure, increased respiration rate (shortness of perception of the stressor. Eustress is seen as a
breath), energy usage, and perspiration, among challenge which someone can work to overcome
others. Physiologically, stress also causes a and is often short lived or temporary. Chronic
weakening of the immune response, a slowing of long-term distress causes all variety of negative
growth, and decreases in kidney filtration. health outcomes, such as cardiovascular
15-17
disease, diabetes, and obesity, all risk factors for
premature death.
The early medical descriptions of stress
were put forth by Hans Selye in the 1930’s. As
a medical student, he observed that chronically-
ill humans, regardless of their specific condition,
often experienced a similar set of late-stage
GR
negative health outcomes, such as gastric
ulcers, high blood pressure, and heart attacks.
Collectively, he called this response the general
adaptation syndrome.
Selye observed that extracts from different
internal organs led to these health changes in
rats, eventually leading to premature death. As
Figure 15.18 A molecule of cortisol (red triangle) a good scientist, Selye also injected a second
diffuses through the cell membrane and binds to group of rats with a harmless saline solution
intracellular glucocorticoid receptors (GR, green). as a control. Surprisingly, Selye observed that
Clinical connection: Ulcers

Ulcers are injuries to the mucous
membranes of the stomach or intestines
resulting in abdominal pain, nausea, and
changes in appetite (although some patients
report no symptoms.) In severe cases, ulcers
can cause bleeding or perforation of the
stomach, which could be fatal. An estimated
4% of people have ulcers, although this is
likely an underestimation.
For several years, ulcers were believed
to be caused solely by stress. However, later
research suggested that colonies of the gut Figure 15.19 H. pylori interacts with stress
bacterium Helicobacter pylori was found to and may result in stomach ulcers.
contribute to the formation of 80% of ulcers, a
discovery that earned Drs. Barry Marshall and in their gut, but not all these people develop
Robin Warren a Nobel Prize in 2005. Today, ulcers. Also, about 30% of people with ulcers
the evidence suggests that neither factor do not harbor H. pylori, and people taking oral
exclusively leads to ulcer formation: Nearly antibiotics that have eliminated their H. pylori
half of all people have the H. pylori colonies colonies can still develop ulcers.
15-18
these control animals also exhibited the general a love for fellow humans). However, it is very
adaptation syndrome. difficult to put a strict biological definition on these
It turns out that even minor stressors, such varied concepts of love.
as the movement of the rat cage, grabbing of the This section focuses on interpersonal
animal, and administering an injection led to an love, of which there are several unique forms,
eightfold increase in plasma levels of epinephrine, each resulting in different behavioral outcomes.
a hormone upstream of the stress response. For example, romantic love drives physical
Selye concluded that the general adaptation attraction, lust, and sexual activity. Parental love,
syndrome was not a result of the injections of on the other hand, encourages self-sacrifice and
organ extract, but rather because he induced a hyper-attentiveness towards a newborn. Some
tremendous stressor to all the rats. behaviors are shared between the two forms of
Like Selye, we use nonhuman models love, such as respect.
to study how the nervous system changes in
response to stress. Rodents can be exposed to Romantic love
chronic-restraint stress, where they are put Romantic love drives much of human
into a narrow cylinder for part of their day. Food behavior and has been documented thoroughly
restriction stress is a rodent model of starvation in the arts all the way from Homer’s Iliad through
or dietary malnutrition. The forced-swim test Shakespeare’s Romeo and Juliet up to modern
is best known as an assessment of depressive Taylor Swift.
behavior, but it can also be used to induce The majority of human societies have
stress. Food restriction and the forced swim test embraced social monogamy, the romantic
increases plasma levels of the neurohormone relationship characterized by a pair of people
corticosterone (the rodent analog of cortisol). who share resources, parenting duties, and
Psychological stressors also induce the exhibit preferential mating. Outside of humans
stress response. Common stress paradigms however, only 9% of mammalian species form
include exposure to socially-dominant bully rats socially monogamous pairs, while at least 75%
or predator-associated cues like fox urine, which
contains a group of chemicals called kairomones.
Kairomones cause behavioral changes in
other species, whereas pheromones refer to
interspecies chemical communication. Social
isolation is also a stressor for rodents, and for
this reason, rats and mice are normally group
housed.
Love
Love can be thought of as an intensely
strong attachment towards a person (romantic
love, lust), a thing (passion project), or concept Figure 15.20 Unlike mammals, most bird species
(patriotism as a love for country, or altruism as form socially monogamous bonds after mating.
15-19
of bird species maintain socially monogamous In addition to changing libido, the sex
relationships (which may explain the origin of the hormones contribute to sexual differentiation and
phrase “love birds”). maturation (mascularization with testosterone,
Dr. Helen Fisher, an anthropologist and such as muscle mass increases and hair growth),
a leader in the field of love research, suggests differences in immune system activity (decreases
that love can be divided into three closely with higher testosterone), and pain tolerance
interconnected components. These three are (higher tolerance with higher testosterone) for
guided in part by different signaling pathways, and example. Progesterone is less of a behavioral
lead to somewhat different behavioral outcomes. driver and functions more as a signal that prepares
female bodies for changes in preparation for
1. Lust childbirth, such as in the uterus and breasts.
Lust (or libido) refers to a very strong
desire for sexual gratification. These behaviors are 2. Attraction
largely driven by the actions of the sex hormones Attraction is characterized by high
testosterone, estradiol, and progesterone, energy investment and preoccupation towards
released downstream of activation of the HPG a small number of people. From an evolutionary
axis. As hormones, they are synthesized from perspective, attraction may have developed
cholesterol and circulate through the bloodstream to discriminate between multiple reproductive
to influence the body in many ways. partners, allowing the focusing of limited
Both testosterone and estradiol contribute resources towards fewer partners.
to sex-seeking behaviors in men and women, In Fisher’s theory, attraction is strongly
where increasing testosterone levels drive up related to the action of dopamine and
sexual desire. norepinephrine. In humans, the reward circuitry
In the brain, the sex hormones strongly (Section 11.2) is involved in feelings of love. Using
influence the medial preoptic area (mPOA) of fMRI, Fisher presented pictures of a patient’s
the anterior hypothalamus. The mPOA contains romantic partner to them and identified increases
a sexually dimorphic area, the part of the brain in the blood flow to dopaminergic midbrain areas
that exhibits the biggest morphological difference such as the ventral tegmental area and the
between males and females: in humans, it is striatum. This finding compares with imaging
about twice as large in males with double the studies that observed increases in blood flow
number of neurons throughout childhood and to insula, premotor, and hypothalamus as well
early adulthood. In the rat, it is up to 8 times as striatum in response to highly erotic, sexual
larger in males than females, and if this area is imagery. These studies suggest that romantic love
lesioned, rats exhibit decreased motivation to and lust have different driving neural structures
engage in sex. underlying these behaviors.
The amygdala also plays a significant role Norepinephrine functions to increase
in mediating lust, and lesions may either result attention, alertness, and energy, which accounts
in hypersexuality (Kluver-Bucy syndrome) or a for the exhilarated feeling you may feel when
decrease in responding to socially-derived sex spending time with a potential partner.
cues.
15-20
3. Attachment An experimental test called the partner
Attachment is the long-term accompanied preference paradigm can be used to assess
by feelings of comfort and emotional stability. vole monogamy. Here, a three-chamber testing
Attachment also contributes to behaviors that apparatus is used where a test vole is placed in
maximize offspring survivability, such as sharing a central chamber. In the other two chambers are
parenthood responsibilities and protectiveness voles who have been harnessed into their rooms,
towards offspring. The major neurochemical unable to leave. The test vole is then free to move
drivers of this form of love are oxytocin and between any of the three chambers. When the
vasopressin. test vole has mated with one of the harnessed
voles, they will choose to spend more time
We have learned about mammalian with their “partner” vole compared to the novel
pair bonding through experiments with prairie “stranger” vole.
voles (Microtus ochrogaster), rodents that are
indigenous to central North America. Atypical of
mammals, prairie voles exhibit social monogamy
after mating, where the two voles will cohabitate
and share parental duties, such as mutual
resource collection, nest building, and caring for
their young.
Figure 15.22 In a partner preference test, a

