Origin of Vertebrate Telencephalon

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Advances in Anatomy
Embryology
and Cell Biology
Editors
F. F. Beck, Melbourne · F. Clascá, Madrid
M. Frotscher, Freiburg · D. E. Haines, Jackson
H.-W. Korf, Frankfurt · E. Marani, Enschede
R. Putz, München · Y. Sano, Kyoto
T. H. Schiebler, Würzburg
F. Aboitiz · J. Montiel
Origin and Evolution

of the Vertebrate
Telencephalon,
with Special Reference
to the Mammalian Neocortex
With 15 Figures
123
Francisco Aboitiz, Dr.
Departamento de Psiquiatría
Escuela de Medicina
Pontificia Universidad Católica de Chile
Santiago
Chile
Juan Montiel, Dr.

Facultad de Ciencias de la Salud
Universidad Diego Portales
Santiago
Chile
ISSN 0301-5556
ISBN 978-3-540-49760-8 Springer Berlin Heidelberg New York
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List of Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2 Evolution of the Vertebrate Nervous System and Telencephalon . . . . . . . . . . 7

2.1 Animal Phylogenetic Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.1.1 Origin and Diversification of Metazoans . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.1.2 Phylogenetic Origins of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . 8
2.1.3 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.2 The Origin of Vertebrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.2.1 Early Theories and Fossil Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.2.2 The Neural Crest and Placodes in Vertebrate Origins . . . . . . . . . . . . . . . . . 16
2.2.3 Olfactory Placode and Epithelium: Association with Adenohypophysis . . . . . 19
2.2.4 Origin of the Telencephalon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.2.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.3 Evolution of the Telencephalon in Vertebrates . . . . . . . . . . . . . . . . . . . . . . 24
2.3.1 Taxonomical Relationships Among Vertebrates and Their Early Evolution . . . 24
2.3.2 Evolution of the Cerebral Hemispheres: Ventral Telencephalon . . . . . . . . . . 28
2.3.3 The Brain of Jawless Fishes and the Organization
of the Ancestral Dorsal Telencephalon . . . . . . . . . . . . . . . . . . . . . . . . . . .. 29
2.3.4 The Pallium in Jawed Vertebrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 31
2.3.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 33
3 Origin of the Mammalian Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

3.1 The First Mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3.1.1 Fossil Mammals and Their Brains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3.1.2 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
3.2 Origin of the Mammalian Neocortex: Hypotheses on Homology . . . . . . . . . 38
3.2.1 Mammalian Brain Expansion and the Origin of the Neocortex . . . . . . . . . . . 38
3.2.2 Hypotheses for Neocortical Origins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.2.3 The Recapitulation Hypothesis: Connectional Evidence . . . . . . . . . . . . . . . 40
3.2.4 The Dorsal Cortex of Reptiles: Subicular and Neocortical Characteristics . . . 41
3.2.5 Differences in Connectivity Between the DVR and the Neocortex . . . . . . . . . 43
3.2.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
3.3 Embryological Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.3.1 Developmental Criteria for Homology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.3.2 Dorsoventral Gradients and Expansion of the Dorsal Pallium . . . . . . . . . . . . 52
3.3.3 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
3.4 The Olfactory–Hippocampal Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . 54
VI List of Contents
3.4.1 A Functional Interpretation of Dorsal Pallial Expansion

in Mammalian Origins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
3.4.2 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
3.5 Origin of Neocortical Lamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
3.5.1 Laminar Organization of the Neocortex . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
3.5.2 Comparison of Mammalian Neocortex and Reptilian Cortex:
Layer Homologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... 60
3.5.3 Is There a Preplate in Reptiles? . . . . . . . . . . . . . . . . . . . . . . ........... 62
3.5.4 Origin of the Inside-out Developmental Gradient . . . . . . . . . ........... 64
3.5.5 Pioneer Neurons and the Transition from a Tangential
to a Radial Synaptic Organization in the Neocortex . . . . . . . . . . . . . . . . . . . 66
3.5.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3.6 Expansion of the Neocortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
3.6.1 Multiplication of Cortical Areas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
3.6.2 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
4.1 An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
4.1.1 Early Neuronal Differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
4.1.2 Patterning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
4.1.3 Diversification of the Hemispheres and Neocortical Origins . . . . . . . . . . . . . 74
4.1.4 Olfaction, the Hippocampus and the Amygdala . . . . . . . . . . . . . . . . . . . . . 75
4.1.5 Cortical Lamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
4.1.6 Tangential Expansion and the Origin of New Areas . . . . . . . . . . . . . . . . . . . 77
4.2 Issues with Evolutionary Theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
4.2.1 Genetic Conservatism Versus Morphological Diversity . . . . . . . . . . . . . . . . 77
4.2.2 Development as a Clue to Evolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
4.2.3 Developmental Processes and Homology Criteria . . . . . . . . . . . . . . . . . . . . 79
4.2.4 Development, Adaptation, and Behavior . . . . . . . . . . . . . . . . . . . . . . . . . . 81
4.3 Final Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Acknowledgements
Some of the results presented in this work have been financed by the Millenium
Nucleus for Integrative Neuroscience.
Introduction 1
1
Introduction
There is little doubt that the vertebrate brain is the most complex structure we
know. As with any complex structure, there is the immediate question about its
origins. How could such a complex design develop from the simplest multicellular
animals? This problem has pervaded the study of evolutionary biology since its
beginnings. Although Darwin (1859, 1871) proposed an impeccable mechanism
(natural selection) for the gradual transformation of species including human
origins, even he sometimes expressed certain doubts about the origin of highly
complex structures. This issue has been highly debated both within science and
outside it. For instance, a rebirth of the old religious argument of intelligent design
has gained unexpected strength in the last few years. In essence, this argument
follows Paley’s (1802) claim that if we find a clock that has been thrown away we
cannot consider that it was created on its own, but rather has to be the consequence
of conscious design. Today, creationists have developed a modern version of this
argument, that of “intelligent information” (Denton 2002). For example, after
sequencing the human genome in 2001, one of Celera Genomics top computer
scientists claimed that this complexity suggested design. Although he clarified not
to be thinking of God, he asserted that “there’s a huge intelligence there” (quoted
in Witham 2002, p 9). As Witham (2002) says, modern computer-literate believers
may soon ask the question of whether the universe is self-running or functioning
on DOS, a Divine Operating System.
In this volume, we have decided to tackle the problem of the origin and evolution
of the vertebrate brain, from the simplest nervous system-like elements that we
can observe in nature. In doing so, we expect to establish a continuity between
the simplest stages and the elaboration of the highly intricate neuronal network
that is the mammalian cerebral cortex. For lack of space, we will have to leave
aside several other brain structures such as the basal ganglia or the cerebellum,
as well as components perhaps comparable to the mammalian cerebral cortex in
other vertebrates; as will be seen, the cerebral cortex alone is sufficient to fill up
quite an extensive review. Our main point will be to present a case for continuous
evolutionary transformation of the central nervous system, from its very origins
to the elaboration of the most complex structure that exists on earth.
In order to pursue our goal, we will have to discuss some basic concepts of
neuroanatomy, embryology, and developmental genetics. This knowledge was un-
available in Darwin’s time, which further emphasizes his genius. We will follow
an approach that has been termed developmental evolutionary genetics, which
seeks to establish a correspondence between embryological processes and the
phylogenetic history of an organism. In other words, if we observe continuity in
development between a fertilized egg and an adult brain, we should also expect
continuity in its evolutionary history. This approach is not new; its roots can be
found in Von Baer’s biogenetic law (Von Baer 1828; see also Gould 1977), stating
that embryos start from a general condition (the unicellular egg), shared by all
2 Introduction
animals, and during development they progressively acquire characters that in-
clude them in successively restricted taxonomical groups. That is, if at early stages
all embryos are similar among them, they subsequently develop characters that
define them as say, vertebrates, then mammals, then primates and then as humans.
This view was further expressed in a more extreme version by Haeckel (1892), who
considered both evolution and development as a linear chain, embryology reca-
pitulating the phylogenetic history of the animal. Thus, the human embryo passed
through stages in which it was first a unicellular organism, then an undifferentiated
metazoan (morula), then a jellyfish (gastrula), then a fish, then a tailed reptile and
so on until he or she became a human. Modern understanding of these hypotheses
acknowledges that in fact, early embryos are readily distinguishable among them,
and that human embryos are human embryos during all development; they do
not pass from a jellyfish stage to a fish stage and so on (Garstang 1922; Gould
1977; Richardson et al. 1997). However, it is also recognized that embryos pass
through successive stages in which they acquire the characteristics proper to each
of the nested phylogenetic categories to which they belong. Thus, there is a general
concordance between embryonic stages and the phylogenetic history.
Recent expressions of this approach have taken the name of “evo-devo” (from
evolution and development) and have been particularly fruitful after the rise of
molecular embryology. This discipline has revealed an exquisite correspondence
in the molecular mechanisms underlying similar embryonic processes in a wide
group of animals, which nevertheless appear quite diverse in their superficial mor-
phology (McGinnis and Krumlauf 1992; Gerhart and Kirschner 1997; Martindale
2005; Pearson et al. 2005). Furthermore, the bulk of comparative molecular and
embryological evidence strongly points toward a relatively conserved embryonic
stage (the zootype) that corresponds to the establishment of the taxonomic group’s
body plan (Slack et al. 1993). In the case of vertebrates, this corresponds to the
point in which the embryo develops the pharyngeal pouches: the pharyngula
stage. Thus, there is high diversity in early developmental processes (mainly due
to species differences in yolk content and early embryonic adaptations), followed
by a convergence in structure at mid-developmental stages, in order to diverge
again as development proceeds toward the adult state. Interestingly, the expres-
sion of specific and highly conserved regulatory genes (homeobox and related
genes) takes place in this converging embryonic stage and participates in pattern-
ing the embryo’s body plan. Homeobox (Hox) and related genes have been found
to be fundamental in anteroposterior patterning in vertebrates, in the fruit fly
Drosophila and in other animal groups, indicating that they represent quite an an-
cient developmental regulatory system (McGinnis and Krumlauf 1992; Krumlauf
1992; García-Fernández and Holland 1994; Martindale 2005; Pearson et al. 2005;
García-Fernández 2005).
In a way, this evidence has produced a turn back to the times of the pre-
evolutionary concepts of Transcendental Anatomy, in which the architectural body
plans were considered to be established by divine intervention; diversity in design
was only the result of variations within a theme, due to adaptations to contingent
Introduction 3
circumstances. This perspective considered adaptation as a constant, universal

feature of living beings. The advent of evolutionary theory, putting its focus on di-
versity rather than on common organization and emphasizing that adaptation was
variable, related to successful reproduction, relegated this perspective to a second
plane for quite a long time (Desmond 1982). As said, the discovery of a common
genetic organization in the body of most animals has produced a strong shift of
emphasis into the commonality of type again, this time observed under the light of
evolutionary theory. We will pursue an evo-devo view to the phylogenetic history
of the brain, showing which genetic processes are shared with other, nonvertebrate
animals to underline the genetic conservatism of morphological evolution; but will
also put emphasis on the dramatic morphological diversification that has taken
place during evolution. It appears that, even given a relatively fixed genetic bat-
tery, developmental morphology has taken quite different courses in the different
lineages, possibly related to the specific circumstances in which characters have
been acquired. Thus, we also intend to emphasize the behavior and way of living
of the ancestral organisms, in order to provide an integrated view of the specific
conditions that led to the divergence of the distinct lineages.
An important theme to be discussed in this section relates to the concept of
homology. We will need to compare structures in different species and will have
to determine whether they are or not comparable structures. There are many
(perhaps too many) criteria to determine the homology between two organs, and
as expected they do not always agree. In one particular instance, the origin of the
neocortex from a reptilian-like brain, this issue has been highly controversial in
the last few years. As the evidence to date indicates strong genetic conservatism
with morphological diversification, we have relied on genetic criteria to determine
the structure that most likely gave rise to the mammalian neocortex.
In general, we will address this issue in the context of a conserved structural
organization of the vertebrate brain. As in the concept of the zootype expressed
above, in vertebrate brains there is a stage of convergence at about the same
developmental stage. For example, a proposal for a neuronal zootype has been
recently outlined, considering the basic embryonic elements that determine the
organization of the vertebrate brain (Deutsch and le Guyader 1998). However, long
before these authors, Bergquist and Källén (1953a,b; 1954) established in the mid-
1900s that all vertebrate brains at the pharyngula stage have a similarly organized
brain, divisible into a series of transverse domains visible as periodic thickenings
of the anterior neural tube, which they termed neuromeres. These thickenings
were proposed to be centers of proliferative activity, separated by regions where
cell division occurs more slowly. Although this view was neglected for a long time,
recent studies have confirmed the presence of seven neuromeres in the hindbrain or
rhombencephalon (rhombomeres), one in the midbrain (mesomere) and six in the
forebrain (prosomeres) (Shimamura et al. 1997; Wilkinson et al. 1989; Fraser et al.
1990; Lumsden 1990; Rubenstein et al. 1994; Puelles and Rubenstein 1993, 2003;
Puelles 1995). Furthermore, it was found that the expression boundaries of different
Hox genes were largely coincident with the rhombomeric segmentation pattern
4 Introduction
and were highly conserved across vertebrate species (Wilkinson and Krumlauf
1990; Nieto et al. 1991; Kimmel 1993).
In the more anterior prosencephalon, which is of more immediate interest to us,
evidence for segmentation was for some time difficult to obtain. However, analyzing
the expression domains of several transcription factors that were activated in the
developing forebrain, Puelles and Rubenstein (1993, 2003) determined that there
was a nice fit with Bergquist and Källén’s description of prosomeric segments,
which is again largely conserved across vertebrates. While in the prosomeres there
is no expression of Hox genes, several homeodomain proteins are expressed, which
perform a similar role to that of Hox gene clusters in more caudal segments. For
example, genes of the Dlx and the Emx (Emx1 and Emx2) families are respectively
expressed in the ventral telencephalon (subpallium) and the dorsal telencephalon
(pallium). Dlx genes are closely related to Hox genes (they appear to belong to the
same cluster) and are homologs to the Drosophila gene distal-less (Dll), expressed
in the embryonic imaginal disks (Panganiban 2000). The linkage between Dlx and
Hox genes also exists in invertebrates such as the nematode, suggesting that the
primordial Dlx and Hox genes were similarly linked. Importantly, in vertebrate
origins there were two duplications of the Dlx-Hox cluster (Digregorio et al. 1995;
Stock et al. 1996). On the other hand, Emx genes are orthologs of the Drosophila
gene empty spiracles (ems), responsible for the formation of head segments (Dalton
et al. 1989; Walldorf and Gehring 1992; Hirth et al. 1995).
Puelles and Rubenstein’s (1993, 2003) prosomeric model has faced some crit-
icisms such as the evidence of cell migration across prosomere borders (but not
across rhombomere borders), the fact that early patterns of gene expression may
be quite dynamic and a static picture like the one presented does not capture
this dimension, or the possibility that the authors have disregarded evidence that
does not support the model (for review see Striedter 2005). However, comparative
evidence has determined that this pattern is highly conserved across vertebrates
(it is observed not only in mammals and birds, where it was first reported, but
also in teleosts and agnathans; Wulllimann and Puelles 1999; Pombal and Puelles
1999), which strongly suggests that it reflects a phylogenetically stable framework
that can be of great utility in species comparisons.
Before starting with our analysis, it will be useful to recall some basic concepts
of neuroanatomy and embryology. In the early embryo, the central nervous system
(CNS) originates from a flat neural plate in the dorsal aspect of the animal, after the
action of inductive signals from the mesoderm. In a process called neurulation,
this plate develops into a hollow neural tube. Eventually, this tube widens in the
cephalic region, forming three main vesicles, from caudal to rostral, the rhomben-
cephalon or hindbrain, the mesencephalon or midbrain, and the prosencephalon
or forebrain (Fig. 1). The latter subdivides into a diencephalon and two telen-
cephalic vesicles (the cerebral hemispheres) that contain the future olfactory bulbs,
the cerebral cortex and the basal ganglia, among other structures. The cerebral
hemispheres have been classically subdivided into a pallium located dorsally and
a ventral subpallium (basal ganglia), both separated by the corticostriatal sulcus
Introduction 5
Fig. 1 Early development of the mammalian forebrain. Initially, the forebrain is subdivided
into three main components, the segmented rhombencephalon (R); the mesencephalon (M)
that contains the main sensory structures in nonmammals; and the prosencephalon, which
is later partitioned into a diencephalon (D) and a telencephalon (Tel). E, eye; ON, optic
nerve
or pallial-subpallial boundary in the ventricle at the equatorial level of the vesicle

