Brain and Behaviour

Ella Herzberg

2-2021

Contents
1 Brain Organization 3
1.1 The 3 main approches to study the Brain: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2 Brain development 4
2.1 Overiew . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.2 Development is both program and flexible . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.3 Brain morphology and function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

3 Sleep and awake cycles 7

3.1 The structure of sleep: EEG and behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.2 Why do we sleep? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3.3 Biological clocks and the role of light . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3.4 Neural basis for sleep and waking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3.5 REM sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.6 Sleep disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

4 Eating 14
4.1 Energy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.2 Processes in eating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.3 Learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
4.4 Neuronal and hormonal signals in eating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
4.5 Satiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4.6 Pathways regulating eating in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4.7 Interaction with metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4.8 Effects of hormones on feeding mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4.9 Eating and reward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.10 Hunger relieves pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.11 Eat disorder - Parder-Willi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

5 Motivation, Reward & the Dopamine System 21

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6 Drug addiction 23
6.1 Cocain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
6.2 Anhedonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
6.3 Good feeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
6.4 Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

7 Sterss 25
7.1 Sterss and cognition - behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
7.2 Physiology of stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
7.3 Anatomical basis of fear conditioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

8 PTSD - Post Traumatic Stress Disorder 28

8.1 Stress and PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
8.2 Brain areas and PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
8.3 Treating PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

9 Depression 29
9.1 Symptoms and approach to understanding depression . . . . . . . . . . . . . . . . . . . . . . . . . . 29
9.2 Antidepressant medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
9.3 Ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
9.4 Environmental hypothesis: early stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

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1 Brain Organization
We can’t see or feel our brain, and when we look at the brain we can’t really tell what it does (in contrast of looking
at the heart).
We understand the brain because of the loss of function we obsserve in others after an injury. We have avidance
from the Egypt Papyrus that even in acient times there were observations like those.
When we try to understand the brain we already know that it connects with the outside world, precived what is in
the outside world, understand what all these perceptions mean and then it acts accordinlly.

1.1 The 3 main approches to study the Brain:

1. Luria - injured patients and eye tracking

Luria focused on 3 functional units of the brain: Regulation of arousal, Sensory inputs, Planning and regulating
action.

Regulation of arousal: To control arousal we have the Reticular formation (or Reticular activating system).
The two major neurotransmitters that regulate the level of excitation and inhibition in the CNS are Glutammet
(excitatory) and GABA (inhibitory).
Clusters of neurons in the brainstem and hypothalamus release neurotransmitters that regulate the level of arousal.
* The levels of consciousness ranging from alertness to coma.
The reticular formation is composed of ascending and descending axons that project to the cortex, the thalamus,
the limbic system, and the spinal cord - control our perception.
There is an optimal level of arousal; if we have too much we can’t focus on a task, and if we have too little we will
be bored.

The Sensory Inputs: Divided into primary, secondary and tertiary areas.
In the primary levels the neurons response to more primitive characteristics. Secondery responses to more com-
plicated characteristics, and tertiary areas will responses to even higher levels of feature. Higher levels are more
integrated than lower levels, process inputs from different senses or modalities.
Higher level processing shows greater lateralization of function, meaning there are more specific functions for each
hemisphere.

Planning and controlling behaviour: the commen model

is that we start in higher levels and going down to more pri-
mary levels (motor cortex). The Frontal-Parietal areas are
consider to be the highest level of planning and understand-
ing behaviour. Perception takes place in the posterior regions
of the brain. The posterior part of the parietal lobe integrates
different sensations from different modalities, this information
projects to the frontal lobe and there we have the highest level
of planning and controlling behavior.

Luria did most of his research on soldiers. He found that a

frontal lobe injury led to lack of ability to describe the spacific about a painting. Also, Luria would monitor the eye
movements that the patient made when he was asked various questions about the painting. He found that patients
with frontal lobe injury did not program their eye movements to fit the task.

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2. Mesulam - Neuroanatomy, brain slices and injuries

Mesulam based his research on divisions of different areas of the Cerebral cortex that made by Brodmann (52 areas
- based on cytoarchitecture, cell architecture).
He claimed that there is a functional reason that the cells are arrange in this way. Mesulam divided the cerebral
cortex into functional regions, stressing that the Brodmann Areas division does not STRICTLY overlap with
behavioural function.
We can divide the brain according to how it helps us integrate information and behave:
• Brain-Enviroment - sensory and primery motor systems enable us to interact with the enviorment.

• Brain-Brain - Cerebral cortex, how we interpet the senses, memory, and execution of actions.

• Brain-Body - the hypothalamus and lower structores that recive information from the body.
Limbic system – connected to hypothalamus that regulate basic survival behaviours (sleep, eating, sex, Nest-building
,temperature). The limbic system have a Cyto-architecture – both nuclear and layered, but not as distinctly layered
as the cerebral cortex.
The paralimbic areas are the most connected to the limbic system (cingulate gyrus, insula, and the frontal pole).
Luria - Heteromodal areas are the most sophisticated, because they do higher order integration of information.
Mesulam - From the anatomical point of view – primary areas are the most developed cytoarchitecturally (we can
see the 6 layers of the cortex).

3. Raichel and others - fMRI, healthy participants

Brain cells require glucose, oxygen and blood. The boold flow is correlated to neural activity. Functional MRI
measures the changes in activity by measuring changes in blood oxygenation. With this method we can learn how
the brain behave without open it.
In 1995 researchers discovered that the brain is active even without a task - ”spontaneosly brain activity”.
The ”default brain”, is a term that is commonly used to reflect thought processes that are not related to performing
an experimenter-directed task. These default areas are the frontal medial and parietal. Studies shown that even
monkeys and rats also have default mode network. In the rat two networks have been discovered: Emotional motor
network and Viscerosensory network.

2 Brain development
2.1 Overiew
Features of the development of the nervous system:
1. Develops from a hollow tube known as the neural tube.

2. The develop is more or less symmetric.

3. Divided into segments (spinal cord).

4. Hierarchical organization (Luria and Mesulam).

5. Peripheral and central nervous systems.

6. Localization of function.

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 After fertilization the cells start to divide and form layers of
”germ cells” ; Endoderm, Medosderm and Ectoderm- Skin and
nervous system.
The neural tube - the neural plate developes a groove and
then begin to fold, starting from the cervical (neck) area and
proceeding anteriorly (towards the head) and posteriorly (to-
wards the tail). This forms the neural tube.

The neural tube divides into 3 primary vesicles by Week

4: Prosencephalon - Forebrain, Mesencephalon - Midbrain,
Rhombencephalon - Hindbrain.
And by week 5 we have 5 vesicles.
The Prosencephalon divide into the Telencephalon (Cerebral
cortex, Limbic system and Basal ganglia) and the Diencephalon
(Thalamus, Hypothalamus and Pineal). The Mesencephalon
does not divide further. The Rhombencephalon divide into the
Myelencephalon (The Medulla) and the Metencephalon (Pons
and Cerebellum).
As the cells replicates, the brain tissu compresses the neural
tube into the cerebral ventricles.
The cerebral cortex grows and becomes convoluted to allow more surface area within the skull. The central sulcus
seperate the frontal lobe from the parietal lobe.

2.2 Development is both program and flexible

There is an overlap between the stages of development, and the sequence does not accure at the same time in all
the brain regions. Primary cortical areas will develop sooner then the association cortex and the hetromotor cortex.
The stages of development are:

• Proliferation: The neural stem cells divide in a symmetric division → 2 idendtical cells, progenitor cells. The
progenitor cells divide asymetrically, they form 2 different type of cells: one will be a neuron or a glia cell,
and the other will continue to divide (a progenitor). The cells are influance from the enviorment in the brain
while develop; different cells divide in defferent times, hence the later divided cell can be influance by the
early divided one. This create diversity in the brain. These progenitor cells produce ”blast”, gliablast or
neuroblast, these are molecules that affect the destiny of the cells.