mated prairie vole will choose to spend more time
with their partner compared to the stranger, both
of which are tethered to their chamber.
Not only do mated prairie voles prefer the

company of their partner, they also demonstrate
behaviors similar to some human romantic
relationships. For example, mated prairie voles
living together display selective aggression against
a stranger, “intruder” voles, a behavior called
Figure 15.21 Prairie voles, rodents found in “mate-guarding”. They also spend significant time
the wild across central north America, form mutually caring for their young, their pair bonding
monogamous relationships after mating. can be modified by psychoactive substance use,
15-21
and they show increased anxiety when they are Because blood relatives share common genes,
separated from their partner vole. increasing the survivability of these family
Other nonhuman studies have compared members has benefits for passing genes to the
the prairie voles with physiologically comparable next generation. In the words of the geneticist
animal models, such as the montane vole Jack Haldane, “I’d gladly give my life for two
or meadow voles. While these other rodents brothers or eight cousins.”
are similar in size, they have slightly different Many behaviors related to mammalian
geographic distributions. Notably, they have motherhood are accompanied by changes in
radically different mating habits, as they exhibit neural activity. Nursing, for instance, is feeding
social promiscuity rather than monogamy. behavior that is regulated through a positive
Comparing between monogamous and feedback cycle. Offspring suckling activates the
promiscuous species has allowed researchers mother’s somatosensory afferents. Through a
to identify several neurotransmitter signals that series of oxytocin-dependent circuits across the
are implicated in pair bonding. Oxytocin and hypothalamus, suckling ultimately increases
vasopressin seem to play important roles in lactation through the milk letdown reflex. Auditory
vole pair bonding, as inhibition of either of these
signals decrease partner preference. Additionally,
differences in dopamine receptor levels and
corticotropin releasing factors are observed
between vole species.
Parental love
Parental love refers to instinctive affection
towards one’s offspring. Parental love behaviors
include nurturing (collecting and sharing
resources), protecting (promoting aggression
against “intruders”), and preparing one’s young
for their adult life (risk assessment training).
In evolutionary theory, parental love serves
to improve the odds of passing of one’s genes
through the following generation. Most large
mammals (humans included) are K-selected
species, which benefit most from a small number
of high-quality offspring that require substantial Figure 15.23 Suckling (bottom left) triggers
parental investment, as opposed to large numbers somatosensory inputs, which send afferents into
of offspring with little investment. hypothalamus (top), increasing blood levels of
An extension of parental love is familial oxytocin. Oxytocin increases accumulation of
love or kinship, the protection and preferential milk in the mammary glands (bottom right), which
support of one’s extended genetic relations. encourages increased suckling.
15-22
sensory inputs such as the sounds of a crying
baby can also trigger this reflex. Sometimes, just
thinking about the baby can induce letdown.
Some changes are dependent on neural
plasticity. For example, after childbirth, the
auditory areas of rodents rewire to become
more sensitive to high frequency sounds. This
adaptation allows the mothers to better detect
the ultrasonic vocalizations that are emitted
by offspring when they are distressed or hungry.
Olfactory areas also change in order to become
more sensitive to the particular odorants given off
by their young, allowing them to better identify their Figure 15.24 Typical face produced in response
offspring. In humans, these olfactory changes to a disgusting stimulus.
result in decreased aversion towards traditionally
aversive stimuli (urine or fecal matter) when they in many European countries, or fermented fish
originate from their children. products, commonly used as a flavor enhancer in
South East Asian cuisine.
Disgust Disgust extends beyond physical or
Disgust is an evolutionarily protective chemical stimuli, and also manifests itself in
emotion that helps protect an organism from thought. For instance, disgust is associated
being exposed to toxic or dangerous substances. with sexual contact leading to low reproductive
It also leads to disease avoidance, which is success, such as with animals or incestuous
why we dislike the smell of rotten foods or fecal relationships. Antisocial behaviors can also
matter, and why we may be repulsed by blood. As provoke the disgust behavior, such as feeling
in the previous examples, disgust often happens physically nauseated when reading about serial
in response to specific sensory stimuli (chapter killers.
9). The canonical “disgust face” is observed
The most common physiological response across several cultures. The curling of the upper
to disgusting stimuli is nausea, which can promote lip and wrinkling of the nose decrease air flow
vomiting. Additionally, nausea decreases appetite, through the nasal cavity, and squinting minimizes
which prevents further intake of potentially toxic eye surface exposure. An opening of the mouth is
compounds. a precursor for spitting out the disgusting flavors.
Disgust is not inherently ingrained and has The insula is involved in mediating
a strong learned cultural component that can be perception of disgust and displays changes in
modified by experience. Americans may be turned activity in fMRI activity in response to disgust-
off by potent moldy cheeses, which are delicacies related cues.
15-23
Clinical connection: Obsessive-compulsive disorder (OCD)
OCD is a common psychiatric condition Some studies implicate abnormal
affecting an estimated 3% of the population, disgust sensitivity as contributing to OCD.
characterized by persistent intrusive thoughts Patients were shown a variety of disgust-
or the need to perform some ritualistic series provoking stimuli, such as unsanitary toilets
of actions or motions. OCD exists on a or parasitic infections. If the threshold of
spectrum, and in severe cases, can severely disgust sensation is particularly low a patient
impair the quality of a patient’s life. OCD is may engage in their perseverative behavior
often treated with psychiatric intervention or more frequently.
SSRIs like fluoxetine (more information in
chapter 16).
Figure 15.25 Morphological differences are observed in the volume of the insular cortex
between people with OCD and neurotypical patients.
15-24
Image credits
Cover: https://pixabay.com/photos/airport-tourism-flying-air-traffic-1515431/
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15.4 https://pixabay.com/photos/cat-cat-hissing-angry-pet-5534007/
15.5 https://commons.wikimedia.org/wiki/File:Papez.jpg modified by Austin Lim
15.6 https://pixabay.com/photos/lion-tailed-macaque-monkey-rare-216227/
15.8 https://upload.wikimedia.org/wikipedia/commons/5/5a/Expression_Of_The_Emotions_In_Man_And_Animals_%28IA_
TheExpressionOfTheEmotionsInManAndAnimals%29.pdf
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15.10 https://commons.wikimedia.org/wiki/File:Amygdala.png
15.11 https://commons.wikimedia.org/wiki/File:1806_The_Hypothalamus-Pituitary_Complex.jpg
15.12 https://upload.wikimedia.org/wikipedia/commons/4/4a/1810_Major_Pituitary_Hormones.jpg modified by Austin Lim
15.13 https://upload.wikimedia.org/wikipedia/commons/b/b4/Sobo_1909_633.png
15.14 https://commons.wikimedia.org/wiki/File:Expression_of_the_Emotions_Plate_VII_(fear1).jpg 15.15 https://commons.
wikimedia.org/wiki/File:Gigi_a_motley_yellow_corn_snake.jpg https://upload.wikimedia.org/wikipedia/commons/e/eb/
Waverlyhillssanatorium.jpg
15.16 https://phil.cdc.gov/Details.aspx?pid=3421 modified by Austin Lim
15.17 https://commons.wikimedia.org/wiki/File:Response_to_stress.jpg modified by Austin Lim
15.18 https://commons.wikimedia.org/wiki/File:DNA_simple2-bn.svg modified by Austin Lim
https://commons.wikimedia.org/wiki/File:Cortisol.png
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15.20 https://commons.wikimedia.org/wiki/File:Two_swans_in_a_lake_(23746714432).jpg
15.21 https://commons.wikimedia.org/wiki/File:Prairie_vole.gif
15.22 https://pixabay.com/vectors/mouse-rodent-gnawer-white-animal-146416/ modified by Austin Lim
15.23 https://commons.wikimedia.org/wiki/File:2922_Let_Down_Reflex-new.jpg modified by Austin Lim https://pixabay.
com/photos/breastfeeding-mother-mother-s-love-1570695/ modified by Austin Lim
15.24 https://commons.wikimedia.org/wiki/File:How_to_express_disgust_(33491312650).jpg
15.25 Disproportionate Alterations in the Anterior and Posterior Insular Cortices in Obsessive–Compulsive Disorder. Song
A, Jung WH, Jang JH, Kim E, Shim G, et al. (2011) Disproportionate Alterations in the Anterior and Posterior Insular Cortices
in Obsessive–Compulsive Disorder. PLOS ONE 6(7): e22361. https://doi.org/10.1371/journal.pone.0022361
DePaul University.
15-25
16-1
Editor: Monica Javidnia, PhD (Rochester University)
The brain can be thought of as a well-