(Fig. 2). In the subpallium, the basal ganglia (involved in motor functions) develop
in the lateral side from two structures that protrude into the ventricle: the medial
and the lateral ganglionic eminences. On the other hand, the pallium has been
subdivided into a medial part (giving rise to the hippocampal formation), a dorsal
part (giving rise to the neocortex or isocortex), and a lateral part (giving rise to the
olfactory cortex), which is connected anteriorly to the olfactory bulb. Although in
the adult stage all these are cortical layered structures, the neocortex is different
from the olfactory or lateral cortex and from the hippocampus or medial cortex in
having six cellular laminae composing it, while the other two structures bear only
three laminae. In the border between pallium and subpallium, several structures
6 Introduction
Fig. 2 Main components of the developing mammalian telencephalon. The telencephalic

hemispheres consist of a ventral part or subpallium, separated from the pallium by a pallial–
subpallial boundary (PSPB). The medial ganglionic eminence (MGE) and the lateral gan-
glionic eminence (LGE) differentiate in the subpallium and give rise to the globus pallidus
(GP) and corpus striatum (CS), respectively. These structures produce inhibitory interneu-
rons for most pallial regions. The pallium consists of a medial pallium (MP) that gives rise
to the hippocampal formation (HP), a dorsal pallium (DP) giving rise to the neocortex (NC),
a lateral pallium (LP) giving rise to the olfactory cortex (OC), and finally a ventral pallial
(VP) territory producing part of the claustroamygdalar complex (AM). In its medialmost
aspect, the pallium is bordered by an embryonic structure termed the cortical hem (CH),
which separates the medial pallium from the choroid plexus (ChP) that differentiates from
the roof plate
develop that collectively make up the so-called cerebral amygdala and other struc-
tures, containing both pallial and subpallial elements. Recent analyses have shown
that in this region an additional embryonic pallial element is distinguishable (the
ventral pallium). In the developing brain vesicle, as in the rest of the neural tube,
cell proliferation takes place in the inner walls, lining the ventricular cavity (the
ventricular and subventricular zones). Then, immature neurons migrate radially
out to make up distinct brain nuclei. In the cerebral cortex, this migration process
makes a long journey to establish a mantle of gray matter in the periphery of the
pallium. However, there is also migration of some cells in the tangential direction,
Evolution of the Vertebrate Nervous System and Telencephalon 7
i.e., in a direction parallel to the surface of the neural tube, in which neurons
originating in the subpallium move dorsally to populate the cerebral cortex.
We will start the second section with a review of the phylogenetic history of the
nervous system from the earliest multicellular animals until the appearance and
diversification of the vertebrate telencephalon. In this section, we will demonstrate
a parallelism between some early embryological processes and the phylogenetic
events that took place during the evolution of the nervous system. In the third
section, we will discuss the origin of the mammalian brain and the mammalian
neocortex. In this part, we will address two main aspects, one concerning the
structure in the reptilian brain that gave rise to the neocortex (i.e., its reptilian
homolog) and the other concerning the origin of neocortical lamination. Finally, we
will discuss all this evidence in the light of current concepts in evolutionary theory.
The different sections will discuss a wealth of material, much of which may not
be retained in the reader’s mind while he or she goes on to the following sections.
In order to make this easier for the reader, each subsection is followed by a brief
summary of the main points discussed previously. Likewise, along the article, we
will be coming back to points made earlier in order to refresh the reader’s memory.
2
Evolution of the Vertebrate Nervous System and Telencephalon
This section discusses the vertebrate brain in a phylogenetic framework. We will

first analyze the origin of nervous systems from the simplest metazoans, to continue
with the origin of a centralized nervous system with an anterior brain in more
advanced multicellular animals. We will discuss the origin of vertebrates, as it is
largely marked by the appearance of new tissues related to the neural plate (neural
crest and placodes) and by the origin of the telencephalic vesicles, possibly in
close relation to the development of the olfactory sense. Then we will provide an
overview of vertebrate evolution with special emphasis on the diversification of
the telencephalon.
2.1
Animal Phylogenetic Relationships
2.1.1
Origin and Diversification of Metazoans
Metazoans (multicellular animals) are subdivided into poriferans (sponges), ra-

diates (ctenophores – comb jellies – and cnidarians – jellyfish), and bilaterian
animals, i.e., those with bilateral symmetry. Radiates are the first animals to show
true germ layers (and hence gastrulation), and nerve cells. They are sometimes
described as adult gastrulas, with an endodermal cavity bearing a single terminal
opening, which may be considered as the mouth or anus (Nielsen 2001). However, in
some species (especially in ctenophores) there are anal pores through which some
Evolution of the Vertebrate Nervous System and Telencephalon 7
i.e., in a direction parallel to the surface of the neural tube, in which neurons
originating in the subpallium move dorsally to populate the cerebral cortex.
We will start the second section with a review of the phylogenetic history of the
nervous system from the earliest multicellular animals until the appearance and
diversification of the vertebrate telencephalon. In this section, we will demonstrate
a parallelism between some early embryological processes and the phylogenetic
events that took place during the evolution of the nervous system. In the third
section, we will discuss the origin of the mammalian brain and the mammalian
neocortex. In this part, we will address two main aspects, one concerning the
structure in the reptilian brain that gave rise to the neocortex (i.e., its reptilian
homolog) and the other concerning the origin of neocortical lamination. Finally, we
will discuss all this evidence in the light of current concepts in evolutionary theory.
The different sections will discuss a wealth of material, much of which may not
be retained in the reader’s mind while he or she goes on to the following sections.
In order to make this easier for the reader, each subsection is followed by a brief
summary of the main points discussed previously. Likewise, along the article, we
will be coming back to points made earlier in order to refresh the reader’s memory.
2
Evolution of the Vertebrate Nervous System and Telencephalon
This section discusses the vertebrate brain in a phylogenetic framework. We will

first analyze the origin of nervous systems from the simplest metazoans, to continue
with the origin of a centralized nervous system with an anterior brain in more
advanced multicellular animals. We will discuss the origin of vertebrates, as it is
largely marked by the appearance of new tissues related to the neural plate (neural
crest and placodes) and by the origin of the telencephalic vesicles, possibly in
close relation to the development of the olfactory sense. Then we will provide an
overview of vertebrate evolution with special emphasis on the diversification of
the telencephalon.
2.1
Animal Phylogenetic Relationships
2.1.1
Origin and Diversification of Metazoans
Metazoans (multicellular animals) are subdivided into poriferans (sponges), ra-

diates (ctenophores – comb jellies – and cnidarians – jellyfish), and bilaterian
animals, i.e., those with bilateral symmetry. Radiates are the first animals to show
true germ layers (and hence gastrulation), and nerve cells. They are sometimes
described as adult gastrulas, with an endodermal cavity bearing a single terminal
opening, which may be considered as the mouth or anus (Nielsen 2001). However, in
some species (especially in ctenophores) there are anal pores through which some
8 Evolution of the Vertebrate Nervous System and Telencephalon
waste is expelled (Martindale 2005). Thus, the endodermal opening (comparable to

the blastopore during gastrulation) would be more akin to a mouth than to an anus.
Bilaterians can be subdivided into protostomes (animals in which, after gastrula-
tion, the blastopore is related to the mouth) and deuterostomes (animals in which
the blastopore relates to the anus, and a new mouth is formed). Deuterostomes have
been traditionally divided in two clades, the first giving rise to echinoderms (sea
urchins and starfish), to the enigmatic worm Xenoturbella (Bourlat et al. 2003),
and to a group of marine burrowing worms termed hemichordates (Fig. 3). The
latter have several characteristics in common with vertebrates, including a post-
anal tail, a branchial system with gill slits, an endostyle, a stomochord that has
been compared to the chordate notochord, and a hollow neural tube in the collar
region of the body (Nielsen 2001). Recently, only the gill slits have been considered
to be homologous in hemichordates and vertebrates, and specifically at the level
of simple ciliated pores without a branchial skeleton. The other characteristics are
claimed to have independently arisen in the two groups (Ruppert 2005).
The second clade of deuterostomes has been classically considered to include
urochordates, or tunicates, and chordates. The former are a group of sessile animals
whose larvae have several characteristics that make them akin to vertebrates such
as a dorsal, hollow nerve chord, a notochord, and gill pores. Chordates have all these
characteristics in the adult state. They have been subdivided into cephalochordates
(exemplified by amphioxus or Branchiostoma, a small, filter-feeding fishlike animal
that lives buried in the sand and occasionally swims) and vertebrates or craniates.
The main differences between these two groups are that Branchiostoma is devoid
of paired appendages, lacks specialized sensory organs, and importantly also lacks
any signs of telencephalic cerebral hemispheres, all of which are characteristic of
vertebrates. Against this traditional conception, a recent report based on molecular
evidence proposes that the group closest to vertebrates are the urochordates (both
groups making a new clade, appealingly termed olfactores). On the other hand,
cephalochordates appear to be more related to echinoderms and hemichordates,
but this is still inconclusive (Delsuc et al. 2006; see Fig. 3). More recently, Bourlat
et al. (2006) confirmed the monophyletic clade olfactores, with cephalochordates
as a sister group. This proposal is supported by anatomical evidence showing that
urochordates have a centralized heart, covered by a pericardium, which resembles
the vertebrate heart more closely than the cephalochordate heart, consisting of
four peristaltic vessels powered by smooth musculature (Schubert et al. 2006).
Below we will see that some neural characteristics also point to a close relationship
between urochordates and vertebrates.
2.1.2
Phylogenetic Origins of the Nervous System
Phylogenetic evidence suggests that the earliest nervous systems originated in
metazoans from diffuse subepidermal plexuses that coordinated contractile mech-
anisms associated to feeding and locomotion (Willmer 1990). In jellyfish (cnidar-
ians), feeding and locomotion are produced by essentially similar mechanisms.
Animal Phylogenetic Relationships 9
Fig. 3 Phylogenetic relations of deuterostomes. According to the most recent phylogenetic

analyses, the urochordates (represented by the mobile larval/sessile adult tunicates) are
the closest relatives of vertebrates. The position of cephalochordates (represented by am-
phioxus) has been recently confirmed to be closer to vertebrates and tunicates than to
echinoderms. Hemichordates are also related to echinoderms. This evidence supports the
concept of a free-living vermiform ancestor for deuterostomes. (Modified from Lacalli 2005,
with permission)
At least in three occasions, this plexus has become condensed into a chord at the
midline to form a central nervous system (Lowe et al. 2003; Holland 2003). This
is consistent with the embryological findings indicating that the default fate of
epidermal cells is to become neuronal, and this is blocked by the expression of

bone morphogenetic proteins (BMPs, especially BMP-4) from the epidermal cells
themselves. The action of inducing factors such as Noggin, Chordin and Follistatin
blocks the BMP pathway and permits the differentiation into neuronal phenotypes
(Sanes et al. 2006).
Genes homologous to the vertebrate neural-inducing factors BMP and chordin
have been found in Drosophila as well (decapentaplegic, dpp; and short gastrula-
tion, sog, respectively), which also participate in inductive processes (De Robertis
and Sasai 1996; Holley et al. 1995). However, more than participating in neuru-
lation or CNS condensation, the ancestral function of these factors seems to be
related to early germ layer specification (Lowe et al. 2006; see below). Neverthe-
less, the mechanisms of neural specification may be comparable in a wide range
of animal groups. In most animals, neurons separate from epithelial cells by de-
lamination and subsequent subepidermal positioning (for review see Sanes et al.
2005). In vertebrates, apart from the internalization that takes place during the
formation of the neural tube, there is also a delamination (with subsequent radial
migration) of precursor cells that originally line the neurocoele into the walls of the
neural tube. Thus, the delamination process may be homologous in invertebrates
and vertebrates. Furthermore, the mechanisms for specifying neural phenotypes
from a proliferating epithelium seem to be comparable across widely different
animal types. In Drosophila, they depend on genetic systems related to the achaete
scute proneural family of basic-helix-loop-helix transcription factors (Alonso and
Cabrera 1988; Skeath and Carroll 1992). These proneural genes of Drosophila have
homologs in vertebrates (Mash1 and other bHLH genes such as those coding
for the proteins Neurogenin and NeuroD1), which serve a similar proneural role
(Ross et al. 2003). Therefore, germ layer and neural specification processes may be
generated by ancestral mechanisms, while neurulation (the formation of a dorsal
neural plate and a neural tube) may be conceived as a particular mechanism by
which the originally diffuse subepidermal nervous system became condensed in
chordate ancestors. In this context, the origin of chordate neurulation has been
recently proposed to result from the redistribution of germ layers (especially the
presumptive mesoderm) in the blastulae of deuterostomes with respect to proto-
stomes, which resulted in a complete topographic rearrangement of the inductive
interactions (Northcutt 2005).
An extremely curious observation, originally made by Geoffroy Saint-Hilarie
in 1822 (Lowe et al. 2003) is that protostomes not only seem to have a different
anteroposterior direction of differentiation (determined by blastopore fate) but
also bear their centralized nervous system in a ventral position, while chordates
show a dorsal neural tube. More recent analyses have shown that genetic markers
of the different embryonic tissues are expressed in inverted dorsoventral positions
in vertebrates and protostomes (De Robertis and Sasai 1996), indicating that the
whole body plan seems to be dorsoventrally inverted in the two main animal
groups (Fig. 4). One hypothesis to explain this finding is that at some point, the
vertebrate ancestor started swimming upside-down. Although difficult to demon-
Fig. 4 Dorsoventral organization in arthropods and vertebrates. These animals are inverted
relative to each other not only in the topographical position of their organs but also in the
patterns of gene expression. ac-sc, achaete-scute; CNS, central nervous system; EN, endo-
derm; MES, mesoderm; N, neurogenin. (With permission from Gerhart and Kirchner 1997)
strate, this proposal is supported by the fact that in some burrowing invertebrates
it is not easy to determine the dorsal or the ventral surfaces, thus making inversion
a relatively likely event (Gerhart 2000). Furthermore, the deuterostome hemi-
chordates have been claimed to be inverted, upside-down versions of chordates,
showing a dorsoventral organization similar to that of protostomes (Nübler-Jung
and Arendt 1996). Unambiguous specification of dorsal and ventral structures is
not easy in hemichordates, and by convention the mouth side had been tradition-
ally considered to be ventral. However, Nübler-Jung and Arendt (1996) noted that
the position of the heart, kidney, and gill slits were located in the so-called dorsal
aspect of the animal (opposite to the mouth), while in chordates these organs are
positioned ventrally, close to the mouth. Moreover, in hemichordates a sensory
nerve chord runs ventrally while a motor chord runs dorsally, in an anatomic or-
ganization that is inverted with respect to chordates, in which sensory neurons are
dorsal to motor neurons. An intriguing detail is that the so-called dorsal tract—at
the other side of the animal’s mouth—is internalized in the collar region of the
body by a neurulation-like process (Willmer 1990).
Recent evidence suggests that the process of nervous system condensation
occurred independently in protostomes and deuterostomes and is posterior to
the acquisition of dorsoventral organization in bilaterians. In other words, the
common bilaterian ancestor of protostomes and deuterostomes may not have had
a centralized nervous system. Despite their general protostome-like dorsoventral