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• Migration: This is the process when cells have to reach their destination in the brain. The cells have to move
from the inner layer of the neural tube to where they are going to function in the cortex. The first layer that
form is layer 6 (inner) and the last to form is layer 1 (outer). The migration can occur vertically along radial
glia that serve as a ladder to the neurons.

• Differentiation: Glioblasts and neuroblasts develop into specific types of neurons or glia cells. There are many
genetic factors that are determen what is the destiny of a certain cell. In mammals the differentiation can be
influance by environmental fuctors as well, this is an advantage because we can try to correct damage that
accures in development.
Researches found in rats that if they replace the location of neurons from the visual cortex to the somatosensory
cortex, the neurons will response to touch and not to light. This demonstrates that the differentiation of the
neuron is not merely predetermined genetically, but is influenced by neuronal activity.

* The transformation of GABA: GABA is the main inhibitory neurotransmitter in the brain, and Glutamate
is the main excitatory neurotransmitter. Other neurotransmitters also take place in the development in the
fetus.
We know that in the adult the concentration of CL – is greater outside the membrane then insdie the cell.
The electrostatic force of CL – pushes it out of the cell (because the inside of the membrane is negative), and
the concentration gradient of CL – draws it inside the cell (because there is a higher concentration of chloride
on the outside).
But in the fetus the concentration of CL – is higher in the cell, due to a potassium/chloride pump that is not
yet develop. When GABA opens the chloride channels the CL – goes out of the cell and couse excitation.
During the brith process there is a change in the concentration of chloride in the cell and GABA becomes
inhibitory. This happens because of the oxytocin hormone (also a neurotransmitter) that release during birth.
It couses the contractions of the uterus and the release of milk.
Excitation in the foetus is important for proliferation, migration, differentiation, synaptogenesis, etc. The
inhibitory effect of GABA during birth is thought to ihibit neurons transmitting pain signals (e.g., squeezing
of the head). Babies born by vaginal delivery show less pain than those born by caesarian section. Another
reasone is to prevent neurotoxicity due to excitation by glutamate if there is loss of oxygen during birth.

Late fetus and after birth events:

• Synaptogenesis: This is the stage when we start to form synapses. Neurites are buds that develop on a
neuron. They are formed from actin and molecules that compose the cytoskeleton. A neurite can potentially
become an axon or dendrite (only one neurite will become an axon). The one neurite that become the axon
will produce substances that prevent the other neurites from developing into axons. At the end of the axon
is a growth cone which will continue to grow until it finds another neuron to make synapse with.
The process of forming a synapse is led by chemicals that are in the neurons. The post-synaptic neuron and
the extra-cellular fluid contain cell adhesion molecules (CAM), that attract the growing axon. In addition to
molecules that attract the axon, there are molecules that repel the axon. The combination of attractant and
repellant molecules shape the path of the growing axon.
Redundancy - more synapses (and neurons) are formed than what the brain needs. Those that are not used
will be eliminated. This also allows the brain the plasticity. Ramon y Cajal was the first that discovered the
redundacy.

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 • Apoptosis and synaptic pruning: Apoptosis – programmed cell death; cells have a death program, (Not to be
confused with neurodegeneration, neurotoxicity). Neurons and axons that don’t form synapses will die. The
destiny of neurons is determined by “growth factors”. Neurotransmitters and enzymes that are involved in their
synthesis serve as growth factors during development, e.g., glutamate, acetylcholine, etc. If a post-synaptic
neuron is destroyed, the presynaptic neuron is deprived of growth factor and will subsequently die.
Researches found that there are diffrences between rats that had grown in a enriched enviorment and laboratory
cages. The first group had thicker cerebral cortices, and performed better on maze learning tasks then the
later group.

• Myelination: Begins in the second trimester and continues at least 2 decades after birth. Posterior areas
become myelinated before more anterior areas, and primary cortex before other cortical areas.
Cortical thinning: The grey matter becomes thinner as white matter becomes thicker. The thinning that is
observed in MRI is thought to be related to Pruning of synapses and Increased myelin. Broca and Wernicke
areas shows increase in grey matter as lenguage develops.

2.3 Brain morphology and function

Advantages and disadvantages of MRI vs histology:

• Histology provides more information on the cell morphology, although there is distortion post-mortem (tissue
shrinkage).

• The number of subjects (children) in post-mortem studies is low.

• Neuroimaging studies allow for repeated measures in the child as h/she grows.

• Allows correlation with cognitive measures, such as IQ.

In general, 3 patterns were observed in changes of cortical thick-

ness with age: Linear, Quadratic (increase, peak, decrease) -
both of these patterns occur more in paralimbic areas. The
third patter is the Cubic (increase, decrease, stable) - most of
the cerebral cortex shows a cubic pattern.
Cortical thickness and IQ - Children with superior intelligence show low cortical thickness in early childhood, a
rapid rise and a sharp decline compared to children with an average or high IQ . Children of superior intelligence
show greatest changes.

3 Sleep and awake cycles

3.1 The structure of sleep: EEG and behaviour
Sleep is measured by:

• Brain activity by EEG.

• Eye movements by EOG - electrostatic potential diffrences.

• Muscle tone by EMG.

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EEG waves in sleep and waking:

β Beta waves, 13-30 Hz. Awake with eyes open. Desyn-

chronized waves.

α Alpha waves, 8-12 Hz. Awake with eyes closed. Synchro-

nized waves.

θ Theta waves, 3.5-7.5 Hz. eyes closed, start of the sleep.

Not frequent in healthy waking adult.

δ Delta waves, 0.5-3 Hz. Slow wave sleep.

During early stages of sleep other waveforms may appear:

• K complex - high voltage sharp wave that can appear in reaction to an external stimulus (like calling the
person’s name).

• Sleep spindle - A burst 12-14 Hz, EEG seem usually in early stages of sleep.

Stages of sleep:

• Non REM

1. The non REM seperate to 3 stages, the last of wich is called Slow Wave Sleep (SWS) and it is characterize
by Delta rhythm.
2. The EEG detects alpha (awake) → theta → delta.
3. Sleep spindles can appear, and K complex can appear if presented with stimulus.
4. if awakened, the person is not immediately alert. The person may report having thoughts, but they do
not have the narrative quality of dreams.

• REM Sleep Characteristics

1. Fast desynchronide EEG waves (similar to β).

2. Low muscle tone.
3. Increased blood flow to sex organs.
4. if awakened, the person will report dream.

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As the night progress the REM sleep gets longer every period.
During REM sleep we can see increase activity in Para-limbic areas, Hyppocampus and association Visual cor-
tex. The decrease activity occur in the Primary Visual cortex and the Dorsolateral prefrontal cortex (exacuative
functions). Based on PET studies.

3.2 Why do we sleep?

• Sleep deprivation leads to increased metabolic rate. Laboratory animals die even if they eat more while sleep
deprived.

• Sleep also may help us recover from oxidative stress.

• Fatal familial insomnia is an autosomal dominant disease. There is neuronal loss in thalamus, medulla and
motor areas.

• Dolphins must be mobile constantly because they live in the ocean. But they do sleep; one hemisphere at a
time.

During sleep, hippocampal cells ”replay” the events that occurred during waking. When we look at the EEG we
can see the sharp wave ripples (SPWR) in the hippocampus, that is represent as an increase of excitability in this
area. Thereby faciliating long term potentiation and strengthening the relevent synapses. This is important for
consolidating the information and transferring it to the cortex.
The place cells - in the hippocampus there are place cells. These cells fires more when the rat is in a particular
location. During SWS, the place cells again fire in the order in which they fired while exploring the runway.
The hippocampus is not the “storage”, the memories are “stored” in the cortex.