oiled machine made up of hundreds of billions of
moving parts, all cooperating in tandem for healthy
behavior and function. There is redundancy in
the way these parts are organized, allowing for
occasional mishaps without any significant loss of
function. But when these parts interact in unusual
or atypical ways, a person may develop some
psychiatric disorder. The conditions described
in this section likely involve dysregulations in
molecules, cells, or circuits, and are therefore Figure 16.1 Environment and genetics both
complex. contribute to these diseases. Studies comparing
As far as we know, the likelihood of twins can be helpful in identifying the influence of
developing these conditions is not exclusively genetics.
determined by either genes or influence from the
environment. Instead, there is probably some Association (APA) has put together a series
influence from both. That is to say, none of these of criteria for psychiatrists to diagnose these
conditions are 100% penetrant; none of them complex conditions. The guidelines are compiled
are dictated exclusively by genetics. Having two in a book called the Diagnostic and Statistical
parents or an identical twin with the condition Manual of Mental Disorders. They are currently
may indicate an elevated baseline risk over the on the fifth revision of the text, referred to as the
population at large, but it is not a guarantee that DSM-5. It’s an imperfect set of criteria, but it is
the disease will manifest. Environmental triggers a start towards understanding these remarkably
and other exposures may lead to a sudden onset complicated conditions.
of the condition; on the other hand, certain factors Many of the treatments we currently have
in the environment may be protective against for neuropsychiatric disorders aren’t always
these diseases. effective. Our ability to treat these conditions
One of the major challenges with depends on our understanding of the disease.
understanding these brain diseases is related The better we understand the causes of these
to the difficulty of making an accurate diagnosis conditions, the wider variety of new therapies
- as almost everything in biology exists on a we can test. Therapeutic strategies for these
spectrum, so do these brain disorders. The conditions are often first tested using cells and
symptoms of these disorders frequently overlap, non-human animal models, but these have
adding another layer of complexity. To help shortcomings. Most of the time, animal models
establish a diagnosis, the American Psychiatric of disease incompletely mimic the symptoms of
16-2
of developing Huntington’s disease (Chapter
10) in humans is associated with the number of
poly-glutamine repeats in the Huntingtin protein.
Developing a genetically modified animal model
that has several poly-glutamine repeats is an
example of a model with good construct validity.
Because humans and non-humans are very
different animals, having the same origin of
disease does not always produce the disease
symptoms.
3. Predictive validity. An animal
model has good predictive validity if the animal
model can be used to predict whether a therapy
would be effective in treating humans with that
same condition. For example, if there were a
genetic mouse model that showed symptoms of
Figure 16.2 The DSM-5 is the manual that is used depression, and an experimental antidepressant
by psychiatrists to diagnose various psychiatric reverses depression in both the mouse and
conditions. humans with depression, the model would be
said to have good predictive validity.
the disease. Animal research concerns itself with Unfortunately, we don’t have any
three different forms of validity. animal models that reproduce the symptoms
1. Face validity. If an animal model of of the most complex human conditions - it is
a disease looks similar to the human condition, almost impossible to create a mouse model of
whether behaviorally or in physical appearance,
we say that the model has good face validity. The
animal exhibits the same set of symptoms that
you would see in a human affected by the same
condition, such as a rat model of post-traumatic
stress disorder (PTSD) where the rat is exposed
to a predator. Future exposure to predator-
associated cues causes the rat to exhibit anxiety
and avoidance, which are symptoms of human
PTSD. In this case, the model has good face
validity.
2. Construct validity. Sometimes, an Figure 16.3 A predator exposure paradigm has
animal model of a disease starts with the same strong face validity because it causes a mouse to
pathological changes in the brain that are become anxious, just like a human when they are
observed in human patients. We say that these exposed to a predator.
models have good construct validity. The risk
16-3
dissociative identity disorder or dyslexia, and or incomplete, modeling only some of the deficits
even if we could, scientists would struggle to seen in humans. Furthermore, most human
quantify the behaviors that we use as diagnostic diseases have many symptoms, and only a few
criteria, which are too subtle to be observed or can be assessed with behavioral tests. We can
quantified in non-humans. And for the animal only study disorders of the brain that have a clearly
models that we do have, they are often imperfect and easily quantifiable behavioral component.

16.2 Major depressive disorder (MDD)
16.3 Bipolar disorder (BD)
16.4 Anxiety disorders

Schizophrenia is a psychiatric condition
affecting just under 1% of people. SZ affects
men slightly more often than women and affects
people of all races. There is a strong association
between low socioeconomic status and the risk
of developing schizophrenia, indicating that
stresses such as neonatal nutritional deficiency
or food insecurity may be risk factors. Other risk
factors that contribute to increased SZ risk include
prenatal drug exposure, heavy drug use during
early adolescence, and childhood adversity.
A diagnosis is generally made while a
person is in their late adolescent years through Figure 16.4 Dr. John Forbes Nash was diagnosed
their thirties. During this phase of life, the brain with schizophrenia before receiving the Nobel
is still undergoing subtle maturation processes, Prize in Economics in 1994.
which may account for why a person is more
vulnerable in these years. After this age, the risk Symptoms of schizophrenia
of developing SZ decreases significantly. Also, The symptoms of SZ can be roughly
the later in life that SZ symptoms appear, the classified into two categories, positive symptoms
better the health outcomes are. and negative symptoms. These phrases are used
It is worth noting that people with SZ to describe whether there is an excess of some
have the neurotypical range of intelligence, with function (positive symptoms) or a deficit of a
the occasional outliers: John Nash, the real-life function (negative symptoms). The symptoms
Nobel prize-winning economist depicted in the do not appear uniformly across patients, so not
movie A Beautiful Mind, was first diagnosed with all patients develop every symptom.
SZ in 1959.
16-4
The most well-known positive symptom
of schizophrenia is hallucinations, perceiving
something that is not there (as opposed to
illusions, which are misinterpretations of things
that are there). Usually, patients experience
auditory hallucinations, but they more rarely have
visual hallucinations. The voices that these people
hear may be consistent or can change over time.
Interestingly, the nature of these hallucinations
is influenced by society. In cultures with strong
ancestor reverence, they may hear the voices of
Figure 16.6 Persecutory delusions, a symptom
their grandparents, whereas people in religious
of SZ, is the persistent belief that someone or
cultures may hear the voices of deities.
something is constantly watching you.
The negative symptoms of SZ may include