organization, hemichordates lack a truly centralized nervous system and have
a diffuse subepidermal neuronal net whose anteroposterior patterns of homeotic
and Hox-related gene expression closely corresponds with the patterns observed
in the developing CNS of vertebrates and in Drosophila (Lowe et al. 2003; Holland
2003). Furthermore, more recent analyses have revealed that a dorsal-ventral axis
based on a BMP-chordin gradient is present in all bilaterian animals (specifying the
ventral-dorsal axis in chordates and the dorsal-ventral axis in protostomes), but
as said its ancestral function seems to be more related to germ-layer patterning
rather than specifically with neural-epidermal segregation and nervous system
condensation (Lowe et al. 2006). Thus, in the case of hemichordates, the BMP-
chordin gradient is present, but the nervous system fails to condense at either side.
Furthermore, the mouth appears on the chordin side, in a position opposite to the
gill slits and equivalent to that of the mouth of protostomes (Lowe et al. 2006).
In chordates, the mouth would have been relocated in close position to the gill
slits (the BMP side, ventral), while in addition, there would have been a process
of CNS condensation on the chordin side, leading to neurulation. Overall, this
evidence is consistent with the hypothesis that the original body organization was
essentially concentrical, with endoderm at the center, surrounded by mesodermal
tissue, and then a neuroectoderm consisting of a diffuse nerve net covered by
the epidermis contacting the outside; in some bilaterians, this concentric pattern
became transformed into a dorsoventral pattern with the acquisition of bilaterality
(Willmer 1990). Supporting this idea, other findings suggest that in radiates the
molecular machinery for dorsal-ventral patterning is already present, in cryptic
form (Finnerty et al. 2004).
There is the possibility that the diffuse subepidermal nervous system of hemi-
chordates results from a secondary reduction of the nervous system (Tautz 2003;
Lacalli 2003), but this seems unlikely considering the basal position of this group
among deuterostomes (Halanych and Passamaneck 2001; see also Vargas and
Aboitiz 2005).
Another proposal for the origin of the vertebrate CNS suggests that it derives
from a set of ciliated bands, including the ciliated apical pole, of some invertebrate
larvae (like the auricularia of echinoderms or the tornaria of hemichordates),
which became internalized during neurulation (Garstang 1928; Fig. 5). Garstang
proposed that these ciliary cells originally served both a locomotory and a sensory
role. This hypothesis has in its favor that after neurulation, cells that line the neural
tube become ciliated. Furthermore, many special sensory receptors (except taste
receptors, which apparently have a different origin; Barlow and Northcutt 1997;
Northcutt 2004) indeed consist of ciliated cells that have become internalized in
neurulation (photoreceptors) or after placodal invagination (olfactory receptors,
inner ear, and lateral line). Some authors have questioned the homologies between
vertebrate sensory receptors and sensory cells of adult urochordates. In amphioxus
and tunicates, the ectodermal sensory cells are mostly primary neurons sending
axons to the CNS. In contrast, vertebrate, placodal-derived mechanosensory cells
Fig. 5 Garstang’s proposal of transformation of a hemichordate larva into a primitive

chordate. The longitudinal band of ciliated cells that acts as a sensory-motor system is
displaced dorsally to make up the neural plate. The apical organ containing ciliated cells
contributes to the formation of the forebrain. (From Young 1962, with permission)
of vertebrates are all secondary neurons that lack axons (Holland 2005). Neverthe-
less, myomeric cells of cephalochordates, which are undoubtedly homologous to
the segmented musculature of vertebrates, send a projection to the neural tube,
which synapses on motor neurons (instead of motor neurons projecting an axon
to the muscle cell, as occurs in vertebrates; Wicht and Lacalli 2005). Therefore, the
presence or absence of a projection to the CNS may not be a determining factor
for establishing homology between these structures. One possibility is that the
ancestral subepidermal nerve net is really the precursor of true, delaminated neu-
rons, while the ciliated cells of the deuterostome larvae correspond more closely
to different types of localized receptors and to the ciliated cells at the interior of
the neural tube. An interpretation related to Garstang’s is that the vertebrate brain
derives from a ciliated apical organ found in some invertebrates like cnidarians
or ctenophorans, which would be comparable to the apical organ of deuterostome
larvae (Martindale 2005). In this context, developmental evidence suggests the
possibility that the most anterior parts of the CNS rely on different inducing sig-
nals than the more caudal regions, which depend on the notochord for induction.
The notochord, secreting Noggin, Chordin, and Follistatin, has its anterior end
at the level of the future thalamus, and the most anterior aspect of the neural
plate (mostly consisting of the prospective hypothalamus and telencephalon) is

supported by the anterior visceral endoderm. The latter expresses the genes Cer-
berus, Frizzled, and Dickkopf, which are necessary for the differentiation of the
forebrain and the anterior part of the head (Hashimoto et al. 2000; Glinka et al.
1998; Kazanskaya et al. 2000; Mukhopadhyay et al. 2001; MacDonald et al. 2004;
Leyns et al. 1997). The products of these genes block BMP and WNT signaling,
thus suppressing both epidermal and posterior neural plate phenotypes. Thus,
a primitive condition might have consisted of a localized anterior (perhaps pe-
rioral) network loosely connected to a diffuse subepidermal plexus; this system
condensed in posterior regions, generating a midline nerve cord closely connected
with the anterior or apical region, which eventually became the anterior CNS (see
Lacalli et al. 1994). This view is partly supported by the proposal that at least the
echinoderm larva dipleurula (ancestral to both the tornaria and the auricularia
of hemichordates and echinoderms, respectively) and the tornaria larva are es-
sentially heads without trunks (according to molecular evidence, they have head
but not trunk markers, as occurs in the adult tunicates; Lacalli 2005). The caudal
nervous system and the rest of the body develop after metamorphosis from this
head region. Furthermore, in the hemichordate larva tornaria, the T-box gene (ho-
mologous to Tbr1 in vertebrates, which is expressed in the olfactory/hypophyseal
placode and in the dorsal telencephalon) is expressed in the apical sensory organ,
close to the eye spot (Willmer 1990; Satoh et al. 2002; see Sect. 2.2.3).
2.1.3
Summary
Vertebrates derive from a basal group of deuterostome animals, whose adult stage
was possibly free-living. A condensation of the diffuse subepidermal neural plexus,
perhaps produced by a reorganization of the blastula, yielded a dorsal central ner-
vous system, which became internalized to form a neural tube. Nevertheless, the
process of delamination of neuronal cells from a proliferating epithelium seems
to be conserved in invertebrates and vertebrates, as within the vertebrate neural
tube prospective neurons delaminate in a similar manner as they do in Drosophila
epidermis. Furthermore, the proneural genetic machinery, marking the beginning
of neural differentiation, is similar in both groups. Ciliated cells, either lining the
neural tube or specialized as localized sensory receptors, may be related to cili-
ated cells observed in deuterostome larvae, which serve as sensory receptors and
also have motile functions. Given that the cephalic end of the vertebrate CNS is
induced by different factors than the caudal end, it is possible that the forebrain
and neighboring regions have a slightly different origin from the more caudal
CNS, originating from an anterior or apical plexus that condensed dorsally. In this
context, the cephalic nervous system seems to be the only one present in deuteros-
tome larvae and in sessile deuterostomes, indicating that the two components of
the CNS are separable.
The Origin of Vertebrates 15
2.2
The Origin of Vertebrates
2.2.1
Early Theories and Fossil Evidence
Early ideas about the origin of vertebrates were largely based on Garstang’s hypoth-
esis that considered vertebrates and protochordates to result from a paedomorphic
transformation of the larval tunicates (i.e., the swimming larva was transformed
into a mobile, reproducing adult; Garstang 1928). However, more recent molecular
and morphological phylogenetic analyses suggest that a free-living, swimming,
or burrowing condition is ancestral to both deuterostomes and chordates, sessile
forms being derived states (see Lacalli 2005; Vargas and Aboitiz 2005). Further-
more, the recent proposal that urochordates are closer to vertebrates than cephalo-
chordates (Delsuc et al. 2006) is consistent with the possibility that both deuteros-
tomes and olfactores (urochordates and vertebrates) were primitively free-living
animals (the most basal form of ascidians, Oikopleura, also has an adult mobile
condition, implying that ancestral urochordates were also free-living; Gee 2006).
Beside embryological evidence, there is some fossil evidence for the origin of
vertebrates. The fossil record provides evidence of the very early appearance of
chordates during the Cambrian period, a time at which most extinct and living
animal phyla also originated (Gould 1989; Conway Morris 1993; Valentine 2004).
In the sediments of the Burguess Shale, a highly rich Cambrian fossil deposit, one
highly publicized fossil, Pikaia, allegedly bearing a segmented musculature and
possibly a notochord, was first claimed to be the earliest chordate (see Gould 1989;
Shimeld and Holland 2005). However, additional studies revealed that the affinities
of Pikaia with either cephalochordates or vertebrates were unclear (Schubert et al.
2006). Subsequently, an additional early fossil, Yunnanozoon, was first described
as a cephalochordate (Chen et al. 1995), then as a vertebrate (Dzik 1995) and later
on as the earliest hemichordate (Shu et al. 1996). Further interesting fossils are
Haikouichthys and the closely related Myllokunmingia, which have been claimed
to be already vertebrates with segmented, chevron-shaped myomeres, paired eyes,
otic capsules, and paired olfactory organs (Shu et al. 1999, 2003a). A problematic
fossil is Haikouella (Mallatt and Chen 2003b; Shu 2003), as some have interpreted
it either as an early deuterostome (Shu et al. 2003b; Shu and Conway Morris 2003)
or as a vertebrate-like chordate (Mallatt and Chen 2003a,b). According to the latter
interpretation, Haikouella had a large brain, lateral eyes, a pharynx with gill slits,
and a ventral heart. Finally, there are Cambrian records of calcified denticles – con-
odonts – that were initially attributed to early vertebrates, but conclusive evidence
for this link came from a nearly complete description of a specimen with a small
eel-like body, a caudal fin and fin rays (Briggs et al. 1983). Further analysis of
these animals revealed that they had well-formed eyes with extrinsic musculature,
comparable to those of agnathans (Briggs 1992; Sansom et al. 1992; Mallatt and
Chen 2003a,b). All this evidence indicates that the origin of vertebrates was an
early event in animal evolution. Importantly, even if urochordates may be phylo-