3.3 Biological clocks and the role of light

Various biological mechanisms have rhythmic patterns that can vary by season (migrating birds), day (sleep/wake),
month (menstrual cycle), etc. The sleep-wake cycle is circadian (around the day).
The basic mechanisms is a gene leads to synthesis of a protein. This protein make the expression of the gene to
decrease. We know that there are genes/proteins involved in the oscillatory loop.
The SCN - The suprachiasmatic nucleus (above the optic chaism). Located in the hypothalamus, this area regulate
hormones and basic cycles like temperature and sleep-awake. The other benefit of the location is the closeness to
the optic nerves - can resive information from the retina about the light.
Some ganglion cells are sensitive to light, They contain a photopigment called melanopsin. Therefore, these ganglion
cells are photoreceptors, and they project to the SCN (and not the LGN of the thalamus). Because the SCN receives
information about light, the “biological clock”, can be entrained to light, as an external stimulus.
The photoreceptors in the ganglion cells project to the SCN. Even if the mouse/person is not aware of the light,
the hypothalamic nucleus (SCN) is still affected by the light, allowing hormone production to be entrained to the
light.
SCN control of circadian rhythms is both neuronal and chemical. If the efferents (axons leaving the area) from
the SCN are injured, the circadian rhythms can be restored after implanting SCN tissue into the ventricles of the
brain. The implanted SCN cells produce a chemical that activates receptors on hypothalamic cells, thereby restoring
circadian rhythms.
The pineal gland controls seasonal rhythms. It secretes melatonin which premote sleep. The SCN is connected to
the pineal indirectly, this enables light to affect seasonal rhythms as well.

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3.4 Neural basis for sleep and waking
There are several type of mechanisms that controls sleep and awake: Circadian (biological clock), Homeostasis
(adenosine and glycogen), and Allostasis (adjustment during times of stress).
Homeostasis - a system that regulates a mechanism around a set point (for example, temperature). In sleep and
awake the homeostasis is of energy use. We have Glycogen in astrocytes that serves as a source of glucose for cells.
As supply of glycogen is getting smaller, adenosine is released from astrocytes and causes sleep. Caffeine blocks
adenosine receptors, hence increased wakefulness.
Allostasis - dynamically regulated system that is modified according to need. For example, we require more glucose
when cold or after exercising.

We have 3 main stages of sleep that controlled by mutually inhibitory brain mechanisms.
The waking network inhibits the Slow Wave Sleep network  The SWS network inhibits the waking network. The
waking network arouses the region that inhibits REM. REM sleep is controlled by a pathway that arouses REM
and another pathway that inhibits REM.

Wakefulness

Networks originating in basal forebrain and brainstem that regulate excitability of thalamus and cortex. These
systems regulate wakefulness, alertness, and attention. Each of the systems plays a role in controlling excitability
and can modify activity as needed.
If the system is based just on GABA or Glutamate we won’t have balance.

The Reticular formation - The Ascending Reticular Activating System:

Ascending means that the cells bodies are in the brain stem and midbrain,
and their axons projects to the higher areas – cortex, thalamus limbic system,
(Reticular comes from network).

Noradrenaline or Norephinepherine:
The cell bodies are in Locus Coeruleus, the axons projects the cerebral cortex,
thalamus, limbic system and cerebellum.
Noradrenaline is studied in the context of signal detection: increased alertness
when responding to specific stimulus which allows correct detection. Moder-
ate excitation – respond to a correct stimulus (hit), do NOT respond to the
wrong stimulus (correct rejection).
If excitation is too great → false alarm.
If excitation is too low → miss.
Electrophysiological recordings of cell activity show that the neurons have a tonic (steady) rate of firing, related to
general arousal level. On top of the tonic rate, there are phasic - increases in firing rate in response to stimuli, at
a specific time. When the tonic is moderate the animal arousal is moderate and it could response phasicly to the
target - and then the monkey showed good preformance. When the tonic was not moderate the monkey had lots of
false alarms.

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Moderate rates of tonic firing of NE neurons, and high phasic firing in response to the stimulus is associated with
optimal levels of attention.

Serotonin:
The cell bodies releasing serotonin are located in the pons and medulla. Axons extend to thalamus, limbic areas,
cerebral cortex, and basal ganglia.
The serotonin changes our sentivity to punishment. Cells increase firing rate when the animal is subjected to
inescapable shock, a situation that causes “helplessness”. Escapable shock - decreased release of serotonin as animal
learns to control the situation.
Serotonin envolves in lots of different behaviors, but it is very hard to say that it has any single binding influence.
This is because the serotonin have many different receptors that have opposing influances on the release and action
of it.

Acetylcholine:
Neurons releasing acetylcholine are grouped in the pons-medulla region and in the basal forebrain. The axons extend
to all parts of the forebrain, midbrain and hindbrain. Basal forebrain neurons involved in neuronal plasticity as a
result of learning.

Histamine:
The cell bodies that release histamine are located in the hypothalamus and sends their axons to the forebrain and
spinal cord. Histamine affects arousal via 2 pathways:

1. Axons project widely to the cerebral cortex.

2. Axons excite the cholinergic neurons in the basal forebrain and in the pons.

Neurotransmitters summery:

• Awake : NE, ACh, 5HT, Histamine - excited.

• SWS : NE, ACh, 5HT, Histamine - less active.

• REM : ACh is active; NE, 5HT, Histamine are Inhibited.

(Ne – neuro epinephrin ; ACh – Acetylcholine ; 5HT – serotonin)

Orexin or hypocretin:
This peptide plays a role in both SLEEP/WAKE and EATING.

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The cell bodies are found in a nucleu in the hypothalamus, and projects to the cortex, thalamus and all the other
nucleus in the Reticular activating system.

Slow Wave Sleep

Neurons in the ventrolateral preoptic area (VLPOA) of the hypothalamus release GABA and inhibit the neurons
in the ARAS that release acetylcholine, noradrenaline, histamine and serotonin. Stimulating this area leads to
appearance of delta waves in the EEG. The neurons of the VPLOA are inhibited axons that project from the same
brain areas that are in the ARAS (reticular formation).
Mutual inhibition of arousal and SWS regions resembles a ”FLIP FLOP” system: ARAS (arousal) and GABA
(SWS) inhibits one another. Any small change can flip the system between on and off, unstable.
For preventing the unstableness of this system we have a stablize mechanism: The hypocretin/ orexin that axcite
the ARAS. Without the orexion, mice showed normal amount of sleep and waking, but had more transitions than
usual.

Regulatory systems : Homeostasis, allostasis, and circadian rhythms

The neural system enables fast reactions (awakening from sleep) and is regulated by a flip-flop system that is
stabilized by orexin neurons.
The homeostatic mechanism results in accumulation of adenosine. Adenosine causes some neurons to inhibit the
orexin neurons (leading to sleep).
Orexin neurons are also affected by satiety and hunger. Orexin neurons receive input from the suprachiasmatic
nucleus (circadian).

3.5 REM sleep

The features of REM sleep:

• Desynchronized EEG - the cortex is active.

• Rapid eye movements.

• Inhibition of skeletal muscle activity (legs, arms...).

• Muscles related to eye movements and muscles autonomic nervous system are not paralyzed.

• Blood flow to sex organs.

• Mental activity, narrative dreams.

• Controlled by REM-ON/ REM-OFF brain areas, as a flip-flop mechanism.

The main diffrence from the neurotransmitters systems that control the awake and SWS, is that the Acetylcholine
is activated (as in waking).
The corrical activity during REM also differ: the paralimbic cortex and the associated cortex increases activity;
while the primary visual cortex and the dorsolateral prefrontal cortex are decrease activity.

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Anatomy of REM sleep

The sublateraldorsal nucleus (SLD) is an area in the pons that have control of the REM ON. The ventrolateral
periaqueductal grey or for short, vl PAG is the REM-OFF region, it is located in the midbrain. The SLD and the
vl PAG inhibits one another. There are multi-synaptic pathways between the SLD (on) and vlPAG (off) that result
in mutual inhibition, a flip-flop system between REM ON and REM OFF.
The SLD neurons activate brain regions that initiate the activity characteristic of REM sleep:

1. Desynchronized EEG : Neurons from the SLD ascend to the basal forebrain and they activate the cholinergic
system. This activates the thalamus → then activate the cortex, and causes fast desynchronized EEG activity.