deficits in expression. One common symptom is
a flat affect, where a patient does not show or
express emotion in situations where you would
expect to see them. A related negative symptom
is alogia, a decrease in the use of language.
People with alogia often use vague language that
is lacking in content or repetitive.
Negative symptoms also include deficits
in motivation or interest. Two closely-related
Figure 16.5 Auditory (and sometimes visual)
negative symptoms include anhedonia, a loss of
hallucinations are a common positive symptom
a sensation of pleasure and the inability to expect
of SZ.
upcoming pleasure. Furthermore, patients with
Relatedly, people with SZ may experience SZ may also exhibit avolition, a decrease in
a variety of delusions, untrue beliefs that cannot goal-directed activity, which can cause a person
be changed despite overwhelming evidence. to stop seeing their friends and cease displaying
The delusions can come and go spontaneously. interest in social gatherings, leading to worsened
Delusions exist in many forms. A paranoid interpersonal relationships.
delusion is when a person believes that they are Other negative symptoms that can present
being spied on, maybe by the government or in SZ are a variety of motor disturbances. Basal
by aliens. A persecutory delusion is a persistent ganglia and cerebellar structural deficits are
thought that the world is out to get them or to do found in SZ, two brain structures involved in
them harm. Delusions of grandeur are when a motor control (see chapter 10), which may explain
person has a tremendously high sense of self- why deficits are observed. One motor difficulty is
esteem, believing that they are royalty or are the catatonia, where a person can hold their body in
reincarnation of God. a highly unusual position for a prolonged period of
16-5
Potential causes of schizophrenia
In a healthy person, dopamine is important
for motor control and motivation, two behaviors
that are changed in patients with SZ. Therefore,
scientists have suggested that abnormal
dopamine signaling may be an underlying root
cause. While the dopamine hypothesis is one
of the earliest theories of SZ, modern genetics
studies have shown that polymorphisms in the
dopamine D2 receptor are risk factors.
Atypical cortical neuron network
development is also likely to be present in SZ.
In the healthy brain, networks of cortical neurons
produce cyclic patterns of activity in the 40 Hz
range, a pattern called a gamma oscillation. These
gamma oscillations result from a combination of
excitatory and inhibitory neurons. In SZ, there
is a decrease in the density of dendritic spines
on the excitatory neurons with a simultaneous
decrease in GABA-ergic signaling, which leads
to unpredictable gamma oscillations.
Figure 16.7 After being moved gently into an

unusual body position, a person with catatonia
may stay in that position for a prolonged time.
time. They may also display stereotypy, a series