genetically closer to vertebrates than to cephalochordates, in overall morphology
the fossils described here resemble more closely amphioxus than urochordates,
suggesting that they had a mode of life more similar to it than to modern tunicates.
2.2.2
The Neural Crest and Placodes in Vertebrate Origins
The neural crest (NC) and placodes (PL) are embryonic regions located in the
region bordering the neural plate, separating it from the rest of the ectoderm. The
NC differentiates at levels behind the future prosencephalon (cerebral hemispheres
and diencephalon), while the placodal region borders the anterior neural plate,
contributing the prospective prosencephalic territory. Cells from the NC migrate
laterally above and below the mesodermic somites to invade several regions of
the embryo’s body. In the trunk and body, these cells give rise to a large part of
the peripheral nervous system and other structures such as pigment cells and
neuroendocrine cells in the adrenal glands. In the cephalic region, NC cells con-
tribute to the branchial skeleton and part of the cranial skeletal tissue. Placodes
differentiate in several types, such as the olfactory placode (giving rise to olfac-
tory epithelium, whose receptors project directly into the olfactory bulb) and the
closely related adenohypophyseal placode (contributing to the anterior pituitary
gland). These structures develop in close contiguity with the olfactory bulb and the
hypothalamus, respectively (Couly and Le Douarin 1985), and in the adult become
closely associated with the anterior end of the neural tube, located in the roof
of the mouth. Other placodal structures are the optic (producing the eye’s lens),
trigeminal (contributing to cranial sensory ganglia), otic (future internal ear), and
epibranchial (contributing to other cranial sensory ganglia). In fish and amphib-
ians, there is also a lateral line placode, which generates the mechanoreceptive
and, in many cases, electroreceptive lateral line system.
In a now classical piece of work, Northcutt and Gans (1983) and Gans and
Northcutt (1983) showed that the majority of shared-derived characters of verte-
brates arise from the differentiation of the NC and PL. For example, the vertebrate
branchial skeleton is a NC-derived character, while the branchial organs of cephalo-
cordates have only a collagenous skeleton. Furthermore, vertebrate paired sense
organs such as eyes, ears, and the olfactory epithelium relate embryologically to
the epidermal placodes. The development of a muscularized branchial skeleton
permitting a more efficient oxygenation and new feeding possibilities, together
with the development of sense organs such as vision, olfaction, and the vestibular
system was possibly related to a more active, predatory mode of life as opposed
to the ancestral filter-feeding condition. Interestingly, Lacalli (2004) has proposed
that these innovations took place at similar times in both early vertebrates and
arthropods, leading to an “arms race” between both groups in their competition
for prey and possibly also in the establishment of predator–prey relations between
them, which speeded morphological evolution.
Since Northcutt and Gans’s (1983) proposal, several subsequent studies de-
termined that in protochordates there are tissues comparable to the NC and PL
(Holland et al. 1996, 2000; Baker and Bronner-Fraser 1997b; Graham, 2000; Shimeld
and Holland 2000, 2005; Jeffery et al. 2004) and a peripheral, visceral nervous sys-
tem, which however, differentiates in situ and does not derive from migratory
NC-like cells as in vertebrates (Lacalli 2004). This evidence is not inconsistent with
Northcutt and Gans’s (1983) original proposal; after all, morphological structures
and their ontogenies do not arise from nothing (Braun and Northcutt 1997). It is
now widely considered that the protochordate ancestor of vertebrates included cell
populations that modified their developmental pathways to yield definitive neural
crest and placodes in vertebrate origins (Shimeld and Holland 2005). Nevertheless,
in cephalochordates or urochordates these tissues never acquire the degree of com-
plexity observed in vertebrates, and their migratory capacities, although present in
some instances, are much more limited than in vertebrates. Interestingly, in the tu-
nicate Eitenascidia a cell population emerging from near the neural tube migrates
through the body and differentiates into pigment cells (Jeffery et al. 2004), which
again supports a close phylogenetic relation between urochordates and chordates.
During amphioxus neurulation, cells of the non-neural ectoderm bordering the
NP, and expressing NC markers such as AmphiDll (ADll, homologous to verte-
brate Dlxs, which mark NC and PL), develop lobopodia and crawl over the neural
plate to meet and fuse in the dorsal midline, but they never migrate to other sites
(Holland et al. 1996, 2000; Holland and Holland 2001). In amphioxus, ADll acts
as an ectodermal marker and its epidermal expression pattern is comparable to
the amphibian XDll2 (Dirksen et al. 1994) and to the zebrafish homolog gene Dlx3
(Akimenko et al. 1994). In higher craniates, Dlx3 is an epidermal marker (Porteus
et al. 1991, 1994; Bulfone et al. 1993b). Nevertheless, in amphioxus, ADll is also
expressed in the alar region of the presumptive forebrain, including the alar region
of the ventral forebrain (Bulfone et al. 1993a,b). In the mid-neurula, cells near the
anterior end of the neural plate become ADll-positive and are incorporated into
the dorsal neural tube. These cells and others that express the gene somewhat later
demarcate a region comprising the anterior three-fourths of the amphioxus cere-
bral vesicle, which has been claimed to be homologous to the craniate forebrain
(Holland et al. 1996). This evidence underlines the close relation between Dll/Dlx
genes and both the developing forebrain and vertebrate neural crest and placodes.
While amphioxus has only one ADll gene, this gene duplicated several times in
vertebrate origins, each new gene becoming restricted to specific tissues in which
the ancestral Dll gene was expressed (for example, Dlx3 in the epidermis, Dlx5 in
the placodal region, and Dlx1/2 in the ventral telencephalon; Holland et al. 1996).
In this context, it is of interest to recall that Dlx genes are closely related to Hox
genes and that vertebrate origins are marked by two duplications of the Dlx–Hox
cluster (Digregorio et al. 1995; Stock et al. 1996). Developmentally, Dlx genes are
expressed more anteriorly than Hox genes, which in the CNS are active at the level
of the hindbrain and spinal cord (Kraus and Lufkin 1999). While the Hox cluster
may have been involved in patterning the trunk region and the posterior CNS, Dlx
genes were more related to the development of the PL-derived sensory organs and
the telencephalon and related cephalic structures.
In a recent review, Meulemans and Bronner-Fraser (2005) proposed that in ver-
tebrate origins, recruitment to the neural plate border of some mesendodermal
genes activated primitive programs in NC precursors, expanding their develop-
mental potential. According to these authors, the ancestral chordate possessed
a neural plate border including lateral neural plate (expressing the neural plate
border specifiers Zic, Pax3/7 and Msx, and the NC specifier Snail) and adjacent
epidermal ectoderm (expressing the neural plate border genes Pax3/7, Msx, and
Dlx3/5). In ascidian urochordates, Snail, Msx, and Zic homologs are expressed
within the neural plate. In cephalochordates, Pax3/7 and Msx are not expressed in
neural plate borders. In vertebrates, neural plate border cells expressing Zic, Snail,
Pax3/7, and Msx also express neural crest specifiers, consistent with co-option of
these genes in the vertebrate lineage. In our view, this evidence points to a closer
similarity of inducing mechanisms between urochordates and vertebrates than
between cephalochordates and vertebrates, thus supporting a close phylogenetic
relation between urochordates and vertebrates (Delsuc et al. 2006).
Furthermore, in both larval tunicates and cephalochordates, there are primitive
sensory organs that serve as navigational aids and may be related to vertebrate
sensory organs (despite some homologic uncertainties). Although there is species
variability, in all larval ascidians there is a balance organ (an otolith) and an ocellus
with a pigment cup, both located in the brain vesicle. In some species, there are
additional sensory structures (Lacalli 2001). Amphioxus has a frontal, medial eye,
consisting of an accumulation of photoreceptive cells in the ventral anterior part of
the forebrain, and a so-called lamellar body more posteriorly and located dorsally
(homologous to the vertebrate pineal organ), plus dispersed photoreceptive cells
along the spinal cord (the Joseph cells and the organs of Hesse; Wicht and Lacalli
2005); and a putative balance sensory organ consisting of the preinfundibular
ciliary bulb cells (Lacalli and Kelly 2003). Most of these structures are found inside
the cephalic tube, and if the homology with vertebrate sensory organs is correct, it
would imply that the differentiation of head placodes permitted the exteriorization
of some sensory organs (such as the inner ear and the olfactory epithelium), and
the generation of paired eyes, directed to the periphery.
In his more recent update of the theory, Northcutt (2005) rejected his original
proposal regarding the origin of the neural crest from a subepidermal plexus
comparable to that of hemichordates. As mentioned above, he instead suggested
that the NC and PL arose as a consequence of a redistribution of the presumptive
territories in the early blastula. This view is partly consistent with the evidence
indicating quite an early embryonic origin of the NC territory, at or even before
gastrulation (Basch et al. 2006). In our view, although the modification of the
gastrula fate maps of deuterostomes could indeed be related to the origin of
neurulation and to the presumptive territory of the NC, much embryological
evidence also points to an important interaction between the ectoderm and the
neural plate during NC and PL differentiation (Baker and Bronner-Fraser 1997a;
Deardorff et al. 2001; García-Castro et al. 2002; Gammill and Bronner-Fraser 2003;
Woda et al. 2003). Thus, while NC and PL precursor tissues possibly appeared
in evolution at quite an early stage, concomitant with the process of neurulation,
the expansion and differentiation of these tissues in vertebrate origins may have
largely depended on neural–epithelial (and mesodermal) interactions, not being
a direct consequence of the derived organization of the early blastula.
2.2.3
Olfactory Placode and Epithelium: Association with Adenohypophysis
There is developmental evidence suggesting a close relation between the vertebrate

olfactory and adenohypophyseal placodes. Early and recent authors have proposed
that these two organs derive from a common structure in vertebrate ancestors
(De Beer 1924; Olsson 1990; Gorbman 1995; Schlosser 2005), which is confirmed
in basal vertebrates such as agnathans, both during development (Leach 1951;
Gorbman 1983) and in the adult (Døving 1998). Schlosser (2005) further claims
that primitively, there was a panplacodal primordium giving rise to all different
placodes, defined by Six1/2 and Eya. According to this author, all cranial placodes
arose by stepwise establishment of new gene regulatory interactions from a rostral
protoplacode that evolved from the anlage of an ancestral rostral neurosecretory
organ. This embryonic anlage may correspond to the vertebrate preoral ectoderm,
immediately rostral to the neural plate, that is, between the future mouth and the
anterior neuropore. This position makes it closely related to the anterior neural
ridge of embryonic vertebrates, which acts as a signaling source to induce both
ventral forebrain development and the anterior telencephalon by the secretion of
factors such as FGF (Couly and le Douarin 1985).
The origin of the olfactory organ from a urochordate- or cephalochordate-like
ancestor is, however, somewhat obscure. As mentioned, adult ascidians (urochor-
dates) are sessile animals in which the trunk region is apparently regressed and
develop as pure head animals (Lacalli 2003, 2005). Their nervous system consists of
a small perioral ganglion comprising the neural gland and the neurohypophyseal
duct, which derive from the larval anterior neural tube (Mackie 1995; Di Fiore et al.
2000). Based on gene expression patterns and on anatomical considerations, Manni
et al. (1999, 2001, 2005) and Mazet and Shimeld (2005) have proposed homology
of these structures with vertebrate olfactory and adenohypophyseal/hypothalamic
placodes. Interestingly, both in the vertebrate adenohypophyseal/hypothalamic
placode and around the neurohypophyseal duct of ascidians, there are migratory
GnRH+ neurons that in vertebrates migrate into the hypothalamus (Manni et al.
2001). Initially, it was thought that in vertebrates, some GnRH+ neurons derived
also from the olfactory placode, but subsequent studies determined that these
actually derive from the cranial neural crest (Whitlock et al. 2003; Whitlock 2004).
In amphioxus there are some receptors dispersed in the front of the head, but it
is not clear if they are comparable to vertebrate olfactory receptors (Lacalli 1999).
The rostral most epithelium (the nose) is innervated by two pairs of anterior
nerves, but apparently they collect mostly mechanosensitive information (Wicht

and Lacalli 2005). Some evidence suggests a common origin of the vertebrate
adenohypophysis (and the olfactory placode) and the cephalochordate preoral or
Hatscheck’s pit, a small opening communicating the anterior end of the neural
tube with the exterior (Nieuwenhuys 1997, 1998a; Sherwood et al. 2005; Schlosser
2005; see Fig. 6). This claim is supported by the location of Hatscheck’s pit in front
of the larval mouth, by the presence of nerve terminals on it and by its being
positive for pituitary-related hormones. Furthermore, the amphioxus AmphiPax6
gene is expressed in the preoral pit of amphioxus, and in the preplacodal region
including the olfactory/hypophyseal placode of vertebrates (Glardon et al. 1997,
1998). Likewise, some cutaneous sensory cells with cilia and microvilli of am-
phioxus (the type 1 receptors) have been claimed to be comparable to olfactory
receptors in vertebrates, as they express placodal markers such as Pax6, Msx, and
Neurogenin (Shimeld and Holland 2005). However, later in vertebrate development,
Pax6 expression is restricted to the lens placode and not to the olfactory placode
(Bhattacharyya et al. 2004). Furthermore, others have contended the hypothesis
of homology between adenohypophyseal placodes and Hatscheck’s pit, claiming
that it is not clear that the latter secretes adenohypophyseal hormones (but admit
its positivity for pituitary-specific transcription factors; Wicht and Lacalli 2005).
Another presumptive homolog to the olfactory epithelium is Kölliker’s pit (Kölliker
1843; Franz 1923), but this is rather a remnant of the neuropore that lacks obvi-
ous chemoreceptors and no nerve terminals have been described on it (Edinger
1906; Tjoa and Welsch 1974). However, this evidence is rather old and it might be
appropriate to revisit it.
Fig. 6 Scheme of a sagittal secion through the cerebral vesicle of the cephalochordate
amphioxus. Ventrally there is a cluster of photoreceptors and more dorsally there is a small
opening, Hatscheck’s pit, which has been considered by some authors a precursor of the
nasohypophyseal duct of early vertebrates. (Modified from Wicht and Lacalli 2005, with
permission)
2.2.4
Origin of the Telencephalon
Another claim made by Nortchcutt and Gans (1983) and by Northcutt (1996a,
2005) regarding vertebrate origins is that the rostral head of vertebrates is a neo-
morphic unit. This statement implies that, together with the NC and PL derivatives,
most anterior brain structures including pretectum, epithalamus adenohypoph-
ysis, preoptic area, telencephalic hemispheres and olfactory sensory organs arose
at relatively the same time. Intermediate forms bearing only some of these char-
acters are considered unlikely to have existed. Alternatively, Butler (2000a,b; 2006)
proposed a sequential acquisition of the different neural characters in vertebrate
origins, with an initial condition similar to that found in the extant amphioxus,
where a frontal eye projects to the tectal region. In an intermediate stage, paired
eyes developed, inducing the origin of a diencephalon. According to Butler (2006),
this stage is perhaps comparable to that of the fossil Haikouella (and maybe to con-
odonts, who also had paired eyes). The final stage is marked by the origin of paired
telencephalic vesicles in the dorsal forebrain. We somewhat agree with Butler in
that this alternative is more likely to occur than a sudden transformation yielding
all characters. However, a macrotransformation is not an impossible event, and
more evidence is needed to determine which hypothesis is correct. Further analyses
of fossil material such as Haikouella or conodonts may help resolve this issue.
Developmental evidence indicates a close relationship between telencephalic
and placodal territories, especially with the olfactory placode. The differentiation
of the forebrain and olfactory bulb depend on inductive interactions with the
olfactory placode (Gong and Shipley 1995; De Carlos et al. 1995; Reiss and Burd
1997). Moreover, at least in zebrafish the presumptive telencephalic territory limits
rostrally with that of the preplacodal region, especially with the olfactory placode,
and there is initially an important overlap between them (Whitlock 2004). Both
NC/PL and the telencephalon are partly determined by regulatory genes of the Dlx
family, such that NC and PL are specified by Dlx genes (particularly Dlx5 in the
placodal region), while at later stages, the ventral telencephalon expresses the genes
Dlx1 and Dlx2 (Holland et al. 1996; Whitlock 2004; see Sect. 2.2.2). Therefore, it is
conceivable that the differentiation of the placodal region yielding sensory systems,
and of the telencephalon, were sequential but closely related acquisitions, in which
one innovation facilitated the development of a second innovative feature.
A related issue concerns the existence of precursors for the telencephalon in non-
vertebrates. In this sense, both Northcutt (1996a,b; 2005) and Butler (2000a,b; 2006)
agree that there are no signs of a telencephalic structure in living nonvertebrate
deuterostomes (Northcutt 2005, claims that even the presence of a mesencephalon
is questionable in amphioxus). Nevertheless, recent comparative developmental
evidence has revealed that embryonic territories comparable to the forebrain can
be found in urochordates and in cephalochordates. Molecular genetic analyses of
the brains of larval urochordates, cephalochordates, and developing vertebrates in-
dicate a strong conservatism of the gene expression patterns in the rostrocaudal di-
mension of the neural tube (Fig. 7). As in vertebrates, Hox genes pattern the caudal-
most aspects of the cephalochordate and tunicate neural tube, while the anterior
neural tube (the brain vesicle) is marked by the expression of the forebrain marker
Otx2 (Williams and Holland 1996). Furthermore, in amphioxus there is a region in
the anteriormost neural tube expressing the gene Brain factor 1 (BF1), which is also
expressed in the vertebrate ventral telencephalon (Toresson et al. 1998), and we have
mentioned the expression of the Dlx-like gene ADll in the presumptive alar fore-
brain (Sect. 2.2.2). Amphioxus also expresses markers of the dorsal telencephalon
of vertebrates. This animal has one T-box gene (see Sect. 2.1.2), which is initially ex-
pressed in the archenteron and is downregulated in the neurula, but later appears in
the preoral pit (Hatscheck’s pit in the adult), which, as we have seen, is claimed to be
comparable to the olfactory/adenohypothyseal placode of vertebrates (Satoh et al.
2002). In other deuterostomes (echinoderms and hemichordates), the T-box gene
is also expressed in the archenteron (Satoh et al. 2002). In vertebrates, there was
a duplication of the T-box gene (Tbr1 and Tbr2), where Tbr2 is confined to the endo-
derm and Tbr1 expression is restricted to the olfactory/hypophyseal placode, but
later both genes appear in the dorsal telencephalon, since they are required for the
development of projection neurons, reelin expression, and proper laminar develop-
ment of the cerebral cortex. Thus, the duplication of Tbr genes in vertebrate origins
may have permitted the co-option of Tbr1 for brain and especially for telencephalic
development. Moreover, this evidence further suggests a close relation between the
olfactory placode, the adenohypophyseal placode, and early telencephalic markers.
Finally, in amphioxus, the notochord reaches levels in front of the neural tube,
supporting it in its entire length. This condition has led some to conclude that
the neural tube of amphioxus may not include CNS structures that in vertebrates
are positioned anterior to the notochord, like the forebrain. However, in larval
urochordates (which again may be closer to vertebrates than amphioxus; Delsuc
et al. 2006), the notochord ends behind the visceral ganglion, which is located
posterior to the cerebral vesicle, a condition reminiscent of that in embryonic
vertebrates, in which the notochord ends at the level of the thalamus (Sect. 2.1.2).
It is thus possible that the position of the notochord in amphioxus represents
a derived condition.
2.2.5
Summary
The origin of vertebrates is marked by the appearance of differentiated tissues de-