2. Rapid eye movements – another pathway goes to the tectum (superior colliculus), and that activates the
pathways that initiate lateral eye movements. Researchers have found in cats, that there is a coordinated
activity that starts in the pons goes in the thalamus and then to the occipital lobe. It is hypothesize that this
activity relates to the eye movement and to the visual aspects of dreaming.

3. Inhibition of spinal motor neurons - There are neurons in the SLD that descend to the spinal cord, and
synapse with the motor neurons. Then they inhibits those motor neurons during REM sleep and paralyzed
the skeletal muscles.

The SLD (REM on) and the vlPAG (REM off) inhibts each other, but there are some other mechanisms that effects
them. In the waking state the ARAS and the Orexin systems activates the vlPAG.
The transition from awake to SWS: Adenosine increase (doe to decrease in glucose) → Orexin neurons are less
active (unless we are hungry) → ARAS becomes less active → SWS becomes more active.
When awake, ARAS and orexin excite REM-OFF. BUT during SWS, they are inhibited. Because ARAS-orexin
neurons becomes less active during SWS, there will be LESS activation of REM-OFF. As REM-OFF becomes less
active, it weakens the inhibition of REM-ON and then REM-ON becomes active, and stimulates the areas that
cause REM sleep.

Awake Glucose decrease Adosine increase

Orexin is less active (unless hungry) excites

ke REM off - vlPEG
when awa
ARAS is less active

ibit
Orexin & ARAS inh REM on - SLD
e
SWS - VLPOA (GABA) activated REM off is less activ

3.6 Sleep disorders

Narcolepsy (type 1)

Narcolepsy is characterize by excessive daytime sleepiness, especially during monotonous activities. Another char-
acteristic is transitioning directly from awake to REM.
Type 1 - Cataplexy - going into REM sleep during waking state, the person hallucinate and paralyzed, but still
conscious. Those ”sleep attacks” is trigered by emotional stimuli.

13
Narcolepsy type 1 is consider to be a failure of the orexion system, which can be related to either:

• Failure to synthesize orexin.

• Dysfunction of one of the orexin receptors.

• Autoimmune disorder attacking orexin neurons. Higher prevalence in people with some autoimmune disease.

• Some patients show low levels of orexin in the CSF.

Concordance in monozygotic twins is low (25%) so there must be environmental causes. There has been an increased
incidence after certain influenza epidemics (H1N1), suggesting an environmental trigger.

Other descriptions of Narcolepsy type 1 are:

• Age of onset and course of illness is variable.

• Short bouts of sleep with frequent transitions - fail in the flip-flop systems.

• Dreams can occur during waking, usually in the transition periods - Cataplexy.

• If dreaming is during the transition from awake to sleep, it is called hypnagogic hallucination, and If dreaming
occurs during the transition from sleep to waking, it is called a Hypnopompic hallucination.
In both cases the person expiriance the dream and but still feels awake.

Drag treatment for narcolepsy:

Modafinil = Provigil : The mechanism of this drug is not known. Antagonized by noradrenergic alpha 1, but it is
not sure that this is the main mechanism.
Methyphenidate = Ritalin or Amphetamine : Blocks reuptake of catecholamines (dopamine and noradrenaline),(Modafinil
does not block catecholamine reuptake).

REM sleep behaviour disorder

This disorder is characterize by REM sleep without inhibition of motor neurons. Person acts out his/her dreams,
can be harmful if injured.
This is a Neurodegenerative disorder (loss of function of neurons). Can also occur following injury to REM ON
(SLD) area.
Treated with benzodiazepines (act on GABA receptors).

SWS disorders

• Night terrors – more common in children.

• Sleep-walking (can include eating).

4 Eating
Eating is basic behaviour related to survival. We are motivated to eat, and will risk danger to obtain food.
There are 2 main functions for food in our body: nutrients to build tissu, and energy.

14
Majur nutrients

• Amino acids – to enable formation of peptides and proteins.

• Carbohydrates.

• Lipids (fats).

The nutrients are needed for tissue formation, maintaining body temperature and energy consumption.

4.1 Energy
Glucose is the main molecule used by cells for energy production.
The brain uses 25% of the glucose and 20% of the oxygen consumed, (there are other molecules that can be
metabolized for energy). Other cells in the body can metabolize glucose or fatty acids, but the brain does not.
There are molecules that servers as reservoirs that can be metabolized for energy for the brain: Glycogen (short
term, storted in liver and muscles), and Adipose tissue (fat, long term).

4.2 Processes in eating

1. Absorptive phase - glucose levels are high: Insulin
(hormone) released from the pancreas, and it is needed
for cells in the body to absorb glucose.
The glucose transporters have insulin receptors, which
bind insulin and enable the transporter to carry glucose
across the lipid cell membrane.
In the brain, the glucose transporters do not have insulin
receptors, glucose can enter the cells without insulin.

2. Fasting phase - glucose levels are low: Glucagon is re-

leased from the pancreas. It stimulates breakdown of
glycogen to obtain glucose, and breakdown of fatty acids
and proteins (more extreme situation). High blood sugar → insulin release

Brain cells require glucose, other cells in the body can Low blood sugar → glycogen release
metabolize fatty acid for energy.

Homeostasis

Homeostasis allows regulation of around a set-point. This regulation requires a mechanism to detect deviations and
a negative feedback system to correct them.
The autonomic nervous system : Sympathetic (fight or flight) and Parasympathetic (rest and digest).
Some researchers prefer to adopt the term ”Allostasis” to indicate that the energy needs are variable and not
fixed. Their use of this term places more emphasis on modification of behaviour by learning and anticipating energy
needs.
To regulate eating behaviour, we must monitor the levels of glucose and lipids in the blood. Then, this information
must be transferred to the brain that initiate the satiety. The communication is both neuronal and hormonal.

15
Regulation of energy

Hormonal regulation at the level of hypothalamus-pituitary.

Neuronal regulation: hypothalamus → medulla→ autonomic nervous system.
There are individual diffrences in metabolism:

• Thrifty metabolism - able to preduse lots of energy reservoirs from a small amount of food.

• Spendthirft, inefficient metabolism - waste of energy (glucose)

4.3 Learning
Learning is involved in regulating eating behaviour.
Preferences or aversion for foods are learned and can conditioned to the taste and smell of the food (or to other
sensory stimuli).
If an animal is fed food that is missing an important nutrient, it will sample novel foods until it finds the food with
the missing nutrient (Rozin 1969). The animal will avoid novel food in general, but if it gets sick after eating a
certain food it will develop an aversion to that taste – conditioned taste aversion (Garcia et al. 1966).

4.4 Neuronal and hormonal signals in eating

We have the Ghrelin as hormonal signal; and the Glucose and Lipids as neuronal signals.

Signals to eat from the body:

• Ghrelin : Peptide hormone released by the stomach & small intestine (the duodenum) in the absence of
food. It acts on hypothalamus to stimulate eating. The ghrelin is released just before meal time to stimulate
eating. The presence of food in the duodenum inhibits the release of ghrelin from the stomach.
Ghrelin is not essential for eating.

Prader Willi syndrome – characterized by over-eating. Ghrelin levels are high even when the stomach is full.

• The Liver : Glucose and lipid deprevation signals to the brain that it is time to eat - neuronal signal, this
signal transforms to the Vagus nerve.
Hepatic portal vein from digestive tract to the liver allows the liver to monitor contents of digestive system
before nutrients are absorbed into the blood stream from the intestines.
If the receptors in the liver does not feel glucose or lipid for a long time they signals to the Vagus nerve. The
vagus nerve stimulates areas in the brainstem that will signal hypothalamic areas that initiate eating.

Vagus nerve : It is one of the cranial nerves (10th out of 12). This is the parasympathetic nerve that goes to all
inner organs.

Signals to eat in the brain:

Two areas of the medulla (Brain stem) have cells that are glucoreceptors - cells that monitor the presence of glucose
in the blood: Area postrema, and Nucleus of the solitary tract.

16
 lack of lipids
or glucose

Liver Vagus nerve Brain stem Lack of food

Eat! Hypothalamus Ghrelin

4.5 Satiety
We have satiety signals from the digestive system to the brain:

1. Short term signals:

(a) Mechanoreceptors for stomach tension.