of repetitive, purposeless behaviors, such as the
persistent rocking of the body or self-caressing.
Negative symptoms may also manifest as a
deficit of a patient’s cognitive abilities, particularly Figure 16.8 Many environmental factors
shortcomings in episodic memory (Chapter 13). contribute to the risk of developing SZ.
They may also present with difficulty in performing
attention-related behavioral tasks.
16-6
Animal models of schizophrenia effectiveness of the antagonist is correlated with
One animal model for SZ is based the ability of that drug to block the D2 receptor.
on the hypothesis that excess dopamine Clozapine, an atypical antipsychotic that functions
leads to the disorder. Introducing high doses as a dopamine receptor antagonist, can decrease
of the drug amphetamine, which increases SZ symptoms as well.
dopaminergic signaling, induces a temporary Unfortunately, pharmacological therapies
schizophrenic-like state in non-human animals. are not always effective in humans. Around a third
The hyperdopaminergic model of SZ produces of patients discontinue their treatment regimen,
cognitive deficits with no changes in memory and around a fifth of them report adverse side
or other negative symptoms. Alternatively, effects such as extrapyramidal motor symptoms,
administration of NMDA glutamate receptor sedation, and weight gain.
antagonists, like ketamine or PCP, is also used A potential new therapy is based on
as a behavioral model of SZ. transcranial magnetic stimulation (Chapter 6).
Other non-human models of SZ are Some evidence suggests that targeted activation
neurodevelopmental models. In these models, a of the cortex can decrease the severity of auditory
pregnant dam is exposed to the compound MAM, hallucinations. There may also be some mild
which causes the newborns to develop atypically improvements in the negative symptoms.
and display behavioral deficits similar to SZ. Approximately 65% of North Americans
Inducing an unusually strong immune response with SZ are smokers, compared to 25% in
in the pregnant mother can also cause atypical the population at large. If they are smoking
development in utero, which causes the animals as self-medication to activate dopamine- or
to experience behavioral deficits after birth. acetylcholine-sensitive networks in the brain,
The biggest limiting factor to developing an this observation may lead to a new therapeutic
animal model is that many symptoms in human SZ, strategy. Alternatively, they may smoke to get
like paranoid delusions or auditory hallucinations, pleasure, which acts to reverse the anhedonia
are impossible to detect and quantify in non- that is one of the main symptoms of the disease.
humans. The PCP model can cause changes
in rodent social behaviors, but it is hard to tell if
this model causes any of the positive symptoms D2R (short)
that you might see in a patient with SZ. Despite D2R (long)
the limitations of these non-human models of SZ, Other DA receptors
they have been helpful in testing the therapeutic Vesicles
Antipsychotics
efficacy of anti-schizophrenia drugs. Dopamine
Treatments of SZ
The dopamine theory of SZ has led to
a few novel therapeutic strategies, especially
in the context of the dopamine D2 receptor.
Figure 16.9 Atypical dopamine signaling is
D2 antagonists decrease hallucinations and
believed to contribute to schizophrenia.
delusions in some patients with SZ, and the
16-7
16.2 Major depressive disorder (MDD)
Depression is a highly prevalent condition MDD is also called unipolar depression
with a lifetime risk of about 18%. Depression to differentiate it from the depression that
gets diagnosed more frequently in women than represents a phase seen in bipolar disorder (See
in men, affecting about 5% of women and 2.5% section 16.3).
of men. Even with treatment, there is a high Clinical depression is often associated
rate of relapse: an estimated 80% of people with another medical or psychiatric condition. For
with depression have more than one episode in example, rates of depression are higher among
their lifetime. The prevalence of depression is people with terminal diagnoses, like cancer. In
similar across both high-income and low-income this case, we say that the two are comorbid.
countries, indicating that biological factors Additionally, a set of particularly challenging
contribute significantly to the disease. circumstances, like the death of a loved one,
could trigger a depressive episode.
MDD represents a severe health risk
across all ages. About 18% of adolescents report
at least one instance of non-suicidal self-injury,
and the lifetime risk for suicide among people
with MDD is estimated to be about 10%.
Symptoms of MDD
The fundamental criteria that are used to
diagnose people with MDD is a depressed mood/
self-esteem, low energy, and anhedonia, the
decrease in sensitivity to pleasure. Because of
the decrease in pleasure, they have a lessened
desire to engage in activities that once produced
happiness, thus leading them to become
withdrawn from their friends and family.
Short-term changes in mood are
completely normal and not clinical. The main
diagnostic criteria for MDD is the severity and
duration of the symptoms. When the depression
begins to affect other aspects of life, including
feelings of worthlessness, changes in sleep
or appetite, difficulty concentrating, or suicidal
Figure 16.10 Spanish artist Pablo Picasso likely
ideation that persist daily for two weeks or longer,
experienced some form of depression, and the
then a person may be diagnosed as clinically
paintings made during his “Blue Period,” like The
depressed.
Old Guitarist (1903), reflect his emotional state.
16-8
Clinical connection: Seasonal affective
To diagnose MDD, a trained psychiatrist or
disorder (SAD)
psychologist would use a combination of
Seasonal affective disorder (SAD) is
interview with a self-report questionnaire such
one type of depression that has a dependence
as the Hamilton Rating Scale for Depression
on daytime sunlight, increasing in prevalence
(HAM-D scale) or the Beck Depression Index.
in the winter and decreasing in the summer.
Items that appear on these sorts of tests include:
The prevalence of SAD is heavily correlated
with distance from the equator: people living
“Feels like life is not worth living”
closer to the poles experience longer nights
“Experience frequent weeping”
in the winter, which increases SAD risk. In
“I blame myself all the time for my faults”
the US, for example, SAD affects about 1%
of people in Sarasota, Florida, but about 9%
To date, there is no biomarker for depression.
of people in Anchorage, Alaska.
Treatments for MDD Light exposure therapy, while
There is currently no completely effective controversial, may show benefits for people
treatment for MDD that reliably works for with SAD, particularly intense broad-spectrum
everyone. The currently accepted strategies light or blue wavelength light. People with
can be divided into behavioral treatments and SAD may have something unusual about
chemical treatments. their intrinsically photosensitive retinal
Cognitive behavioral therapy (CBT) ganglion cells.
is a therapist-guided form of talk therapy that
may help a person manage their depression. In
CBT, a patient’s behavior, including their coping
mechanisms, erroneous thoughts, and emotional
responses, is analyzed through careful clinical
examination and patient self-reflection. Then,
the patient is taught mechanisms to counteract
those maladaptive behaviors and replace them
with adaptive behaviors. For example, a person
undergoing CBT for MDD might learn to identify the
moments when they dwell on something negative
in their lives, and then learn to tell themselves
“that thought does not function to make my day
better. Let’s start the day by getting out of bed
and see what happens next.” It should be known
that CBT is not exclusively for the treatment of Figure 16.11 Light exposure therapy may be
MDD; CBT can also be effective for anxiety, effective at treating some cases of seasonal
OCD, PTSD, insomnia, substance use disorders, affective disorder.
behavioral addictions, and many others.
16-9
A wide variety of drugs are used for the Monoamine oxidase (MAO)
treatment of depression. The first-generation Baseline
antidepressants were developed in the 1950s and
1960s. These drugs acted to increase the action
of the monoamine neurotransmitters: primarily
dopamine, norepinephrine, and serotonin.
Dopamine DOPAC
Our body uses an enzyme called monoamine
oxidase (MAO) which degrades these chemicals
into inactive components that do not signal at
Monoamine oxidase (MAO)
receptors. These first generation antidepressants +MAOI or
block the action of MAO; biochemically, we call TCA
them monoamine oxidase inhibitors (MAOIs).
In the presence of an MAOI, the neurotransmitter
signal remains in the synapse longer, similar to
how an acetylcholinesterase inhibitor increases Dopamine DOPAC
ACh signaling (Chapter 10).
Most of the MAOIs, while sometimes Figure 16.12 MAOIs and TCAs both increase
effective, have fallen out of fashion clinically neuronal signaling by decreasing the metabolic
because of the adverse side effects associated degradation of neurotransmitters, such as
with their biochemical activity (however, they are dopamine.
still commonly used in treatment of Parkinson’s
disease). Some of them interact dangerously Unfortunately, these tricyclics may produce
with foods rich in tyramine (particularly fermented many severe side effects, such as seizures,
foods, such as aged cheeses or beer, as well tachycardia, and heart attacks, so prescriptions
as beans and processed meats), an amino acid must be monitored closely. The tricyclics are still
that is degraded by MAO. Excess tyramine can prescribed today for several other nervous system
activate the sympathetic nervous system, and disorders, ranging from insomnia to neuropathic
body levels of tyramine can rise to dangerous pain, but due to their potential cardiotoxicity,
levels in the presence of an MAOI, leading to they are not often the first line of treatment in
adverse cardiovascular events like stroke. depression.
Many of the common MAOIs, like Our current, most often prescribed class of
phenelzine and isocarboxazid, can be damaging compounds for MDD, called the third-generation
to the liver. Some MAOIs also produce unwanted antidepressants, are focused on boosting
side effects, such as psychosis or nausea. the signaling activity of serotonin. Instead of
A different class of antidepressant drugs preventing degradation, like the MAOIs, these
called the tricyclic antidepressants (TCAs), compounds block the reuptake of serotonin out
named for the shape of their chemical structure, of the synapse. These chemicals are called
was also developed around this time. They selective serotonin reuptake inhibitors
generally act as monoamine reuptake inhibitors, (SSRIs), of which fluoxetine (Prozac) is one of
resulting in elevated neurotransmitter signaling. the most well-known examples.
16-10
Baseline Our newest treatment options for
+SSRI
depression, recently approved by the FDA in March
of 2019, is ketamine, a dissociative anesthetic
typically used as a veterinary tranquilizer and a
recreational club drug. Branded as esketamine, it
Serotonin can be administered rapidly via nasal spray. The
Serotonin Serotonin strength of esketamine is the speed of its action.
After taking a dose, the antidepressant effects of
the substance can be observed within hours.
For severe or treatment-resistant
depression, electroconvulsive therapy (ECT)
is a treatment option. Introduced in 1938, the
Figure 16.13 Third-generation antidepressants procedure has since been refined over the years
act to increase neurotransmission at the synapse (it is currently performed under anesthesia) and
by inhibiting reuptake. is considered to be well-tolerated and highly
effective. However, side effects include aches,
While SSRIs can be effective at reversing nausea, and memory loss.
the side effects of depression, they are not perfect One future therapy that is currently making
drugs. One shortcoming is that a person needs to significant medical advancements in curing
be on the drug for 2-4 weeks before they start depression is the use of psychedelic drugs,
to experience a clinically meaningful reversal particularly psilocybin – a substance found in
of depressive symptoms. This finding is highly some species of wild mushrooms. As a potent
unusual since the pharmacological, molecular- serotonergic agonist, a single dose of psilocybin
level effects of SSRIs take place within hours has been shown to decrease depression scores
after taking the medication. Similar to SSRIs, in various self-report studies with little to no
SNRIs (serotonin and norepinephrine reuptake adverse side effects.
inhibitors) can also be used to treat depression.
One of the unsavory side effects of Animal behavioral tests of depression
SSRIs is serotonin syndrome, a set of somatic Behavioral neuroscientists have developed
changes resulting from excessive serotonergic a variety of tests to assess the effectiveness of
signaling. In mild cases, a person may have an antidepressant drugs in non-humans. They are
elevated body temperature, excessive sweating, roughly divided into two categories.
rapid heart rate, and elevated blood pressure. In 1. Despair-based tests. One symptom of
more severe cases, a patient may have severe depression is that a person “gives up,” a behavior
fevers or seizures. Serotonin syndrome can that can be modeled in a variety of rodent tests.
happen in the event of an SSRI overdose, or One such example is in a tail suspension test.
as a consequence of some interaction between The mouse is held by the tail upside down. While
an SSRI and other drugs like MAOIs, MDMA it does not cause injury to the animal, they do
(ecstasy), amphetamines, or cocaine. experience discomfort, and will generally struggle
16-11
to either free themselves or to get upright again. frequently as a healthy rat but give that rat an
The sooner they stop struggling (more time spent antidepressant, and they will prefer the sweet
immobile), the more despair they experience, or water.
the more depressive they are. Giving a mouse An intracranial self-stimulation paradigm
an antidepressant like fluoxetine causes them to can also be tested here in the context of
fight for a longer duration. depression (see chapter 11). When an electrical
A similar test to assess “giving up” is the stimulator is placed in a reward area of the brain
forced swim test. Here, a rodent is put into and the rodent is trained to perform some operant
a container with some water. While they are task to receive activation of these areas, we find
naturally buoyant and are not at risk of drowning, that depressed mice do not activate these areas
they do not like being wet and will try to swim of their brain as much as one on antidepressants.
so that they can climb out of the water-filled
container. As in the tail suspension test, they
are unable to escape their predicament, and will
eventually become immobile. Giving them an
antidepressant decreases time spent immobile.
Figure 16.14 The tail suspension test (left) and