rived from the neural crest, of paired sensory organs derived from the epidermal
placodes, and of paired telencephalic hemispheres (Fig. 8). Concomitantly, at least
two duplications of the Hox-Dlx cluster were involved in vertebrate origins. While
Hox genes have been mostly involved in patterning the brain stem and spinal cord,
Dlx genes mark neural crest, placodes, and ventral telencephalic structures. Al-
though in larval urochordates and in cephalochordates, sensory organs are located
within the brain vesicle, in vertebrates, some of these organs differentiate in the
Fig. 7 Gene expression patterns in the anterior brain of hemichordates, urochordates,

cephalochordates and vertebrates, indicating homology of the anterior vesicle with the
vertebrate forebrain
placodal domain and localize outside the CNS. The origin of the olfactory epithe-
lium is not yet clear, but is apparently related to the adenohypophysis, which has
been associated with the preoral or Hatscheck’s pit of amphioxus (although there
are dissenting opinions). In the amphioxus forebrain, there are some telencephalic
Fig. 8 Diagram depicting the main characters of the ancestral vertebrate brain, bearing
paired sense organs, an olfactory system, and paired cerebral hemispheres. The animal also
had a notochord, segmented musculature, and a branchial skeleton. Note that contrary to
amphioxus, in which the notochord reaches the anterior tip of the animal, the notochord
does not reach the forebrain, which is supported by a prechordal platform. (Modified with
permission from Lacalli 2005)
markers that suggest a close relation between the olfactory/hypophyseal placode

and the ventral telencephalon. In cephalochordates there is also expression of
a vertebrate dorsal telencephalic marker (T-box/Tbr1), but this is located in the
preoral pit, possibly related to olfactory structures. Thus, it is possible that this
gene was subsequently co-opted for dorsal telencephalic differentiation. In this
context, it is of interest to recall that in vertebrate development, early telencephalic
fates are initially of ventral character (mainly in response to FGF8 emanating from
the anterior neural ridge). Subsequently, exposure to Wnts and BMPs form the
overlying ectoderm prompts some cells to acquire a dorsal phenotype (Gunhaga
et al. 2003). This sequence is broadly consistent with a phylogenetic sequence in
which there is an initial differentiation of a ventral forebrain, related to the ol-
factory epithelium and adenohypophysis (perhaps related to Hatscheck’s pit in
amphioxus); later, there is differentiation of olfactory structures and an originally
ventral telencephalon that eventually acquires a dorsal component.
2.3
Evolution of the Telencephalon in Vertebrates
2.3.1
Taxonomical Relationships Among Vertebrates and Their Early Evolution
Vertebrates – or craniates – are divided into agnathans (jawless vertebrates) and

gnathostomes (jawed vertebrates like most fishes and all terrestrial vertebrates).
Evolution of the Telencephalon in Vertebrates 25
Agnathans are subdivided into the more primitive myxinoids such as the hag-
fish, and cyclostomes such as the lamprey. Among gnathostomes, chondrychthian
fishes are represented by sharks, rays, and related cartilaginous fishes, while the
osteichthies are the bony fish like trouts and most fish we know. Sarcopterygians
are a group of bony fish that are considered related to the ancestors of terrestrial
vertebrates, as they bear lobed fins that resemble primordial limbs, and some have
developed lungs to breathe air. Terrestrial vertebrates are divided into anamniotes
(amphibians), who put their eggs in water and have a larval aquatic stage; and
amniotes (reptiles, birds, and mammals), whose eggs are covered by an amniotic
fluid and can be placed outside water. The amniotic cavity locates either within the
egg shell such as in reptiles, birds, and monotreme mammals, or develops inside
the maternal uterus such as in marsupials and placental mammals (see Fig. 9).
As mentioned, some of the earliest vertebrate fossils appear to be represented
by the conodonts, soft-bodied vertebrates that had not yet developed an ossified
skeleton. Skeletal agnathan fossils date from the early Silurian, and are commonly
termed ostracoderms (shell-skinned), as they developed an extensive exoskele-
ton that could have the form of a solid carapace, large bony plates, or scales
(Carroll 1988). These animals were probably not excellent swimmers, but those
with light, flexible armors and a fusiform body may have lived in the open water.
Those with heavier armors and a dorsoventrally flattened body were probably
benthonic. Ostracoderms clearly show paired eyes, large semicircular canals, and
nasal openings, indicating a well-developed olfactory system. Two major groups of
ostracoderms have been recognized according to the structure of their nasal open-
ings: the pteraspids or diplorhins were considered to represent the more primitive
condition in which there are paired nasal sacs and external narial openings. On
the other hand, the presumably more advanced cephalaspids or monorhins had
Fig. 9 Phylogenetic relations among vertebrates. Turtles (Chelonia) are now considered to
be more related to lepidosaurians than to stem reptiles
a single, medial nasal sac and narial opening that is confluent with the hypophyseal
duct. Some of these animals may have developed electric organs.
Hagfishes, considered to represent the most basal group of living agnathans,
were initially proposed to evolve from the more primitive diplorhins (Stensio 1964).
In fact, myxinoids were considered to represent a primitive clade, the outgroup
of the clade formed by lampreys and jawed vertebrates. On the other hand, the
configuration of the endocranial cavities of monorhins suggested a brain structure
similar to that of the lamprey Petromyzon. In this animal, the anterior portion of
the brain stem is expanded laterally to locate the telencephalon just below the nasal
cavity that leads to the nasohypophyseal opening, which continues ventrally into
the area of the hypophysis (Moy-Thomas and Miles 1971). More recent reports
suggest that modern agnathans have no direct relations with fossil ostracoderms,
being more basal than these and related the fossils like Haikouichthys. The rest of
the vertebrates are an outgroup of cyclostomes, and subdivide into conodonts and
ostracoderms. Jawed vertebrates originat as a sister group of osteostracans. a clade
of monorhin ostracoderms (Gess et al. 2006).
One of the most important advances among primitive vertebrates was the origin
of jaws, allowing a truly predatory way of life. The earliest jawed fishes appear in
the lower Silurian period. These are called placoderms, but are not closely related
to modern cartilaginous or bony fish. Most were benthonic and probably poor
swimmers, despite the clear presence of pectoral fins. They had no teeth but rather
bony plates in the margin of their jaws.
Beside the fossil placoderms, two major radiations took place: cartilaginous
fishes and bony fishes. Although these two groups differ in many respects, the
structure of their jaw and the pattern of tooth replacement indicate that they
have a common ancestry that is separate from that of the placoderms (Carroll
1988). These two taxa also share the absence of an exoskeleton and the presence
of well-developed paired fins. Both groups developed as good swimmers, but
bony fish developed a swimbladder, while cartilaginous fishes attempted to solve
the problem by developing cartilage instead of bone, and a large, oil-filled liver
that greatly reduces their specific gravity. Early cartilaginous fish radiated in the
Devonian period, producing a series of different families with unclear relationships
among them. As mentioned, the extant members of this class include sharks, rays,
and the deep-sea holocephalians.
On the other hand, osteichthyes or bony fish became an extremely diverse group
that has dominated marine and freshwater environments since the paleozoic. This
class is divided into two major subclasses, the highly diversified ray-finned or
actinopterygian fishes such as the trout and the much less common lobe-finned
or sarcopterygian fishes, including the coelacanth and the lungfish. The lobe fins
of the latter represent the ancestry of the limbs of terrestrial vertebrates. Fur-
thermore, considering that the teleostean swimbladder is a derivative of the lung
sacs of lobe-finned fishes, it is possible that the common ancestor of ray-finned
and lobe-finned fishes was phenotypically close to the early members of the sar-
copterygia. In fact, the more basal extant members of the actinopterygia (polypter-
iforms or brachiopterygians) bear lobed fins and vascularized lungs (Nieuwenhuys

1998b, c).
Tetrapods originated from a group of primitive sarcopterygians, possibly living
in quiet freshwater ponds. The earliest tetrapods were large-bodied fossil amphib-
ians living in the Devonian period that vaguely resembled modern crocodiles,
and bearing fishlike characteristics such as lateral line canals, a tail fin, opercular
bones, as well as fully tetrapod features such as a massive ribcage and robust feet
with digits. Representatives of this group are Acanthostega, Ichthyostega and the
possible basal amniote Tulerpeton (Jarvik 1980, 1996; Coates and Clack 1990, 1991).
Recent interpretations, supported by the discovery of gill bars in Ichthyostega,
consider that these animals had a fully or largely aquatic lifestyle, using their limbs
to swim rather than to walk (Clack et al. 2003). In the Carboniferous period, a large
radiation of these early amphibians took place, in which animals were progres-
sively adapting to live on ground. Among these were the herbivorous diadectids
and the crocodile-like limnoscelids, which are possibly the closest relatives to the
amniotes. One of these lineages eventually became fully terrestrial, developing
internal fertilization, an amniotic egg, reduced skin permeability partly provided
by scales, a water-reabsorbing cloaca that excreted solid uric acid to retain water.
These were the first reptiles, whose earliest known member is possibly Casineria,
but its affinities are dubious because of poor conservation of the skeleton. More
definite amniote features are present in the small-bodied Hylonomus, Paleothyris,
and Westlothiana, members of the Prothorothyrididae family (Clack 2002).
These animals represent the stem reptiles, usually considered to be the earliest
amniotes in the planet. Reptiles have been classified on the basis of the pattern of
openings in the dermal skull behind the orbits. In primitive reptiles such as the
prothorothyridids (subclass anapsida), there are no openings and the roof of the
skull is completely covered by bone. Members of this class include fossil reptiles,
and some authors have placed turtles among them, based on the absence of
cranial openings in this group (see Carroll 1988). For this reason, turtles have been
considered in many instances to be the reptiles closest to the point of reptilian–
mammalian divergence, and their brains have been considered as models of
the ancestral amniote brain. However, some paleontologists have considered the
inclusion of turtles into the subclass anapsida somewhat arbitrary, as it disregards
many other aspects that strongly suggest that this group is rather a highly derived
one (see Carroll 1988). Moreover, recent phylogenetic analyses based on morphol-
ogy and on molecular evidence place turtles as a rather modified group of reptiles,
with no direct relation to the ancestral anapsids (Mannen and Li 1999; Rieppel and
Reisz 1999; Zardoya and Meyer 2001). Therefore, the absence of temporal openings
in the skull of turtles may be secondary and not reflect an ancestral condition.
The diapsid reptilian condition, in which there are two postorbital skull open-
ings, possibly originated from a group of anapsid reptiles. This subclass repre-
sents most living reptiles and includes two main groups: lepidosaura, with lizards,
snakes, and a primitive New Zealand reptile called the tuatara; and archosaura,
which includes crocodiles, dinosaurs, and birds. According to some phyloge-
netic analyses mentioned above, turtles may also belong to the diapsids. There
is also the subclass parapsida, represented by fossil marine reptiles (Clack, 2002;
Carroll 1988).
The last reptilian subclass is represented by the synapsid condition (with a cra-
nial opening in the cheek region of the skull), exemplified by the mammal-like
reptiles from which the first mammals emerged. Synapsids appear at about the
same time as the stem anapsids: Protoclepsydrops is considered to be a synapsid
as old as the early anapsid Hylonomus (Carroll 1988), but the classification of the
former has not been confirmed (Reisz 1986). In any case, there are indisputable
synapsids of the pelicosaur group only slightly younger than Hylonomus, namely
Archaeothyris (Reisz 1972). The general consensus is that amniotes are a mono-
phyletic group that nevertheless diverged into the stem reptiles (protorothyridids)
and the mammal-like synapsids (pelicosaurs) at quite an early stage.
2.3.2
Evolution of the Cerebral Hemispheres: Ventral Telencephalon
Agnathans already possess a differentiated telencephalon, although its organiza-