(b) Nutrients in digestive tract:
i. CCK cholecystokinin - Secreted in small intestine due to the presence of fat. It stimulate the vagus
nerve that inform the brain about the fat – cessation of eating.
Mice that don’t produce CCK are not overweight, indicating redundancy. This is not an exclusive
mechanism for regulating food intake.
ii. PYY peptide YY - Secreted in small intestine. The secretion is proportional to the caloric value of
the food, (Water alone will not induce PYY secretion).
iii. Negative feedback to ghrelin production (as discussed before).
iv. Insulin - The pancreas produces insulin while absorptive phase. There are neurons in the hypotha-
lamus that have insulin receptors and monitor the level of blood insulin, even though the brain is
not dependent on it.

2. Long term signals:

(a) Glucoreceptors in brain and liver.

(b) Leptin is preduse by the adipose tissue (fat) and makes us stop eating. Leptin also inhibits ghrelin.
Mice that don’t produce laptin are obese.

We can devide the mechanisms that regulates eating to 2 groups; according to the influence on the body in their
absence:

• Normal body weight:

1. No ghrelin or no ghrelin receptors.

2. Cut vagal nerve from digestive tract.
3. No CCK.

• Obese:

1. No insulin receptors in the brain.

2. No leptin.

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 Food negative
feedback Ghrelin

ibit
inh

Fat tissu Leptin Stop eat! Vagus nerve CCK secrete

Hypothalamus PYY secrete

Stomach tension

Small intestine
Pancreas Insulin

Food

4.6 Pathways regulating eating in the brain

The medulla receives signals from the vagus nerve and it also have glucoreceptors thet monitor the glucose levels
in the blood.
The vagus nerve is activated by low levels of glucose and lipids to promote eating. The vagus nerve ends in the
”nucleus of the solitary tract” and the ”area postrema”, and those areas also have glucoreceptors.
Therefore the vagus nerve is affected by: Presence/absence of glucose, lipids and presence of fat in the liver and
small intestine.
These peripheral signals combined with the CNS glucoreceptors in the medulla that activate neurons which will
activate/ inhibit the hypothalamic nuclei that stimulate eating.

The solitary nucleus receives the information about eating and nu-
trients is located near to the nuclei that regulate sensory and motor
funcion of the mouth and throat. The feeding is regulated by neu-
rons that originated in the solitary nucleus and the area postrema.
Axons from those areas ascend to the hypothalamus and release neu-
ropeptide Y (NPY).

NPY :
NPY is a peptide that increases eating when injected, including bit-
ter tasting food (which animals tend to avoid). NPY also increases
motivation of animals to work for food.
AgRP - agouti related peptide: is co-released with NPY.
Ghrelin (the hormone released by the stomach): activates NPY neu-
rons in the hypothalamus, thereby INCREASING the excitation and
tendency to EAT.

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The Arcuate nucleus (ARC) ARC also release NPY and its neurons synapses in the Lateral hypothalamus (LHA)
and the Paraventricular nucleus (PVN). The LHA is the area that stimulate the eating behaviour by releasing
Melanin concentrating hormone (MCH) and Orexin.
The MCH and orexin stimulate appetite. There is an increase in both locomotor activity and orexin release before
a meal and decrease after a meal. Orexin regulates activity and feeding, increased activity helps the animal seek
food.

4.7 Interaction with metabolism

Another pathway from the arcuate nucleus synapses in the Paraventricular nucleus (PVN) of the hypothalamus.
Neurons in the PVN then descend to the brainstem to affect the autonomic nervous system: Increase in parasym-
pathetic and a decrease in sympathetic activity.

4.8 Effects of hormones on feeding mechanisms

• Increase eating : Ghrelin and leptin have opposite effects: Ghrelin excites and leptin inhibits the NPY/AgRP
neurons in the medulla and in the hypothalamus.
Hormones participate in the regulation of eating behaviour independently of the vagus nerve.

• Decrease eating : Anorexigenic peptides:

1. CART - cocaine and amphetamine regulated transcript. Amphetamine and cocaine decrease appetite
hence decrease eating.
2. α MSH - α melanocyte stimulating hormone.

These 2 peptides are co-released from the same neurons, that located in the arcuate nucleus. Leptin (from
adipose tissue) excites neurons that release α-MSH/CART, and inhibits neurons that release NPY/AGRP.
REMEMBER: Mice without leptin become obese.

Ghrelin inhibits the neurons that secrete CART and α-MSH.

AgRP (which increases eating) and αMSH (which decreases eating), bind to the same receptor MC4. There are
peptides with opposite effects on eating that bind with the same receptor.
αMSH is an agonist on the MC4 receptor.
AgRP act as an Inverse Agonist - an agonist that binds to the receptor and reverses the ongoing activity of the
receptor. It causes the opposite effect as the agonist.

19
The MC4 has a constitutive activity, the receptors are active all the
time. Receptors often have a second messenger; that is the cyclic
AMP in this case. The cyclic AMP produced on a regular basis,
but AgRP blocks this. This explains how AgRP produces increased
eating by acting on the same receptor as αMSH.

4.9 Eating and reward

Dopamine : The dopamine cell bodies are in the ventral tegmental
area and substantia nigra of the midbrain. The axons projects to
the forebrain (Nucleus accumbens, Striatum, Frontal cortex). An-
imals will perform an operant response (e.g, bar press) to receive
stimulation of these neurons or injection of dopamine agonists.
Dopamine neurons have ghrelin receptors. Ghrelin modulates the dopamine neurons while promoting appetite.
Dopamine neurons increase firing rate if ghrelin is injected into the VTA. Activation of dopamine neurons in the
midbrain ventral tegmental area (VTA) is related to pleasure/ reward.

Leptin inhibits eating behaviour because it modulates the sweet taste sensitivities. It does not affect the other
tastes. Leptin induces outward flow of K+ , which increases inhibition in the neurons.

Endocannabinoids increase the sensitivity to sweet taste, but not to other tastes at the level of responsivity of
the gustatory nerves. The response of animals that was given natural ligand for the cannabis receptor was greater
to sweet, than the response of animals that received a control substance.

4.10 Hunger relieves pain

Acute pain causes animals to stop eating and tend to the part of the body that hurts. Inflammatory pain is long-
lasting and the animal must eat to survive. The peptides that promote eating normally also suppress the response
to inflammatory pain and enable the animal to eat. If the animal is hungry and have an inflammatory pain, it will
feel less pain.
When an animal is hungry the activity of neurons that release AgRP is increased. These neurons also project to
an area in the brainstem that mediates the behavioural response to inflammatory pain. The AgRP neurons inhibit
the pain via action on a certain receptor for NPY.
Conclusion: The peptide system that encourages eating will also reduce inflammatory pain to enable the hungry
animal to eat.

4.11 Eat disorder - Parder-Willi

Prader-Willi is a genetic developmental disorder linked to chromosome 15 (3 different genotypes).
It characterize by:

• Severe overeating – hyperphagia, including non-food items (associated behaviour problems - theft, etc).

• Sexual maturation delayed/impaired.

• Low metabolic rate.

• Mild intellectual disability and psychiatric disorders may be present.

20
Hypotheses of dysfunction in P-W syndrome:

• Evidence for hormonal dysfunction is unclear as there are conflicting reports.

• Brain activation studies suggest less function in areas of interoception (perception of internal senses).

• Addiction- Hyper-responsiveness of reward circuit in response to food.

5 Motivation, Reward & the Dopamine System

Thorndike’s Law of Effect:

Behaviour is shaped by evaluation of the outcome of the action, based on experience.

Pleasure → Greater probability that the behaviour will be repeated.
Aversive → Lower probability that the behaviour will be repeated.
Greater probability that a behaviour that allows the animal to escape or to avoid the aversive stimulus will be
performed.

Operan conditioning

Positive reinforcement : a reward after a certain behaviour (increased responding), a panishment after a certain
behaviour (decreased responding).
Negative reinforcement : if the animal escpae or avoid an aversive stimulation.