the forced swim test (right) are despair-based
tests that assess depression-like behaviors in
non-humans.
2. Reward-based tests. These tests seek

to measure the severity of anhedonia, one of
the main symptoms of depression. For example,
a rodent may be presented with a two-bottle
choice task, where they are put into a cage with
two different bottles to drink from: one filled with
standard water, and the other filled with a more
desirable sugar-water solution. A depressed
rat will not drink from the sugar-water bottle as
16-12
16.3 Bipolar disorder (BD)
A person with bipolar disorder (BD) more. The word “bipolar” is often misused in
experiences phases of clinical depression pop culture. Frequent changes in mood from
as described above, and at other times they happy to sad does not characterize BD. In fact,
experience mania, a state of exhilarating for a person to be diagnosed with rapid-cycling
high energy. During this state, they may sleep bipolar disorder, they need to experience four
very little, have difficulty concentrating, and mood transitions annually!
experience pressure of speech: a perceived need BD is usually diagnosed in adolescence
to speak very rapidly to get their thoughts out. and early adulthood. As with depression, there
They might make poor financial or life decisions, are some genetic factors involved, since a family
such as deciding to abruptly leave their family history of BD is a risk factor. Concordance rates
behind. Historically, BD has been called “manic for identical monozygotic twins are estimated
depression.” Notably, actress Carrie Fisher and to be between 35%-80%. But, environmental
musician Demi Lovato both struggled with BD. influences may be the precipitating factor in the
The estimated prevalence of BD is around onset of BD.
2.5%, but the disease is often misdiagnosed in BD is diagnosed into two categories,
the clinic as MDD. One reason this happens is based roughly on the severity of symptoms.
that more people are aware of the symptoms of Bipolar 1 disorder is the more severe of the two
depression, and these symptoms are generally conditions, with a clinical diagnosis made when a
more easily observed. Mania is more difficult to patient experiences depressive or manic events
identify, since in mild cases it may be hard to that cause significant social or occupational
distinguish from a person just “being in a really impairment, or hospitalization to prevent serious
good mood.” self-harm. A diagnosis of bipolar 2 disorder is
For a diagnosis of BD according to the less severe, but the behavioral changes are
DSM-V, a mood cycle has to last for a week or still noticeable by friends and family. A related
diagnosis is cyclothymia, where a person
Mania has alternating mood states that shift from
Bipolar I depression to hypomania, a less severe state
Hypomania of mania. Like most other disorders, BD exists
on a spectrum, and these labels only exist for
simplicity.
Cyclothymia
Minor
depression Treatments for BD
The main issue with BD therapy is
Depression bringing the patient to some “middle” state:
Bipolar II
an antidepressant may treat the depression
Figure 16.15 Severity of symptoms is used clinically phase, but could also swing the patient into
to differentiate between Bipolar I, bipolar II, and mania. Similarly, a mania-controlling drug
cyclothymia. could initiate depression.
16-13
Currently, our most reliable therapy for BD symptoms, as can extending the length of daytime
is lithium drugs. These compounds are described light exposure; oppositely, decreasing daily light
as mood stabilizers since they act to move the exposure can induce depressive behaviors.
patient’s mood to the center, rather than being at Exposure to amphetamine can increase manic
either the high end of mood (mania) or the low behaviors, while withdrawal from the drug can
end (depression). The way lithium acts to reverse induce depression. Clearly, neither of these
the symptoms is still unknown, and it probably models for BD exhibit strong validity.
acts on multiple pharmacological targets.
The main downside of this therapy is
that lithium is very toxic. It has a very narrow
therapeutic window: blood levels of lithium lower
than 0.6 mEq/L produce no effect, and anything
above 1.5 mEq/L causes delirium, tremor, fatigue,
and deadly side effects like seizures and coma. It
is also harmful to the kidneys after long exposure.
Therefore, a person taking lithium drugs regularly
undergo therapeutic drug monitoring (TDM), a
procedure by which the concentration of lithium
is assayed. TDM requires frequent visits to a
hospital. Usually, patients get multiple blood
draws in the first month when they start lithium
treatment, decreasing to one test every 2 months,
before decreasing to about four times a year.
BD is very challenging to model in non-
humans. A genetically modified disruption of
the circadian rhythm can induce mania-like
Blood lithium concentration
2 mEq/L
Toxic range
1.5 mEq/L
Therapeutic range
1 mEq/L
0.5 mEq/L
No effect
Time
Figure 16.16 Therapeutic drug monitoring is