tion is somewhat different than that of gnathostomes. The ventral telencephalon
of agnathans is quite a simple structure, containing a medial septum and a lateral
striatum. In myxinoids (hagfishes), the septum is unpaired and is wedged between
the olfactory bulbs on the ventral side of the brain, receiving olfactory projections
via the medial olfactory tract (Wicht and Northcutt 1993). However, the numerous
neurochemical dissimilarities between this structure and the gnathostome septum
have made some authors question their homology (Wicht and Northcutt 1994).
In cyclostomes (lampreys), a septal nucleus receives secondary afferents from the
olfactory bulb (Polenova and Vesselkin 1993). The striatum of lampreys is better
known (Nieuwenhuys and Nicholson 1998), receiving numerous terminal arboriza-
tions with several neurotransmitters including dopamine, which in gnathostomes
has proved to be a reliable marker for this structure. Furthermore, the lamprey
subpallium contains a large number of neurosecretory cells, which project to the
infundibular region and contribute to the preopticohypophysial neurosecretory
system (Pombal et al. 1997a,b; Nieuwenhuys and Nicholson 1998). This underlines
the relation between the subpallium and the basal forebrain in this group.
As far as is known, the evolution of the basal ganglia has been rather conser-
vative in the history of jawed vertebrates (Parent 1986; Medina and Reiner 1995;
Marín et al. 1998; Smeets et al. 2000). However, a few changes in striatal input
have taken place in mammals. For example, in amphibians the major striatal input
comes from the dorsal thalamus, but in reptiles and birds it comes from a structure
termed the dorsal ventricular ridge (DVR). In mammals, this input comes mainly
from the neocortex (Guirado et al. 2000; Parent and Hazrati 1995a,b). In addi-
tion, some authors have described in mammals an emphasis of projections from
the basal ganglia to the dorsal thalamus, which in turn projects to the neocortex
(Brauth 1990; Medina and Reiner 1995). Perhaps this has some relation to the loss
of the pretectal pathway from the basal ganglia to the optic tectum (in mammals,
the optic tectum is significantly reduced in relative size) and may be concomitant
with the development of the mammalian corticospinal tract. In reptiles, projec-
tions from the basal ganglia to the dorsal thalamus appear to be less developed,
although there has been an independent development of pallidothalamic connec-
tions in birds (Brauth 1990). Another difference in output relates to the pathways
connecting the basal ganglia with the mesencephalic optic tectum. There are mul-
tiple pathways for this connection, of which the most important are a ventral route
via the substantia nigra, which is present in all tetrapods, and a dorsal route via the
pretectal nuclei. The pretectal pathway is most developed in anurans, some lizards,
turtles, crocodiles, and birds, although it is weak or absent in urodeles, some lizards,
snakes, and mammals, suggesting that it is a highly variable trait (Marín et al. 1998).
The ventral telencephalon of jawed vertebrates also contains structures like the ol-
factory tubercle in the ventral striatum, which receives olfactory information and
has relations with the olfactory cortex and the olfactory nucleus, corresponding to
lateral and medial pallial components, respectively (Butler and Hodos 1996).
2.3.3
The Brain of Jawless Fishes and the Organization of the Ancestral Dorsal Telencephalon
Myxinoids have a highly distorted brain in which there are four paired ventricles
in the embryo (two telencephalic and two diencephalic); these ventricles become
obliterated in the adult, and there is a fusion of the anterior walls of the diencephalic
vesicle with the posterior walls of the telencephalic vesicle. This region gives rise
to an evaginated component termed the central prosencephalic complex, which
includes paired cerebral ventricles containing both telencephalic and diencephalic
components, but its functions and connectivity remain obscure. This component
has been compared to the medial pallium of other vertebrates (Jansen 1930),
but this proposal has been challenged (Wicht and Northcutt 1998). Nevertheless,
recent embryological evidence indicates that the medial pallium corresponds to
the caudal forebrain, and it is separated from the more posterior thalamus by
the zona limitans intrathalamica (Kimura et al. 2005). Therefore, the topographic
position of the hagfish medial prosencephalic complex might be consistent with
the embryonic position of the medial pallium. Furthermore, the zona limitans
intrathalamica of mammals might perhaps be comparable to the region in which
the telencephalic and diencephalic walls fuse in myxinoids, as this region is a focus
of extensive neuronal proliferation and migration.
The pallium of agnathans receives an extensive olfactory projection, covering it
almost completely (Northcutt 1996a; Northcutt and Puzdrowski 1988; Wicht and
Northcutt 1992, 1993, 1998; Wicht 1996; Northcutt and Wicht 1997). The olfactory
bulbs are particularly well developed in both myxinoids and cyclostomes, but in the
latter olfactory structures resemble much more closely those of jawed vertebrates.
In hagfishes, the olfactory bulbs receive numerous olfactory nerve bundles (about
ten per side) and project to the telencephalon in three main bundles: the medial,
the lateral, and the ventral olfactory tracts, respectively innervating the septum,
the pallium, and the basal forebrain. The pallium of hagfishes is unique in that it
has a superficial cortical mantle of gray matter that is subdivided into several layers
or fields. It also has reciprocal connections with diencephalic regions including
the dorsal thalamus, with a strong tectothalamic-telencephalic component, and
has interhemispheric connections (Wicht and Northcutt 1993, 1998). Despite this
complexity, in myxinoids it is not possible yet to recognize ventral, lateral, dorsal,
and medial components with certainty (Myojin et al. 2001), which has led some
authors to propose that the entire pallium is homologous to the lateral pallium
of higher vertebrates (see Butler and Hodos 1996). (As mentioned, these animals
also have the above-mentioned central prosencephalic complex, which might be
comparable to the medial pallium.)
Although in the lamprey the olfactory bulbs are clearly evaginated, evagination
is not complete in the caudal telencephalon, forming the telencephalon impar in
which the two hemispheres are fused in the midline (Nieuwenhuys and Nicholson
1998). In the lamprey, this structure contains the septum (ventral pallium), the
primordium hippocampi (dorsal pallium), and parts of the corpus striatum (sub-
pallium). In elasmobranchs, dipnoans, the coelacanth Latimeria and amphibians,
a telencephalon impar can still be observed, but is much less extensive and most
telencephalic structures are evaginated. Lampreys already show a subdivision into
at least medial, dorsal, and lateral pallium. A ventral pallial field has not been yet
reported in agnathans, but if fate-mapping evidence is correct in positioning the
olfactory bulb in this subdivision (Cobos et al. 2001), this should also be a primitive
vertebrate characteristic. As in most jawed fishes, in the lamprey, dorsal thalamic
projections, particularly from the tectothalamic route, end in the small medial pal-
lium, which nonetheless also receives olfactory projections (Northcutt and Wicht
1997). Most olfactory projections end in the expanded lateral pallium, and there
is a subhippocampal lobe that has been homologized to the gnathostome dorsal
pallium, also receiving olfactory input. Therefore, while the agnathan pallium is
entirely olfactory, there is also a substantial diencephalic projection, which in hag-
fishes is spread over the pallium, overlapping with secondary olfactory afferents,
but in lampreys is confined to the medial pallium (where it also overlaps with
less dense secondary olfactory projections; Northcutt and Wicht 1997; Wicht and
Northcutt 1998). The projection from dorsal thalamus to the medial pallium is
shared with several gnathostomes, excluding amniotes (Northcutt 1995).
This evidence led Wicht and Northcutt (1998) to propose a tentative morpho-
type of the ancestral gnathostome brain, in which extensive olfactory projections
to the pallium and also thalamopallial projections are a primitive character for ag-
nathans. Nevertheless, ascending spinal or bulbar lemniscal systems do not reach
the dorsal thalamus, which is innervated mainly by tectothalamic or collothala-
mic projections (lemniscal systems end in the mesencephalic tegmentum, which
in turn projects to the thalamus; Ronan and Northcutt 1990; Butler and Hodos
1996). This condition is also observed in most fish (with some exceptions), with
tetrapods the first group in which the development of a strong ascending lemnotha-
lamic system is consistently evident (Ronan and Northcutt 1990; Muñoz et al. 1994,
1997). Nevertheless, there are direct retinothalamic visual projections that reach
the telencephalon at least in all jawed vertebrates (cartilaginous fish: Ebbesson
and Schroeder 1971; Schroeder and Ebbesson 1974; Smeets 1990; Northcutt 1990b;
bony fish: Nieuwenhuys and Meek 1990; tetrapods Butler, 1994a,b).
Finally, in all vertebrates, the pallium also receives projections from the preoptic
region, and there is a projection from the posterior tuberculum to the subpallium
and sometimes to the pallium (in agnathans, Polenova and Vesselkin 1993; Wicht
and Northcutt 1998). Furthermore, the pallium projects to the thalamus and tectum
in hagfish and lamprey, indicating that these connections are primitive.
2.3.4
The Pallium in Jawed Vertebrates
An early scenario of gnathostome brain evolution implied that the pallium was
dominated by olfactory afferents in most fishes, while in terrestrial vertebrates,
thalamic projections restricted the extension of olfactory afferents, confining them
to the lateral pallium and related structures (Ebbesson and Heimer 1970; Smeets
1983). However, it was later found that all jawed fishes display several pallial fields
(medial, dorsal, lateral and more recently, ventral), and an olfactory projection
restricted to lateral regions (for review see Northcutt 1995; Northcutt and Kaas
1995), which dramatically changed the concept of early brain evolution.
The acquisition of predatory lifestyles by the early gnathostome vertebrates,
involving the further development of other sensory modalities, implied the pro-
gressive development of ascending visual, somatosensory, and lateral line afferents
to the pallium via the dorsal thalamus. The expansion of these sensory projections
was concomitant with the enlargement of the telencephalic components receiving
the respective inputs (Northcutt 1981; Northcutt and Puzdrowski 1988; Wicht and
Northcutt 1992, 1993; Striedter 1997; Wicht 1996). With the exception of amphib-
ians, which are considered to have a secondarily simplified brain (Northcutt 1981;
Neary 1990), this phenomenon is also evident among terrestrial vertebrates. Nev-
ertheless, this expansion process appears to have been a relatively late event in the
evolution of each vertebrate class (the basal exponents usually bear quite simple
brains), and pallial morphology evolves via clearly divergent lines in each group.
In cartilaginous fishes, a division between a pallium and a ventral subpallium
is generally acknowledged, but there is no agreement on their precise boundaries.
The pallium is subdivided into medial (hippocampal), lateral (piriform), and the
dorsal or general pallium between them. The latter component occupies most of
the telencephalic roof and is further divided into an internal or central component
(which is the largest and located in the midline; recall the telencephalon impar of
cyclostomes), and a superficial or cortical region. Little is known about the afferents
to this region, but its output is directed to the hypothalamus. As mentioned, the
medial pallium receives most collothalamic sensory projections from the dorsal
thalamus, and the lateral pallium receives most olfactory projections, together with
connections from some ventral telencephalic structures including the septum and
the superficial striatum (Smeets 1990).
The brains of bony fish are noticeable because their hemispheres do not show the
typical evaginated appearance, but their medial pallia separate from the midline,
opening the ventricular cavity, which remains covered by a thin layer of choroid
plexus (Butler 2000c). This process, termed eversion, results in the inversion of the
topography of cell masses, where the ventricular zone becomes the most superficial
aspect and the pial surface becomes internal to it. This is reminiscent of a condition
in which the neural tube has failed to close in its anterior region (Nieuwenhuys
and Meek 1990). Interestingly, a relatively similar condition is observed in the
holocephalans (basal cartilaginous fishes), in the lobe-finned coelacanth and in
the lungfish Neoceratodus; in these species, the hemisphere walls are separated and
are connected by an extensive ependymal membrane (Smeets 1998; Nieuwenhuys
1998d,e). This perhaps suggests that the brain of ancestral gnathostomes had its
medial pallia largely separated at the midline by an extensive mantle of choroid
plexus. This condition may have facilitated the eversion process in bony fish, which
according to Striedter and Northcutt (2006) occurs as a consequence of the very
small size of ray-finned fish embryos, which does not permit evagination of the
hemispheres, forcing these cell masses to squeeze into the space rostral to the eyes.
The pallium of lungfishes and amphibians is generally evaginated and consists
in large part of periventricular cells that show a limited degree of radial migration;
these cells do not make up a true cortical architecture. This has been interpreted to
be a manifestation of neoteny or paedomorphosis (i.e., retention of a juvenile stage;
Ten Donkelaar 1998c). The amphibian pallium has been subdivided into lateral,
dorsal, medial, and ventral components (Holmgren 1922; Neary 1990; Bruce and
Neary 1995; Puelles 1995; Brox et al. 2004; Moreno and González 2006). Based in
large part on the relative absence of direct olfactory input and on the presence
of at least thalamic visual and somatosensory projections, the medial pallium has
been considered to be comparable to both the medial/dorsomedial cortex and the
dorsal cortex of reptiles (Bruce and Neary 1995; see also Ten Donkelaar 1998b,c).
On the other hand, the dorsal pallium receives substantial input from the main
olfactory bulb and has been compared to parts of the lateral and olfactory cortices
of reptiles and mammals. The lateral pallium of amphibians is subdivided into
a dorsal component, also comparable to parts of the lateral cortex of amniotes, and
a basal part which has been compared to the basolateral amygdalar complex of
mammals and to the DVR of birds and reptiles. In amphibians, there is also a caudal
striatum (subpallial) considered to be homologous to the striatal amygdala of
reptiles and to the central amygdalar complex of mammals (Bruce and Neary 1995;
Moreno and González 2003, 2004, 2005; Moreno et al. 2004; Laberge et al. 2006).
The reptilian pallium has a three-layered cortex, consisting of a medial and
a dorsomedial moiety (both comparable to the mammalian hippocampal forma-
tion), plus a lateral (olfactory) cortex (Ulinski 1990), and finally a dorsal cortex
(equivalent to the archistriatum accessorium, or Wulst, of birds) located between
these two, part of which receives visual projections from the dorsal lateral genic-
ulate nucleus, as well as some somatosensory input (Medina and Reiner 2000). In
reptiles and birds, many nonolfactory sensory projections (visual, auditory, and
somatosensory) terminate in the DVR (Ten Donkelaar 1998b; Ulinski 1983), which
in birds consists of three components, originally termed the archistriatum, neos-
triatum, and hyperstriatum. The DVR was originally considered to be part of the
basal ganglia (Elliot Smith 1919; Johnston 1923), but subsequent studies (Karten
1968, 1969; Karten and Hodos 1970; Nauta and Karten 1970) established that this
structure receives a strong sensory input, which was claimed to support a pallial
origin. Furthermore, histochemical analyses probing acetylcholinesterase activ-
ity determined that the limits of the corpus striatum were located immediately
ventral to those of the DVR (Parent and Olivier 1970; Parent 1986; Ulinski 1983).
Considering these findings, a more recent nomenclature has changed these names
into arcopallium (for archistriatum), nidopallium (for neostriatum), mesopallium
(for the hyperstriatum ventrale), and hyperpallium (for the hyperstriatum ac-
cesorium, or Wulst; Reiner et al. 2004; Jarvis et al. 2005). The DVR is the most
expansive telencephalic component of reptiles and birds and is a main integra-
tory center in their brains. In reptiles, it consists of an anterior part (ADVR) and
a posterior or basal part (PDVR). The output of the ADVR is directed mainly to
the subpallial corpus striatum and to the PDVR. The latter (corresponding to the
archistriatum/arcopallium in birds) has been compared to parts of the mammalian
amygdala and projects mainly to the hypothalamus (Lanuza et al. 1998, 1999; Ten
Donkelaar 1998b; Novejarque et al. 2004).
Finally, mammals are characterized by the possession of the neocortex or iso-
cortex, which originates during development at least in large part from the dorsal
pallium (Rakic 1988; 1995; Northcutt and Kaas 1995; Voogd et al. 1998). The iso-
cortex receives ascending sensory input from the thalamus and projects to the
hippocampus and to the amygdala, as well as sending output to many lower brain
centers including the thalamus, corpus striatum, various brainstem nuclei, and the
spinal cord. In the adult brain, medial to the isocortex is the hippocampal formation
(medial pallium), and lateral to it is the olfactory cortex (lateral pallium). Finally,
there is a highly complex claustroamygdaloid complex in the ventral pallium.
2.3.5
Summary
The first vertebrates (agnathans) were free-living animals with well-developed