Olds and Milner discovered (by accident) that stimulation of the medial forebrain bundle in the hypothalamus
is rewarding. Animals do not become satiated with brain stimulation and will forego food and water in order to
press the bar for stimulation.
Animals will perform an operant response for brain stimulation in many areas of the brain, we will focus on the
medial forebrain bundle: a pathway between the brainstem and basal ganglia, limbic system and frontal cortex.
The reward that is based on stimulating this bundle of axons depends on the integrity of dopamine neurons in the
axons from the midbrain to the limbic system and frontal cortex.
The dopamine neurons cell bodies are in the VTA (ventral tegmental area) and substantia nigra. the axons ascend
to the mideal forebrain boundle and terminals in the nucleus accumbens and striatum (basel ganglia and limbic
system).

Release of Dopamine from those neuron was found to be link with:

• Natural rewards (food, sex...).

• Many drugs of abuse: cocaine, heroin, cannabis.

• Dopamine antagonists injected into the nucleus accumbens blocks operant and classical conditioning based
on these rewards (food, drugs, sex, brain stimulation).

It was also confirmed with optogenetic stimulation (more precise method) of the dopamine neurons in rats. To test
the stimulus effects the researchers used classical conditioning.

21
Human Studies

In the last decade of the 20th century, many studies were done with fMRI to show increased activity in the nucleus
accumbens or orbital frontal cortex when people viewed “rewarding” stimuli.
But there are problems with fMRI studies: Pleasurable stimuli increase activity in the nucleus accumbens, but does
increased activity in the accumbens imply that the person feel pleasure? (Reverse inference)
One way to find out is to see if there is a correlation between the increased accumbens activity and the behaviour
of the person towards the stimulus that increased the activity.

Theories of dopamines’s role

1. Schultz - reward prediction error (RPE) :

The reward prediction error theory is based on studies in which action potentials from DA (dopamine) neurons
in the monkey’s brain were recorded during a classical conditioning experiment. The firing rate of the dopamine
neurons predicts wether the reward is going to come or not.

• CS (condition stimulus) – Light, Tone, or picture presented on a screen.

• US (uncondition stimulus) – juice.
• CR (condition response) – licking the juice spout.

First, they presented a CS (picture) followed by a US (reward). The neurons increase their firing rate after
the monkey receives the juice or food. As they continued to train the monkeys, they found that the firing
rate of the neurons predicted the onset of the US.
Reward prediction error - As the monkey learned that the CS predicts the US, there was an increase in firing
of the DA neurons after the CS and NOT after the US.
Different CSs predict different amounts of juice. The firing rate of the DA neurons is correlated with the size
of the expected reward.
The DA response to the duration of the delay from the CS to the US. The longer the animal has to wait the
less the DA fires. When the animal gets the reward the firing rate is greater if the wait was longer.
The firing rate also corresponds to the relative value of the US.

2. Bromberg-Martin - Revised theory, Motivational salience :

Some neurons increase their firing rate to both positive and aversive stimuli. These motivate and arouse the
animal to ALL relevant stimuli (and not to the value of the stimulus) – Motivational salience.
The dopamine neurons have 2 different roles:

(a) Saliencs coding DA neurons - The stimulus is important.

(b) Value coding DA neurons - the value of the stimulus is important.
* Both types will response for an alerting signal as well. The neurons will respond to a novel stimulue if
the animal is quiet and awake and not motivated by something more interesting (like inaccessible food).

The Habenula

The lateral habenula in the dorsal part of the midbrain, has neurons that react in an opposite way to the midbrain
DA neurons. Those neurons increased firing rate to aversive signals and decreased firing rate to rewarding signals.
Stimulation of the habenula was successfully used to treat depression.

22
6 Drug addiction
Research in rats has established that many “drugs of abuse”
increase the release of dopamine in the nucleus accum-
bens and that blocking dopamine receptors will reduce self-
administration of these drugs (pressing a bar to obtain the
drug).
This is true of: Alcohol, cannabis, nicotine, cocaine and am-
phetamine.
Drug from the opiate family (morphine, heroin) are reward-
ing even after the DA receptors in the nucleus accumbens are
blocked by an antagonist. This is because there are opiate
receptors on the post-synaptic glutamate neurons in the ac-
cumbens.
All the dugs of abuse stimulate the Dopamine neurons in the VTA, or the post synaptic glutamate neurons in the
nucleus accumbens.

6.1 Cocain
Cocain is a psychostimulant which has been the subject of much of the research in the laboratory and in human
drug users.
Amphetamine, cocaine, methamphetamine and methylphenidate inhibit reuptake of catecholamine. Amphetamine
also causes the DA transporter to operate in reverse and actually release more dopamine.
Drugs of abuse stimulate the reward circuit but what causes addiction?
There are two theories:

1. Enhanced positive reinforcement, increasing the craving for the drug.

2. Negative reinforcement. Drug withdrawal causes symptoms that are opposite to those of the drug: anhedonia
(lack of pleasure). The drug relieves these aversive feelings.

If we take the drug we feel much better, the reword system react to this feeling (stimulus) and down-regulate the
system – nothing is enough to the person anymore. Then you become anhedonic and want to take the drug again,
becouse you don’t feel good in any other way.

6.2 Anhedonia
The “high” that one gets from drugs is likely to be greater than those of everyday life. It is “too good to be true”
and is stronger than a normal physiological expression of reward.
Repetitive stimulation of neurons causes neural adaptation → tolerance to the effect of the drug.
Tolerance: With repeated use, the neural system becomes less sensitive and a higher dose is needed to establish the
same effect.
Physiological systems compensate for the increased stimulation by down-regulating the system that is being stim-
ulated.
Examples of down-regulation that can lead to tolerance: Endocytosis of post-synaptic receptors. Receptors number
and sensitivity is constantly being adjusted and modified. After stimulation, the post-synaptic receptors can be
removed from the membrane to the cytosol.

23
The drug may be metabolized more efficiently. This is a known effect for metabolism of alcohol.

6.3 Good feeling

Roy Wize emphasized the hedonic aspects of drug use and the craving at the earliest stages of drug use.
Wise measured the interval between bar-presses for cocaine in rats that had 4 hour access to cocaine daily. As the
days goes by the intervals between the bar press becomes smaller, the rat presses more “compulsively” for the drug,
The rat enjoy more from the reward.

Synaptic currents were measured from DA neurons in brain slices of rats that had been treated with Saline or drugs
24 hr before recording.
The ratio of AMPA/NMDA (glutamate receptors) current was higher in the neurons of the rats that had received
the drugs once (in the post synaptic neuron).
Conclusion: Basal level of excitability in these neurons increases.
But this effect lasted between 5-10 days and it appears after 1 treatment.

6.4 Withdrawal
George Koob emphasizes the role of the withdrawal symptoms on the recidivism. The “anti-reward” system is
blocked in the presence of the drug and becomes sensitized. When the drug is withdrawn, the anti-reward system
is expressed as an aversive state. In the case of opiates, there is actually pain upon withdrawal. The person seeks
the drug to combat this negative feeling.

Plastic changes after chronic drug use

After long term use other intracellular adaptive mechanisms are increased. One of those mechanism is expression
of a transcription factor called CREB [cAMP response element-binding protein] in the nucleus accumbens.
CREB can decrease the release of DA in the accumbens by different mechanisms, thereby causing what are referred
to as opponent process effects. These processes leads to down-regulation of the response to DA and is one of several
mechanisms of what is known as opponent-processes or the “anti-reward” system.
The opponent processes are not felt as long as the drug is present. But when the drug is no longer there, they will
become evident: Instead of pleasure the person will feel anhedonia. The threshold for pleasure can be elevated by
tolerance to the euphoric effects of the drug. This mean that the person is less likely to feel pleasure from anything
but the drug.

Classical conditioning to drug cues

The cues associated with the drug reinforcement can induce craving in a person who is trying to stop using the
drug. Presenting the CS (after withdrawal) triggers the association between the CS and the US, and strengthens
the response (Reconsolidation).