important for people taking lithium for BPD since
the medication is ineffective at low doses, but
toxic at high doses.
16-14
16.4 Anxiety disorder
Anxiety is something that everyone has though it does not actually pose a genuine threat.
experienced at many points in their life. An Most people with specific phobias will go to great
anxious person may experience cardiovascular lengths to avoid exposure to their particular phobia
symptoms such as elevation of blood pressure trigger. These phobias are often influenced by
and heart rate, shortness of breath, profuse social and cultural conditions.
sweating, and a state of panic. In many ways, the Developing a specific phobia has a lifetime
anxiety response is similar to the fight-or-flight prevalence of about 7%, but only a very small
response observed during sympathetic nervous number of people with specific phobias ever
system activity. seek treatment for their phobia. Like other forms
However, a clinical diagnosis of anxiety of anxiety, there is a range of severity of these
is different from the passing anxiety that we phobias.
all experience. Anxiety disorders can be very
common, and lifetime prevalence estimates
suggest 29% of people could develop clinically
significant anxiety over their life span.
According to the DSM-V, anxiety disorders
have different presentations.
1. Generalized anxiety disorder (GAD).
People with GAD experience a constant sensation
of being overwhelmed, accompanied by fear and
worry. Many times, this worry is not about a single
concern, but rather a combination of issues all at
once, such as financial issues, relationship issues, Figure 16.17 A person with a specific phobia
uncertainty of the future, and many others. GAD such as agoraphobia, the fear of unfamiliar
is much more severe and persists longer than the environments where they have little control over
normal worries that affect everyone. their circumstance, may experience a panic
In GAD, worry persists for several months attack in a crowd.
and is uncontrollable. There are also associated
cognitive symptoms, such as fatigue, irritability, 3. Panic disorder. A person with panic
difficulty with concentration, and changes in sleep disorder experiences frequent panic attacks,
patterns. characterized by sudden increases in heart
2. Specific phobias. With specific rate, shortness of breath, dizziness, and sudden
phobias, a person develops the anxiety-related numbness or tingling (panic attacks can also be
symptoms (cardiovascular and psychological seen in specific phobias, but are not observed in
changes) in response to highly specific stimuli, GAD.) In panic disorder, these panic attacks may
such as snakes, enclosed spaces, deep ocean, occur independently of external influences.
or public speaking. The person with the phobia Pharmacologically, there are a wide
perceives the stimulus to be a great threat, even variety of drugs that can be used to treat anxiety,
16-15
broadly called anxiolytics. The first-line therapies The maze is a raised platform, with four arms in
are usually SSRIs, the same class of compounds the shape of a plus sign. Two of the arms have
that are used in depression treatment. Other walls surrounding the sides, while the other two
anxiolytics, such as the benzodiazepines are open, exposed on all sides. The rodent is
alprazolam or clonazepam, act as positive free to move between any of the arms as they
allosteric modulators which increases the effect choose. Standing in one of the open arms,
of the GABA system. Benzodiazepines are not where they can see the floor far below them, is
always preferred since they may have abuse an anxiety-provoking condition. Under normal
potential and can be addictive. Opioids and circumstances, rodents choose to spend more
norepinephrine inhibitors can also decrease time in the arms that are surrounded by walls.
anxiety. But if you give these animals an anti-anxiety
The exact cause of anxiety is still drug, they increase the time spent in the open
unknown. One theory suggests that anxiety arms, indicating a decrease in the behavioral
is a maladaptive evolutionary response to our expression of anxiety.
modern living conditions. The argument is based
on the observation that an anxiety response
looks a lot like a mild version of the fight-or-flight,
sympathetic nervous system response: both
elicit cardiovascular and respiratory changes.
For 99% of the evolutionary history of Homo
sapiens, we benefited from the sympathetic
nervous system as a reflex to improve the odds
of survival in dangerous situations. However,
our modern civilized living conditions over the
past few centuries have been very tame in
comparison to the risks that our earlier ancestors
experienced. The relative ease of living has let
the main function of the sympathetic nervous
system fall into disuse. The theory argues that
people experience GAD because a part of them
encourages sustained activity in the sympathetic
Figure 16.18 An elevated plus maze is one
nervous system. Although thought-provoking, this
behavioral test for measuring anxiety behaviors
theory can’t be tested experimentally and offers
in non-human animals.
no explanation about a biological mechanism
that can help to develop a therapy.
A related behavioral test is the open field
Animal behavioral tests for anxiety test. The test apparatus consists of a large, flat
As with depression above, there are non- area where the rodent can move around freely,
human behavioral tests used to assess anxiety and some method to track the animal - either an
in rodents, such as the elevated plus maze. aerial view camera or a series of parallel invisible
16-16
infrared beams that can locate the animal in
the field. In the wild, rodents, as prey animals,
prefer to spend more time close to the sides of
the testing arena up against the wall, avoiding
the wide-open space in the middle where their
instinct warns them that they may be snatched
up by some predator. However, if you give the
rodent an anti-anxiety drug, they will spend more
time venturing into the middle of the open field.
Another non-human model of anxiety is the
predator exposure paradigm. In this paradigm,
an ethologically-relevant stimulus is presented
to the rodent, such as one of their naturally
occurring predators. In this paradigm, rodent
anxiety presents itself as a freezing response, an
autonomic nervous system activity spike, and a
reduction in non-survival behaviors. Although the
predator exposure paradigm has good predictive
validity, they may struggle with poor face validity,
since the anxiety measures also may appear as
many of several other conditions, such as PTSD
or stress.
DePaul University.
16-17
Cover https://pixabay.com/photos/lewy-body-dementia-dementia-2965713/
16.1 https://pixabay.com/photos/children-twins-girls-young-652270/
16.2 https://upload.wikimedia.org/wikipedia/commons/4/4b/Dsm-5-released-big-changes-dsm5.jpg
16.3 https://pixabay.com/photos/cat-animal-cute-pet-room-play-3162458/
16.4 https://upload.wikimedia.org/wikipedia/commons/a/a9/John_Forbes_Nash%2C_Jr._by_Peter_Badge.jpg
16.5 https://upload.wikimedia.org/wikipedia/commons/a/a6/Schizophrenia_image.jpg
16.6 https://pixabay.com/photos/hiding-boy-girl-child-young-box-1209131/
16.7 https://wellcomecollection.org/works/wv5n6jjx
16.8 https://upload.wikimedia.org/wikipedia/commons/7/7f/Schizophrenia_risk_factors-PLOS.png
16.9 Amato D, Kruyer A, Samaha A-N and Heinz A (2019) Hypofunctional Dopamine Uptake and Antipsychotic Treatment-
Resistant Schizophrenia. Front. Psychiatry 10:314. doi: 10.3389/fpsyt.2019.00314
16.10 Pablo Picasso, The Old Guitarist
16.11 https://commons.wikimedia.org/wiki/File:Light_Therapy_for_SAD.jpg
16.14 https://upload.wikimedia.org/wikipedia/commons/8/89/201407_tail_suspension_test.png
https://upload.wikimedia.org/wikipedia/commons/e/e0/201407_porsolt_forced_swim_test.png
16.15 https://upload.wikimedia.org/wikipedia/commons/f/f0/Bipolar_disorder_subtypes_comparison_between_
Bipolar_I%2C_II_disorder_and_Cyclothymia.svg modified by Austin Lim
16.17 https://pixabay.com/photos/crowd-of-people-crowd-football-fans-1488213/
16.18 https://upload.wikimedia.org/wikipedia/commons/a/ab/ElevatedPlusMaze.svg modified by Austin Lim
16-18
Orders of magnitude
Number Power Name Prefix Example in biology (approx)
of 10 (symbol)
0.000000000000000001 10-18 Quintillionth atto- (a)
0.000000000000001 10-15 Quadrillionth femto- (f)
0.000000000001 10-12 Trillionth pico- (p)
0.000000001 10-9 Billionth nano- (n) 20 nanometers = synapse length
0.000001 10-6 Millionth micro- (µ) 10 micrometers = neuron diameter
0.001 10-3 Thousandth milli- (m) 2 milliseconds = duration of action
potential
1 100 1.7 meters = height of a human
1,000 103 Thousand kilo- (k) 20 kilohertz = highest pitch humans
can hear
1,000,000 106 Million mega- (M)
1,000,000,000 109 Billion giga- (G) 86 billion = neurons in the brain
1,000,000,000,000 1012 Trillion tera- (T) 150 trillion = synapses in the brain
1,000,000,000,000,000 1015 Quadrillion peta- (P)
1,000,000,000,000,000,000 1018 Quintillion exa- (E)
Measurement Unit (short) Examples