senses and already had a conspicuous telencephalon receiving a strong and
widespread olfactory projection covering large extensions of the pallium, as well
as some ventral pallial components such as the septal area and olfactory bulbs.
While more basal aspects of the telencephalon may have been associated with the
ventral forebrain and were possibly related to motor functions, the more dorsal
regions were mainly olfactory but also received dorsal thalamic input from the
collothalamic system. Although in hagfishes it is difficult to separate different
pallial components (perhaps the central prosencephalic complex relates to the
34 Origin of the Mammalian Brain
medial pallium, while the rest of the pallium consists of a laterodorsal pallium),
in the lamprey it is already possible to separate medial, dorsal, and lateral
components of the pallium, as in gnathostomes. In the latter, olfactory projections
became largely restricted to the lateral pallium. Interestingly, the medial pallium
receives a strong input from the dorsal thalamus, largely conveying sensory
information that is relayed in the mesencephalon. This condition persists in most
fish, but changes in tetrapods, in which information from lemniscal systems
also reach the thalamus and project to the telencephalon. In early gnathostomes,
the hemispheres increased in size and may have originally tended to an everted
condition in which the medial hemispheres are separated by an extended sheet of
choroid plexus. This trend is readily apparent in bony fishes, in which hemispheres
become everted. However, cartilaginous fishes developed a prominent dorsal
pallium with an internal nucleus centered at the midline (the central nucleus), thus
closing the two hemispheres and generating an evaginated brain. Lungfishes and
amphibians are characterized by a juvenilized brain with evaginated hemispheres
as well. Amniotes are the first true land vertebrates, as they are able to reproduce
on land. Amniotes split very early in two main lineages: stem reptiles, or anapsids,
and mammal-like reptiles, or pelycosaurs. These early animals had very simple
brains, which were possibly similar to those of present-day amphibians, where
olfactory input reaches the lateral and the dorsal pallium, while dorsal thalamic
projections reach the medial pallium. Reptiles develop a small cortex, consisting
of medial, dorsomedial, dorsal, and lateral fields, plus a large periventricular
structure termed the dorsal ventricular ridge, receiving most collothalamic input.
Lemnothalamic inputs are sent mostly to the dorsal cortex. Mammals develop
a large, six-layered neocortex that is topographically equivalent to the reptilian
dorsal cortex and receives both lemnothalamic and collothalamic inputs.
3
Origin of the Mammalian Brain
This section reviews the origin of the mammalian brain, especially the neocortex,
which is the most salient and expanding neural component in this group. We will
first discuss the fossil evidence on early mammals and their brains, and will follow
with a comparison between reptilian and mammalian brains. In the reptilian brain,
the lack of any structure obviously corresponding to the mammalian neocortex
is quite evident. For this reason, there have been intense controversies in relation
to the possible reptilian homologs to the neocortex. One such approach is based
on connectional evidence indicating a similar sensory input between parts of
the neocortex and the reptilian dorsal ventricular ridge; while other evidence,
based on connectional and developmental criteria, suggests homology between
the whole mammalian neocortex and the reptilian dorsal pallium. We will discuss
these different approaches, and will propose a hypothesis for neocortical origins
based on a dorsalization mechanism by which the dorsal pallium expanded in
medial pallium, while the rest of the pallium consists of a laterodorsal pallium),
in the lamprey it is already possible to separate medial, dorsal, and lateral
components of the pallium, as in gnathostomes. In the latter, olfactory projections
became largely restricted to the lateral pallium. Interestingly, the medial pallium
receives a strong input from the dorsal thalamus, largely conveying sensory
information that is relayed in the mesencephalon. This condition persists in most
fish, but changes in tetrapods, in which information from lemniscal systems
also reach the thalamus and project to the telencephalon. In early gnathostomes,
the hemispheres increased in size and may have originally tended to an everted
condition in which the medial hemispheres are separated by an extended sheet of
choroid plexus. This trend is readily apparent in bony fishes, in which hemispheres
become everted. However, cartilaginous fishes developed a prominent dorsal
pallium with an internal nucleus centered at the midline (the central nucleus), thus
closing the two hemispheres and generating an evaginated brain. Lungfishes and
amphibians are characterized by a juvenilized brain with evaginated hemispheres
as well. Amniotes are the first true land vertebrates, as they are able to reproduce
on land. Amniotes split very early in two main lineages: stem reptiles, or anapsids,
and mammal-like reptiles, or pelycosaurs. These early animals had very simple
brains, which were possibly similar to those of present-day amphibians, where
olfactory input reaches the lateral and the dorsal pallium, while dorsal thalamic
projections reach the medial pallium. Reptiles develop a small cortex, consisting
of medial, dorsomedial, dorsal, and lateral fields, plus a large periventricular
structure termed the dorsal ventricular ridge, receiving most collothalamic input.
Lemnothalamic inputs are sent mostly to the dorsal cortex. Mammals develop
a large, six-layered neocortex that is topographically equivalent to the reptilian
dorsal cortex and receives both lemnothalamic and collothalamic inputs.
3
Origin of the Mammalian Brain
This section reviews the origin of the mammalian brain, especially the neocortex,
which is the most salient and expanding neural component in this group. We will
first discuss the fossil evidence on early mammals and their brains, and will follow
with a comparison between reptilian and mammalian brains. In the reptilian brain,
the lack of any structure obviously corresponding to the mammalian neocortex
is quite evident. For this reason, there have been intense controversies in relation
to the possible reptilian homologs to the neocortex. One such approach is based
on connectional evidence indicating a similar sensory input between parts of
the neocortex and the reptilian dorsal ventricular ridge; while other evidence,
based on connectional and developmental criteria, suggests homology between
the whole mammalian neocortex and the reptilian dorsal pallium. We will discuss
these different approaches, and will propose a hypothesis for neocortical origins
based on a dorsalization mechanism by which the dorsal pallium expanded in
The First Mammals 35
response to signals emanating from the medial hemisphere (cortical hem), the
lateral hemisphere (cortical antihem), and the frontal hemisphere. Then we will
address the origin of cortical lamination, as the mammalian neocortex consists
of six laminae, instead of the three laminae found in the reptilian brain; and the
origin of the inside-out developmental gradient that is observed in the mammalian
neocortex. In this process, the subventricular zone, a late embryonic proliferating
compartment, probably played a special role. We will also offer a scenario in which
olfaction was an especially important sense in early mammals and contributed
to early neocortical expansion. Finally, we will briefly discuss the growth and
diversification of the cerebral cortex in the mammalian radiations.
3.1
The First Mammals
3.1.1
Fossil Mammals and Their Brains
The first radiation of mammal-like reptiles (synapsids) gave rise to the pelycosaurs,
which were relatively large, lizard-like animals. In the upper permian, pelycosaurs
were gradually replaced by their descendants, the therapsids. The hands and feet
of the latter faced more directly forward instead of being oriented sideways as
in other reptiles, which gave those animals a more mammalian-like gait. Some
therapsids grew to achieve large sizes, and they are classified into carnivorous and
herbivorous therapsids. Most therapsids became extinct by the end of the Triassic,
but one group of carnivorous therapsids, the cynodonts, survived well into the
Jurassic (Kemp 2005; Carroll 1988).
Cynodonts were relatively small-bodied and had a more mammal-like jaw
musculature, but the ear ossicles were still attached to the lower jaw, as they are in
reptiles. From cynodonts arose the eucynodonts or mammaliaforms, which include
Jurassic fossils such as Sinoconodon and Morganucodon, whose gross morphology
resembled that of some present-day insectivores (Rowe 1996a,b). True mammals
descend from eucynodonts, and are defined by the presence of a single dentary bone
making up the inferior mandible and the complete detachment of the middle ear
ossicles, as in the fossils Hadrocodium (Z.X. Luo et al. 2001, 2002), Gobiconodon, and
Repenonamus (Wang et al. 2001; however, according to these authors, Hadrocodium
is a juvenile form and it is not clear whether it had a fully mammalian middle ear).
Further evolution of mammals includes the origin of monotremes, marsupials, and
placental mammals. Triconodon is another interesting fossil, originally considered
to be close to Morganucodon (Carroll 1988), but according to newer analyses it has
been classified as a true mammal, perhaps belonging to the therians (marsupials
and placental mammals; Rowe 1996a,b).
Endocasts are molds of the cranial cavity of fossil animals. Analysis of these
casts indicates that early mammal-like reptiles (therapsids) had quite narrow, tubu-
lar hemispheres with no signs of telencephalic expansion (Hopson 1979; Quiroga
1980; Kielan-Jaworowska et al. 2004; Kemp 2005; see Fig. 10). Furthermore, in
cynodonts the volume of the endocast was much larger than the volume of the
brain, because ossification of the braincase was not as complete as in mammals
and it is not possible to observe anatomical details of the brain. In true mammals,
anatomical fissures and folds are much more clearly shown in the endocast, indi-
cating a narrow fit between the braincase and the volume of the brain. Increase
in brain size from cynodonts to early mammals is clearly shown in a comparison
of their respective encephalization quotients (EQ, i.e., brain size given a specific
body size). EQs of mesozoic mammals are twofold higher than those of advanced
cynodonts (see Kielan-Jaworowska et al. 2004). This is closely correlated with an
increase in the width of the braincase relative to skull width (Z.X. Luo et al. 2001).
(Interestingly, modern primates also have a brain that is about twice the size of
the brain of an average mammal of the same size; see Aboitiz 1996.) The brain-
case in stem mammals is narrower than in modern mammals, but is significantly
wider than in nonmammalian cynodonts despite having a much smaller body
size. For example Morganucodon, a primitive mammaliaform taxonomically in-
termediate between Triconodon and smaller-brained, more primitive therapsids,
shows only partial expansion of the brain. In this species, widening of the pari-
Fig.10 Brain endocasts from fossil mammaliaforms and Didelphys (living marsupial). Brain
expansion took place as a late event, closely associated with the origin of true mammals.
(Modified from Aboitiz et al. 2003, with permission)
The First Mammals 37
etal parts of the hemispheres can be observed (Kielan-Jaworowska et al. 2004;

Rowe 1996a,b). Admittedly, endocast information can be difficult to interpret,
since there are few anatomical details to identify as landmarks. Nevertheless, this
feature may be partly attributed to the early development of the dorsal cortex –
a possible precursor of the neocortex – in Morganucodon. Concomitant with the
increase in size of the neocortex, the cerebellum also underwent a dramatic ex-
pansion in early mammalian evolution, with a clear differentiation of the vermis
and an enlargement of the cerebellar hemispheres (reviewed in Kielan-Jaworowska
et al. 2004).
A dramatic increase in brain size, resulting from a generalized growth of the
isocortex, occurs in the recent fossil mammals Triconodon and Hadrocodium. In
these fossils, the detachment of the auditory bones from the mandible to form the
mammalian middle ear coincides with enlargement of the brain (Rowe 1996a,b;
Z.X. Luo et al. 2001). However, in other fossil mammals such as Repenomanus
and Gobiconodon, braincases are narrow despite detachment of the ear ossicles
(Wang et al. 2001). Therefore, brain expansion may have occurred after the ori-
gin of the middle ear, more than the reverse, i.e., brain enlargement trigger-
ing ossicle detachment for mechanical reasons (Wang et al. 2001; Gilissen and
Smith 2003).
The development of auditory projections into the neocortex was likely an im-
portant factor in the expansion of the latter and may have contributed to enhanced
hearing (Aboitiz et al. 2003c). In this context, the mammalian auditory cortex
contains binaural cells, many of which are interconnected interhemispherically
by fibers of the corpus callosum (Pallas 2001) and may participate in spatial lo-
calization of sounds. On the other hand, the DVR of birds and reptiles has few
or no interhemispheric connections, which may limit telencephalic auditory spa-
tial processing in these animals. Early mammals also developed a keen sense of
smell but apparently lost in part their visual ability to distinguish colors, which
is consistent with their presumed nocturnal habits (Jerison 1973; Kemp 2005). In
many protomammals, the intranasal bones formed a complex system for retaining
water and heat (Hillenius 1994). Furthermore, mammals developed a diaphragm
that made respiration more efficient. These conditions were probably of benefit for
the expansion of olfactory capacities, as protomammals had large olfactory bulbs
relative to their brains (Stephan 1983; Kemp 2005).
In this context, it is of interest to note that the two largest-brained vertebrate
taxa are birds and mammals, both of which also developed homeothermy. It is not
unlikely that the increase in basal metabolism permitted the expansion of an en-
ergetically costly brain (Hopson 1979). Nevertheless, at least among mammals the
relation between metabolic rate and brain size is a highly debated topic (for reviews,
see Aboitiz 1996 and Striedter 2005). An additional possibility, not exclusive with
the latter, is that the increased activity associated with an elevated metabolism
co-evolved with the acquisition of a progressively more complex, goal-oriented
organization of behavior.
3.1.2
Summary
Although early mammal-like reptiles diversified into several branches, their brains
as seen in endocasts are surprisingly simple, perhaps more similar to present-day
amphibian brains than to the differentiated brains of extant reptiles. The origin of
true mammals is a late evolutionary event in the lineage of mammal-like reptiles,
and is marked by the detachment of the middle-ear ossicles from the lower jaw,
which served to increase auditory acuity. Early mammals also had large olfactory
bulbs, indicating a well-developed sense of smell, but apparently their visual system
was reduced as a consequence of their nocturnal habits. These events (especially
the detachment of the middle-ear bones) are related to a subsequent increase
in brain size, mainly due to expansion of the neocortex and cerebellum. As in
birds, brain expansion may have been related to the acquisition of endothermy,
which permitted a more active behavior and provided energy requirements for the
development of a costly large brain.
3.2
Origin of the Mammalian Neocortex: Hypotheses on Homology
3.2.1
Mammalian Brain Expansion and the Origin of the Neocortex
The neocortex or isocortex is a six-layered organ that is located between the three-
layered lateral or olfactory cortex (lateral pallium) and the medial or hippocampal
cortex (medial pallium, also bearing three main layers), in a topographic position
corresponding to that of the dorsal pallium (Rakic 1988; Voogd et al. 1998; see
Fig. 11). This structure is unique to mammals, is a conserved feature of all mam-
malian brains and is responsible for most of the increase in forebrain size in early
and late mammalian evolution. Although in reptiles there are some laminated cor-
tical structures (dorsal, medial, and lateral cortices), these never acquire the degree
of tangential expansion and laminar differentiation that is observed in the mam-
malian neocortex. Furthermore, in reptiles, most sensory projections are delivered
to the noncortical DVR instead of to the neocortex, as is observed in mammals
(Fig. 11). In view of these differences, it has not been easy to determine the structure
homologous to the neocortex in reptiles. In other words, the question of the ances-
try of the mammalian neocortex, i.e., of which structure in the ancestral amniote
brain gave rise to it, has not been solved despite about two centuries of studies in
comparative neuroanatomy and neuroembryology. This problem is further com-
plicated by the absence of a single criterion to establish homology of neural struc-
tures. Commonly used criteria for similarity are connectivity (Bruce and Neary
1995; Butler 1994a,b; Karten 1969, 1997; Medina and Reiner 2000; Reiner 2000),
neurochemistry (Reiner 1991, 1993), and embryonic origins (Aboitiz 1992, 1995;
Källén 1951; Puelles et al. 1999, 2000; Smith Fernández et al. 1998; Striedter 1997).
Origin of the Mammalian Neocortex: Hypotheses on Homology 39
Fig. 11 The cerebral hemispheres of reptiles and mammals. The pallium of reptiles has
a cortex, subdivided into medial/dorsomedial (MC), dorsal (DC) and lateral (LC) compo-
nents; and a dorsal ventricular ridge (DVR). The medial and dorsomedial cortices of reptiles
have been compared to the hippocampal formation (HP) of mammals; and the lateral cortex
is considered homologous to the mammalian olfactory cortex (OC). The dorsal cortex of
reptiles resembles both the mammalian entorhinal cortex (adjacent to the hippocampal
formation; not shown) and the neocortex (NC). There is no agreement with respect to the
homology of the dorsal ventricular ridge. Some authors claim that this structure corre-
sponds to the lateral neocortex, and other authors argue that it relates to the mammalian
claustroamygdaloid complex (AM). PT, pallial thickening. (Modified from Northcutt and
Kaas 1995, with permission)
Unfortunately, when intending to identify structures homologous to the isocortex,