Sterss

In addition to the anhedonia the person become stress. We crave drugs to feel pleasure → We take drugs to escape
the pain of drug withdrawal → Anhedonia is stressful.

The stress response developed in order to allow an animal to expend energy intensely in a short period of time at
the expense of processes that are involved in building and repairing tissue.

24
There are two major processes which are initiated by neurons projecting from the amygdala to the hypothalamus:

1. Activation of the hypothalamic-pituitary-adrenal (HPA) axis which releases cortisol in the blood.
HPA: hypothalamus release CRH (Corticotropin releasing factor ) → the patiutary release ACTH → Adrenal
gland release cortisol → the cortisol will affect receptors in the patiutary and hypothalamus → inhibits the
release of ACTH and CRH.

2. Activation of the sympathetic nervous system.

7 Sterss
7.1 Sterss and cognition - behaviour
Different studies support conflicting conclusions with regard to the role of stress in enhancing or impairing cognitive
function.
Anecdotal evidence suggests that stress helps to consolidate associated stimuli and events, such as “where were you
when...?”. But experimental studies do not always support this claim. To resolve this problem, Diamond looked at
the effect of stress on LTP (long term potentiation) in the amygdala and hippocampus.

Fear conditioning

Warning stimulus Aversive stimulus Espace - negative reinforcement

With repeted trails Avoidance

If the animal developed avoidance it will not get the aversive stimulus, but will continue to preform the avoidance
response - this response will not extinct.

Mowrer’s 2-factor theory states that the Tone-Shock association leads to conditioned fear.
Fear is the aversive stimulus that the animal will escape when performing what is called an avoidance response.
And avoidance is really escape from fear.

Fear conditioning is the behavioral model for some psychopathology. Behavioural therapy is based on the principle
of extinction of the conditioned fear. With humans there is also the “cognitive” element CBT, but the principles
are based on research on fear extinction.

7.2 Physiology of stress

The HPA axis and the noradrenaline system

The HPA axis - Hypothalamus, Pituitary and Adrenal.

The amygdala is the main area of the brain that precive sensory
stimuli that predict pain. It projects to the hypothalamus →

25
that produces a hormone (CRH) → the CRH goes to the pituitary that also produces a hormone (ACTH) → ACTH
affects the adrenal gland outer layer that secrete cortisol.
The hippocampus and the anterior cingulate cortex inhibits the stress response.
*Cortisol and Corticosterone is known as a glucocorticoids.

Cortisol

Cortisol has 2 main types of receptors that are designated Type 1 and Type 2 and they are defined by different
levels of AFFINITY for cortisol.

• Type 1: High affinity receptor – Most of these receptors in the hippocampus are bound during daily routine
functions, easy bind.
Type 1 receptors reduce the hyper-polarization at the end of the action potential. Less hyper-polarization
→ refractory period is less → easier for the neurons to become excited again, this increase the ability for
long term potentiation and learning. If a glutamate cell in the hippocampus is firing at a moderate rate, the
shorter period of hyperpolarization will increase excitability and facilitate cognitive function.

• Type 2: Low affinity receptors – Will bind cortisol only if it is in a high concentration, as during the stress
response.
Type 2 receptors increase the hyper-polarization at the end of the action potential. This occurs during stress
and reduces the excitability of neurons.

Diamond et al. found changes in NMDA receptor sensitivity after stress. These changes were different in hippocam-
pus and amygdala:

• NMDA receptors in the hippocampus are activated for a short time and then desensitized which might explain
impaired episodic memory.

• NMDA receptors in the amygdala remain sensitive for a long time (minutes to hours). This could account for
“flashbulb memory”, the memory of the sensations and emotions.

Diamond suggests that the difference in the effect of stress on the amygdala and hippocampus explain some of the
seemingly conflicting data.

The stress effects on the body

Another arm of the stress response is :

1. Activation of the sympathetic nervous system.

2. Activation of ascending noradrenergic neurons of the reticular formation. Moderate tonic firing rate allows for
better performance in signal detection tasks → alertness. High firing rate will lead to distraction and ’false
alarms’.

* more information in the Sleep chapter.

There are descending pathway from hypothalamus to brainstem to activate sympathetic nervous system.
Secretion of adrenaline/noradrenaline from the medulla of the adrenal gland also activate stress.

Then we can see on the person: Increased heart rate and blood flow to skeletal muscles, Pupil dilation; and
Behavioural responses to danger: Fight, Flight, Freeze (alert but immobile).

26
Perception of feeling

Psychologists and physiologists debate whether the physiological reaction causes the emotion or whether the phys-
iological and emotional response are concurrent.

• William James – peripheral feedback theory: Feeling depends on perceiving and interpreting peripheral phys-
iological responses. Meaning that the emotions drives from feeling the change in the physiological state of the
body.

• Cannon–Bard theory: Emotion and physiological reaction are concurrent. Stimulation of the hypothalamus
in a cat produced “sham rage”- a behaviour that resembled the “fight” response. Cannon- Emotions originate
in the hypothalamus which receives sensory information from the thalamus. The cortex is not required for
the basic emotion, Cortex is involved in feeling – interpretation of the emotion.
Papez emphasized the importance of “paralimbic” areas, particularly the cingulate gyrus. Paralimbic cortex
is anatomically most closely linked to the limbic system.
Damasio proposed the “somatic marker hypothesis”. Feelings are derived from interpretation of the physio-
logical response.

7.3 Anatomical basis of fear conditioning

Le Doux found that the lateral amygdala (LA) nucleus receives
sensory input from the thalamus and the cortex. Conditioning
involves LTP so that the “weak” auditory stimulus is strength-
ened when presented with the “strong” somatosensory (foot
shock) stimulus. The location of the “Hebbian synapse” is in
an adjacent amygdala region. The output from the amygdala
to other brain areas is through neurons whose cell bodies are
in the central nucleus (CE).
Amygdala output to hypothalamus, midbrain (PAG) and
medulla – the sympathetic and parasympathetic systems.
Additional output to areas involved in reward and goal directed behaviour: Nucleus accumbens, Ventromedial
caudate, Ventral putamen.
PAG – lateral – defensive behaviour.
Ventrolateral – withdrawal and quiescence – how does an animal act in pain?
Amygdala output to these areas arrests goal directed behaviour.

Le Doux also found that stimulation of the frontal cortex was able to inhibit the response of the basle lateral nucleus
to those fear stimuli.

Fear conditioning and reward conditioning are both mediated by connections between limbic and cortical areas.
Neurons show diverse patterns of correlated activity (Most of the neurons they sampled were NOT correlated). The
pattern of correlated activity predicted the behavioral response to the cues.

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8 PTSD - Post Traumatic Stress Disorder
8.1 Stress and PTSD
The trauma is the uncondition stimulus, and the symptoms are the conditioned response.
Translational Research - looking at basic mechanisms in the laboratory in animals. By trying to analyze how we
can decrease the conditioned response we may find ways to help people that have PTSD.

PTSD patients vary greatly in:

• Origin of trauma (war, rape, crime, natural disaster, etc.)

• Demographic variables such as sex (gender).

• History of past trauma.

8.2 Brain areas and PTSD

In order to ask which relevant areas potentially have brain damage, we go back to basic preclinical research. The
areas that are important for conditioning and extinction are:

1. Amygdala - necessary for fear conditioning.

2. Hippocampus – context memory, episodic memory; Findings in people with PTSD are not clear.

3. The frontal cortex: The Ventromedial prefrontal cortex (VMPFC) and the Anterior cingulate cortex.

The prefrontal cortex and amygdala

When a person increase his emotions regards to a negative picture the activity in the amygdala is increased. When
decrease negative emotions, there is a negative correlation between the activity in the ventromedial prefrontal cortex
and in the amygdala.
Similar to the rats in Le Doux’s studies who had electrical stimulation of the infralimbic cortex, activation of the
ventromedial prefrontal cortex is associated with decreased activity of the amygdala when the person is down-
regulating negative emotions.

People with PTSD have impaired functioning or smaller volume of the VMPFC or ACC (anterior cingulate cortex).