Length Meters (m) Length of wavelength of visible light: 500 nanometers
Length of a typical neuron: 20 micrometers
Height of a typical human: 1.7 meters
Volume Liters (L) Volume of cytoplasm in a single spin: 0.1 femtoliters
Volume of CSF in ventricles: 150 milliliters
Weight Grams (g) Weight of typical brain: 1.3 kilograms
Weight of typical grown adult human: 70 kilograms
Time Second (s) Duration of action potential: 2 millisecond
Velocity Meters per second Speed of slow action potential propagation: 0.1 m/s
(m/s) Speed of fast action potential propagation: 100 m/s
Concentration Molar (M) Calcium ion concentraion in cell: 100 nanomolar
Sodium ion concentration in ACSF: 140 millimolar
Temperature Celsuis (C) Freezing point of water: 0 Celsius or 273 Kelvin
Kelvin (K) Typical body temperature: 37 Celsius or 310 Kelvin
Electrical potential Volts (V) Charge of a typical neuron: -70 millivolts
Current Ampere (A) Current passing through single ion channel: 5 picoamps
Resistance Ohm (Ω) Typical input resistance of neuron: 200 megaohms
Conductance Siemens (S) Conductance through single ion channel: 10 picosiemens
Capacitance Farad (F) Capacitance in neuron: 100 picofarads
Magnetic field Tesla (T) Strength of fMRI machine: 5 Tesla
Frequency Hertz (Hz) Range of human hearing: 20 Hertz to 20 kilohertz
Loudness Decibels (dB) Pain threshold: 130 dB
Conversation: 65 dB
Appendix
Neurotransmitters and their receptors
Ionotropic receptors Excitatory
Metabotropic receptors Inhibitory
Amino Acids
Acetylcholine Glutamate GABA
nAChR M1 AMPA mGluR1 GABAA
M2 NMDA mGluR2 GABAB
M3 Kainate mGluR3 GABAC
M4 mGluR4 Glycine
M5 mGluR5 GlyR
mGluR6
mGluR7
mGluR8
Monoamines
Endocannabinoids
Catecholamines
Serotonin Histamine CB1
Epinephrine
5-HT1 H1 Dopamine Norepinephrine CB2
5-HT2 H2 D1 α1
Adenosine
5-HT3 H3 D2 α2
A1
5-HT4 H4 D3 β1
A2A
5-HT5 D4 β2
A2B
5-HT6 D5 β3
A3
5-HT7
Appendix
Brodmann areas and functions
Brodmann area Name Function

1, 2, 3 Primary somatosensory cortex (S1) Touch sensory and perception
4 Primary motor cortex (M1) Voluntary motor control
5 Superior parietal lobule Identification of objects based on somato-
sensory cues (stereognosis)
6 Premotor; supplemental motor Limb movement planning
7 Posterior parietal association area Integration of visual and motor
8 Frontal eye fields Visual perception and motor, saccades
9, 46 Dorsolateral prefrontal cortex High order executive functions
10 Anterior prefrontal cortex High order executive functions
11, 12 Orbitofrontal area Emotion, decision making
13, 14, 16 Insular cortex Emotion, empathy, taste, homeostasis
15 Anterior temporal lobe Social knowledge and memories
17 Primary visual cortex (V1) Vision, pattern recognition
18 Secondary visual cortex (V2) Vision, illusory contours
19 Associative visual cortices Vision, color, motion, depth
20 Inferior temporal gyrus Visual memory, face perception
21 Middle temporal gyrus Visual memory, emotional recognition
22 Superior temporal gyrus Language comprehension, attention, hear-
ing
23, 31 Posterior cingulate cortex Emotions
24, 32, 33 Anterior cingulate cortex Emotions, attention, decision making
25 Subgenual area Inhibition of emotion, decision making
26 Ectosplenial area Emotions
27 Presubiculum Emotions, head direction
28, 34 Entorhinal cortex Memory, navigation, smell, emotions
29, 30 Retrosplenial cortex Memory, navigation
35, 36 Perirhinal cortex Perception, memory
37 Fusiform gyrus Facial processing, perception
38 Temporopolar area Socio-emotional processing, smell
39 Angular gyrus Reading, speech, perception
40 Supramarginal gyrus Language perception and processing
41, 42 Auditory cortex (A1) Hearing
43 Gustatory cortex Taste
44, 45, 47 Broca's area Language, movement planning, cognition
48 Retrosubicular area Memory
49 Parasubicular area Navigation
52 Parainsular area
Appendix
Location of Brodmann areas
Lateral view
Midsagittal view
Appendix
https://commons.wikimedia.org/wiki/File:Cholinergic_synapse.svg
https://commons.wikimedia.org/wiki/File:Human_Brodmann_areas_(K._Brodmann,_1909,_p._131,_Fig._85-86).jpg
DePaul University.
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1

Chapter 2: Anatomy of the Nervous System

Chapter 3: Cellular Anatomy of the Nervous System

Chapter 4: Electrical Properties of Neurons

Chapter 5: Signaling Between Neurons

Chapter 7: Sensation and Perception: The Visual System

Chapter 8: Sensation and Perception: The Physical Senses

Chapter 9: Sensation and Perception: The Chemical Senses

Chapter 11: Neuropharmacology and Substance Use

Chapter 12: Sleep and the Circadian Rhythm

Chapter 14: Lateralization and Language

Chapter 15: Emotion

Chapter 16: Diseases of the Brain

Dr. Ben Marcus

Dr. Harriet de Wit

1.1 What is Neuroscience?

1.1 What is Neuroscience?

“Visual” brain areas

Acetylcholine Figure 1.3 The brain is remarkably flexible,

intricate than any artificially created system thus

Observational study Figure 1.6 The Adverse Childhood Experiences

As complex as the brain is, naturally “Forming memories causes new

Figure 1.14 Neuroscience is made up several academic disciplines.

2.1 Central nervous system (CNS)

2.1 Central nervous system (CNS)

Anatomical language of the brain

Figure 2.3 A cartoon illustration of the brain showing anatomical langauge.

Visualizing the brain

Major lobes of the cortex

Clinical connection: Phineas Gage

Figure 2.11 Drawing of the spinal cord and the

Dorsal root ganglion

1. Somatic nervous system

Heart ↑ heart rate ↓ heart rate

Respiratory system Dilate bronchi Constrict bronchi

Abdominal blood Vasoconstriction Vasodilation

Pancreas ↓ activity ↑ activity

Kidney + bladder Inhibit urination Stimulate urination

Gonads + genitalia ↑ Muscle ↑ blood flow

the sacral areas. The parasympathetic nervous 3. Enteric nervous system

Table 2.16 The twelve cranial nerves and their function.

Cranial Nerve Function Description

CN I Olfactory nerve Sensory Sense of smell

CN II Optic nerve Sensory Sense of vision

Brain circulation and cerebral blood flow

Peripheral blood Brain blood

Intracellular Tight junction

Healthy child Child with hydrocephalus

Arachnoid mater Dura mater

Clinical correlation: Meningitis

For the majority of human history, the

3.1 Characteristics of neurons

3.1 Characteristics of neurons

Along the dendrites of some neurons, it is

Length Length Length Length:width Width 2 or more heads

memories about our childhood over long periods microns in diameter.

Figure 3.10 The axon hillock acts as an integration

Figure 3.12 Diagram of an axon terminal, showing

proteins that can carry other proteins along the