8.3 Treating PTSD

If a disorder is related to fear conditioning, can it be alleviated with behavioural therapy?
When the CS is presenting without the US, we will expect to see Extinction.
Extinction is a learning process that involves activating genes and forming proteins – similar to the molecular
processes involved in consolidation of memory. Both involve CREB-mediated processes (as mentioned for addiction)
and upstream molecular changes. Extinction also entails forming new connections with frontal cortex and/or
hippocampus to inhibit the amygdala stress response.
During extinction the neural connections become labile (unstable) within a certain time window. New learning –
the CS predicts safety if it is not followed by US. New learning recruits the frontal lobe areas.

Reconsolidation: When the CS is presented, the CS-US neural pathway is excited. For a brief period of time,
the memory is labile and new proteins are formed to ”reconsolidate” the memory. Studies in rats showed that if

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the formation of new proteins is blocked by injection of antibiotics in the amygdala, the rat will no longer show
freezing to the sound of the CS tone.

This means that CS presentation can result in reconsolidation, but if repeated in a certain window of time when
the connections are labile, extinction can occur.

Strategy for treatmen: present CS to make the connections labile → in this time window, continue to present
CS without US to achieve extinction.

PTSD treatment with Cannabis

Several mechanism of action have been found including: limiting release of neurotransmitter, limiting action of
second messenger and even limiting glutamate synthesis via its action on astrocytes. We will only look at the
effects on memory reconsolidation.
Reserchers found that THC blocks reconsolidation of fear conditioning in rats. The THC had a long lasting effect;
The rats were re-tested on day 22 and those who had received THC still showed less freezing.
To test the pharmacological specificity of the THC for cannabis receptor CB1, the experiment was repeated using
a double injection of THC and an antagonist (AM251) into the cortex. Only rats that received THC without the
antagonist showed a reduction in freezing upon re-exposure to cage in which they had received a shock.
Cannabis has 2 psychoactive components: THC and cannabidiol (CBD). CBD is not known to cause psychotic side
effects. They injected a sub-effective dose of THC combined with CBD and found that the combination prevented
reconsolidation of the fear response.

9 Depression
9.1 Symptoms and approach to understanding depression
• Vegetative symptoms involving changes in sleep and eating patterns (more or less than usual).

• Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings
of restlessness or being slowed down). Fatigue or loss of energy nearly every day.

• Predominantly depressed mood or in the case of bipolar depression fluctuations between manic and depressed
mood. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every
day (not merely self-reproach or guilt about being sick).

• Rumination - Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a
specific plan, or a suicide attempt or a specific plan for committing suicide.

Evidence for hereditary and environmental etiology

From twin studies: 69% concordance in monozygotic twins vs 13% concordance in dizygotic twins.
The research in depression was guided by the ex juvantibis (from Latin “from what pleases”) approach in medicine.
This is based on the assumption that the drug that “relieves” the symptoms of a disease is attacking the source of
the disease - then we can understand the source. For example, if you are diabetic and have low glucose momentarily,
it will save you if you ingest glucose.

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Patients with tuberculosis were treated with iproniazide, a drug that inhibits monoamine oxidase, the enzyme that
metabolizes monoamines. It was observed that this drug improved the mood of patients, so they decided to try it
on depressed patients, and it also improved their mood.
This led to drug company development of drugs that enhanced the action of the monoamines, particularly serotonin
and noradrenaline. In parallel, genetic research focused on candidate genes involved in uptake serotonin.

9.2 Antidepressant medication

Tricyclic anti-depressant
Drugs that are in this group act as: Specific serotonin reuptake
inhibitors (SSRI), specific noradrenaline reuptake inhibitors, or
serotonin noradrenaline reuptake inhibitors.
Treatment is based on prevention of monoamine reuptake into
the presynaptic terminal.
The more modern drugs are labelled “specific” only because com-
pared to the tricyclic anti-depressants, their action is more lim-
ited to one type of transporter. But they are not more efficient
that the older tricyclic drugs.
About one third of patients are refractory to treatment with
anti-depressants called Treatment resistant depression (TRD).

MAO (monoamine oxidase) inhibitors

Tyramine is found in certain foods. It is metabolized by MAO. People who use MAO-inhibitor drugs must avoid
foods that raise amine levels: chocolate, some alcoholic drinks, dried fruit, cured meats, aged cheese, pickled foods.
Newer drugs are reversible inhibitors of MAO (RIMA). When the level of the substrate (e.g., tyramine) is elevated,
MAO can be activated.

Serotonin

A low-tryptophan diet can worsen symptoms of depression. This can be alleviated by SSRI medication. Tryptophan
is the precursor of serotonin → decrease in serotonin in the brain → worse symptoms.
However, some patients react better to inhibitor of noradrenaline reuptake rather than to SSRI.
Despite many studies that examined levels of serotonin or noradrenaline markers in blood, CSF or other peripheral
tissue, we cannot conclude that there is a serotonin or adrenergic “deficiency”.

Time to effect

Antidepressant effect onset is usually at least 3 weeks.

There are at least 14 different receptors: presynaptic, post-synaptic, heteroreceptors, etc. When the synapse is
“flooded” by blocking serotonin uptake, it is difficult to isolate those responsible for the therapeutic affect.

9.3 Ketamine
The treatment of depression focused mainly on the monoamines, as per the ex juvantibis logic that was mentioned.
The importance of the monoamines in the regulation of sleep/wake cycles, attention and reward has been outlined
in previous chapters.

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However, the slow onset of the therapeutic effect and the large number of patients who don’t respond to the typical
antidepressants has led researchers to explore a drug that acts on glutamate.
Ketamine is an antagonist of the NMDA receptor, but it actually increases the release of glutamate.

Researchers found that the Ketamine has a rapid anti-depressant effect that last longer. It also peaks at 24-72
hours after the injection, and it dissipates after about 2 weeks.
People who were resistant to typical anti-depressants respond well, but need repeated injections.

Hypothesized mechanism of action:

Ketamine blocks NMDA receptors on interneurons that inhibit glutamate neurons. This causes disinhibition of
neurons that release glutamate.
Glutamate transmission is increased in the medial prefrontal cortex in patients with treatment resistant depression
after takin ketamine.

9.4 Environmental hypothesis: early stress

Women who underwent early life stress (ELS) were 4 times more likely than those who didn’t to be diagnosed with
depression as adults.
The researchers found higher levels of ACTH following the social stress in the women who had early life stress.
When they compared the benefits of Drug treatment, Psychotherapy or Both, the women with ELS benefitted more
for psychotherapy. Integrating therapy with medication provided no added benefit.

Animal research

Animal models of depression usually involve some form of early stress that has lasting impact on brain development
and HPA axis function.
Manipulations that lead to depressed behavior in the offspring:

• Maternal deprivation.

• Prenatal stress (of the pregnant animal).

• Poor maternal care or entropy (unpredictable maternal care): The less nesting material the mother had, the
higher the corticosterone levels in the pups’ blood. The number of times the mother went in and out of the
nest was correlated to higher levels of the stress hormone in the pups’ blood and to lower body weight.
The unpredictable maternal care affects the development of the pups. When the pups become adult they
shown higher levels of corticosterone, and lower levels of mRNA for the hypothalamic hormone CRH (CRF)
- effects of early stress.
Another study showed that as adolescents, rats that were raised by mothers that had inadequate nesting
conditions showed more signs of (rat) depression → Early stress increases the risk for depression.

Human research

Participants are shown negative pictures and instructed to downregulate their negative emotions using reappraisal.
The researchers found a negative correlation between activity in the amygdala and VMPFC.
When they looked at the activity in depressed vs healthy controls, they found that the control participants showed
the predicted negative correlation whereas the depressed patients showed a positive correlation.

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They found that the healthy controls showed less activation of stress-reactive areas: amygdala and insula when
their pupils were more dilated (negative correlation). The depressed patients showed a positive correlation. The
harder they tried, the more activity in the amygdala and insula were.

By focusing on glutamate, researchers hope to find drugs to rectify the imbalance between frontal-limbic connectivity.

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