there have been discrepant conceptions derived from these different approaches.
3.2.2
Hypotheses for Neocortical Origins
Two alternative hypotheses have been raised regarding the origins of the mam-
malian isocortex, which have been elegantly summarized by Northcutt and Kaas
(1995) as the recapitulation hypothesis and the out-group hypothesis. Proponents
of the recapitulation hypothesis suggest that a DVR-like structure existed in the
common ancestor of mammals and reptiles, which somehow became transformed
into parts of the isocortex in the origin of mammals. This perspective is mostly
based on studies on adult neuronal connectivity, and more specifically on the pat-
terns of termination of thalamic afferents to the telencephalon (Karten 1968, 1997;
Nauta and Karten 1970; Shimizu and Karten 1993). Karten’s approach was origi-
nally challenged on topographical and developmental grounds by Aboitiz (1992a,b;
1993, 1995), who proposed that the mammalian neocortex as a whole derived from
the reptilian dorsal pallium, while the reptilian DVR originated deep to the lateral
pallium. Later, Bruce and Neary (1995), Striedter (1997), Smith-Fernández et al.
(1998), and Puelles et al. (1999, 2000), based on connectional and developmen-
tal evidence, proposed homology between the DVR and parts of the mammalian
ventral pallium, including the lateral amygdala and the dorsal claustrum. This
claustroamygdalar proposal was first stated by Holmgren (1922) but remained
unacknowledged for a long time. These considerations were summarized in the
out-group hypothesis (Northcutt and Kaas 1995), according to which the common
ancestor of reptiles and mammals would have had a cerebral hemisphere similar
in its topographic organization to that of present-day amphibians. In this case,
the most likely candidate for homology with the isocortex is the reptilian dorsal
pallium. Below, we will consider some of the evidence argued in favor of each of
these hypotheses.
3.2.3
The Recapitulation Hypothesis: Connectional Evidence
Butler (1994a,b) classified dorsal thalamic nuclei as either lemnothalamic or

collothalamic. Lemnothalamic nuclei receive their main sensory projections
from lemniscal ascending systems, which do not synapse in the mesencephalic
colliculi, like the visual thalamofugal pathway (which relays on the lateral
geniculate nucleus), and the spinothalamic and dorsal column somatosensory
pathways (relaying in the ventral posterior thalamic nucleus). On the other hand,
collothalamic nuclei receive sensory projections from the mesencephalic colliculi
(like the visual tectofugal and the auditory pathways). Visual projections from
the superior colliculus (or optic tectum) end in the posterior thalamic nuclei
(mainly the pulvinar nucleus in mammals, and the nucleus rotundus in birds and
reptiles), while auditory projections from the inferior colliculus end in the medial
geniculate body of all amniotes.
Lemnothalamic nuclei project to the dorsal cortex of reptiles and birds, and
to the more medial/dorsal aspects of the neocortex of mammals (such as the
striate or primary visual cortex and the somatosensory cortex), whereas collotha-
lamic nuclei project to the anterior DVR (ADVR) of reptiles and birds, and to
more lateral/ventral regions of the mammalian neocortex (the extrastriate visual
cortex and the auditory cortex). The recapitulation hypothesis of homology be-
tween the ADVR and parts of the mammalian neocortex has been largely based
on the comparative analysis of the collothalamic and lemnothalamic projections
in birds and mammals. Shortly, the hypothesis specifies homology between the
reptilian/avian dorsal cortex and the dorsal neocortex of mammals, and between
the reptilian/avian ADVR and the lateral neocortex of mammals. Furthermore,
relying on similarities in intrinsic connectivity, it has been proposed that different
components of the avian DVR correspond to specific neocortical layers in mam-
mals. In this perspective, the avian ectostriatum or entopallial nucleus, the general
nidopallium (Reiner et al. 2004) and the archistriatum/arcopallium correspond to
the mammalian visual extrastriate cortical layers IV, II–III, and V–VI, respectively
Fig. 12 Karten’s hypothesis (1969, 1997) of the equivalent circuit in the mammalian neo-
cortex and the avian dorsal ventricular ridge (DVR). I, II, III, IV, V, VI represent distinct
neocortical layers; Arc, arcopallium; En, entopallium (a component of the nidopallium); H,
hyperpallium; N, nidopallium; P, pulvinar; R, nucleus rotundus
(Karten 1997; Nauta and Karten 1970; Shimizu and Karten 1993; Veenman et al.
1995; Wild 1997; see Fig. 12). Recent studies indicate that avian areas of the DVR re-
ceiving sensory projections display markers such as RORB/Nr/1/2 and the voltage-
dependent potassium channel EAG2/KCNH5, which are also found in layer IV of
primary sensory areas of the mammalian neocortex (Schaeren-Wiemers et al. 1997;
Dugas-Ford and Ragsdale 2003). (Nevertheless, these markers are also detected in
thalamorecipient areas of the avian Wulst, belonging to the dorsal pallium.) Related
hypotheses have proposed equivalence between the postero-dorsolateral nidopal-
lium (neostriatum) and the mammalian prefrontal cortex (Gagliardo and Divac
1993; Divac et al. 1994; Güntürkün 2005) and between the arcopallium (archistria-
tum) and the cortical frontal eye fields of mammals (Knudsen et al. 1995).
3.2.4
The Dorsal Cortex of Reptiles: Subicular and Neocortical Characteristics
The recapitulationist hypothesis has been largely based on the comparison be-
tween avian and mammalian brains. However, in reptiles the situation is slightly
more complicated, as it has been argued that lemnothalamic systems reaching
the dorsal cortex are not strictly comparable to those in mammals (see Martínez-
García 2003; Guirado 2003). For example, somatosensory projections to the dorsal
cortex have not been observed either in lizards (Bruce and Butler 1984a,b; Lohman
and Van Woerden-Verkley 1978; Neary and Wilczynski 1977) or turtles (Hall and
Ebner 1970). In the case of visual projections, the thalamic lateral geniculate nu-
cleus projects to a region that in turtles includes the dorsal cortex and the pallial
thickening (a thickening in the lateral aspect of the pallium that is observed in
some reptiles; see Fig. 11), and in lizards is restricted to the pallial thickening (Hall
and Ebner 1970; Kenigfest et al. 1997; Lohman and Van Woerden-Verkley 1978).
In addition, multimodal projections from the dorsal thalamus reach the basal
ganglia and the dorsal pallium in both amphibians and reptiles (Wilczynski and
Northcutt 1983; González et al. 1990; Marín et al. 1997; Ten Donkelaar 1998a,b,c;
Guirado et al. 2000; Martínez-García 2003; Guirado 2003). In amphibians, there are
multimodal projections, carrying both lemnothalamic and collothalamic informa-
tion to the mediodorsal (and lateral) pallium from the anterior thalamic nucleus
(Vesselkin et al. 1971), and in reptiles a similar projection reaches the medial and
dorsal cortices from the dorsolateral anterior thalamic nucleus (Bruce and Butler
1984a; Desan 1988; Lohman and Van Woerden-Verkley 1978; Belekhova and Ivazov
1983; Ivazov and Belekhova 1982). A more recent hodological study in the turtle de-
termined that the dorsomedial anterior nucleus of the thalamus projected mostly
to the ipsilateral medial cortex, while the dorsolateral anterior nucleus projected to
the dorsomedial cortex, and the dorsal lateral geniculate nucleus projected to the
dorsal cortex, thus making a mediolateral topographic map between the distinct
thalamic nuclei and the cortical regions (Zhu et al. 2005). (This work also described
a descending pathway linking cortical regions [especially medial cortex] with the
brainstem red nucleus via the suprapeduncular nucleus of the hypothalamus, thus
providing an indirect cortical control of the red nucleus that in mammals becomes
direct.)
Considering this evidence, it has been proposed that the visual projection
from the lateral geniculate is a derived rather than an ancestral feature of rep-
tiles (Martínez-García 2003; Guirado 2003). According to these and other authors
(Powers 2003), the multimodal dorsomedial pallium of amphibians and reptiles
resembles more the mammalian hippocamposubicular cortex. This proposal is
supported by anatomical evidence indicating that, like the entorhinal cortex, the
reptilian dorsal cortex has important connections with the medial/dorsomedial or
hippocampal cortices (Hoogland and Vermeulen-Vanderzee 1989; Northcutt and
Ronan 1992; Guirado and Dávila 2002; Martínez-Marcos et al. 1999).
Furthermore, behavioral evidence in lesioned animals indicates that the reptil-
ian dorsal cortex does not participate in vision but rather in learning and memory
(Powers 1990). Lesions in the dorsal cortex produce deficits in acquisition and
reversal of pattern discriminations (Blau and Powers 1989; Cranney and Powers
1983), spatial discriminations (Grishman and Powers 1990), and in a variety of
other learning tasks (Grisham and Powers 1989; Avigan and Powers 1995; Day
et al. 2001; Peterson 1980; Petrillo et al. 1994; Moran et al. 1998), which strongly
relate this structure with the medial (hippocampal) cortex, which participates
in spatial and other forms of learning in a variety of vertebrates (Grisham and
Powers 1989; O’Keefe and Nadel 1978; Rodríguez et al. 2002a,b). Thus, the dorsal
cortex of reptiles may be compared to the entorhinal cortex of mammals, but
also containing a direct visual sensory input that, if perhaps not being the true
homolog of the mammalian visual cortex, serves to feed visual information to the
hippocampus for establishing sensory associations during learning. Furthermore,
the dorsal cortex of reptiles differs from the amphibian dorsal pallium in that it
receives much stronger dorsal thalamic inputs, lacks direct projections from the
olfactory bulb, and projects to several extratelencephalic targets (Bruce and Butler
1984a,b), characters that are reminiscent of the mammalian neocortex.
3.2.5
Differences in Connectivity Between the DVR and the Neocortex
There is also some connectional evidence that points to differences between the
reptilian DVR and the mammalian isocortex. Firstly, the mammalian extrastriate
visual cortex receives an important input from the primary or striate visual cortex
(Montero 1993; Rosa and Krubitzer 1999). Although in reptiles, projections from
the dorsal cortex to the DVR have been described (Ten Donkelaar 1998b; Ulinski
1990), these are much less prominent than the striate-extrastriate connections
of mammals. Secondly, the mammalian isocortex projects reciprocally to the en-
torhinal cortex and from there to the hippocampus (Haberly 1990; Rosene and Van
Hoesen 1987; Van Hoesen 1982), while in reptiles few connections if any have been
reported from the DVR to the medial/dorsomedial cortex or hippocampus (Ten
Donkelaar 1998b; Ulinski 1983, 1990). Moreover, based on comparisons of connec-
tivity, Bruce and Neary (1995) have argued that the reptilian DVR is most similar
to the mammalian lateral amygdala, since both structures receive projections from
collothalamic nuclei and both project to the corpus striatum, the striatal amygdala,
and the ventromedial hypothalamus. (More precisely, the reptilian ADVR would
correspond to the mammalian basolateral amygdala, while the whole DVR might
correspond to the whole lateral amygdalar nucleus.) On the other hand, the iso-
cortex projects to many other brain regions in the brainstem and spinal cord, and
does not project to the hypothalamus. These authors claim that fewer changes in
connectivity are required by assuming homology between the lateral amygdala of
mammals and the DVR of reptiles than by considering homology between the iso-
cortex and the DVR. An additional difference between sauropsids and mammals
is that the corpus striatum receives its major projection from the ADVR and from
the isocortex, respectively. Nevertheless, the basolateral amygdala of mammals and
the dorsal cortex of reptiles also project to the corpus striatum (Bruce and Neary
1995; Ten Donkelaar 1998b), which is consistent with the similarity of connections
between the ADVR and the mammalian basolateral amygdala, and between the
dorsal cortex of reptiles and the mammalian isocortex. Note that other hodological
studies have concluded that the mammalian basolateral amygdala corresponds to
the reptilian posterior DVR (PDVR) and lateral amygdala, instead of the ADVR
(Martínez-García et al. 2002; Moreno and González, 2004, 2006; Moreno et al. 2004;
Novejarque et al. 2004; Laberge et al. 2006).
In this context, one particularly controversial issue concerns the thalamic lat-
eral posterior/pulvinar (LP/P) nucleus of mammals and its presumed homology
with the reptilian and avian rotundus nucleus. The mammalian LP/P, receiving
projections from the superior colliculus and projecting to the extrastriate visual
isocortex, has been long considered to be homologous to the reptilian or avian

nucleus rotundus, which receives projections from the optic tectum and sends
efferents to the ADVR (Butler 1994b). Furthermore, Major et al. (2000) described
marked similarities in the dendritic morphology of motion-sensitive tectopulv-
inar neurons in mammals and the tectorotundal neurons in birds. In both groups,
such neurons have dendritic arborizations that end in monostratified arrays of
spiny terminal specializations called bottlebrush endings. The homology between
the LP/P and the rotundus nuclei has been a strong element in the theory of ho-
mology between the lateral isocortex and the ADVR, since these two nuclei have
been considered to form part of the collothalamic, tectofugal visual pathway in
mammals and reptiles, respectively. According to Bruce and Neary (1995), because
in mammals, the thalamic nuclei projecting to the lateral amygdala belong to the
intralaminar complex, these nuclei and not the LP/P nucleus should be considered
homologous to the thalamic nucleus rotundus of reptiles and birds. In this line,
some reports have claimed that the mammalian LP/P nucleus receives a different
type of tectal projections than the reptilian rotundus. In birds and reptiles, the
rotundus nucleus receives input from early-born cells in the deep tectal stratum
griseum centrale, while in mammals the tectopulvinar cells are presumably late-
born and located in the more superficial stratum opticum (Dávila et al. 2000, 2002;
Guirado et al. 2000; Redies et al. 2000; Yoon et al. 2000). These authors subdivide
the thalamic nuclei into three tiers: the intermediate and ventral tiers receive pro-
jections from the mesencephalic colliculi, and the dorsal tier receives projections
from lemniscal systems. According to this view, the reptilian nucleus rotundus
and the mammalian intralaminar nuclei might correspond to intermediate tier
nuclei, while the mammalian LP/P might be a dorsal tier nucleus that acquired
a tectal input in the origin of mammals. This interpretation was recently chal-
lenged, among others, by Güntürkün (2003), who claims that in the mammalian
superior colliculus, the distinction between superficial and deep layers is deter-
mined by the position of the stratum opticum. However, in birds and reptiles the
stratum opticum is more superficially located and it is not possible to establish
a clear-cut distinction between superficial and deep layers. Furthermore, Gün-
türkün argues that according to the data reported by Altman and Bayer (1981),
in mammals there are no birth time differences between those collicular neurons
projecting to the LP/P or to the posterior or intralaminar nuclei (see also Katoh and
Benedek 1995), and that the birthdates of the tectorotundal pathway of birds and
the colliculo-LP/P pathway in monkeys are quite similar if the differences in devel-
opmental times are taken into account (Wu et al. 2000). Güntürkün then dismisses
the three-tier concept of thalamic organization by assuming lack of evidence,
and argues that quite many differences in connectivity between the intralaminar
and the rotundal nucleus would have to be explained if these were considered
homologous.
Some of these arguments have been recently contested by Guirado et al. (2005),
who observed that telencephalic projections of the posterior/intralaminar complex
of the mammalian thalamus can be compared with the telencephalic projections
of the nucleus rotundus. More specifically, the mouse suprageniculate nucleus

(which receives fibers from intermediate and deep collicular strata, thus according
to these authors being more comparable to the tectorotundal projection in birds),
shares a number of afferents and efferents with the nucleus rotundus, such as
the corpus striatum, the lateral amygdala in the ventral pallium, and the dorsal
claustrum in the lateral pallium. These authors contend that the mammalian
intermediate stratum of the superior colliculus corresponds to the stratum griseum
centrale in birds and reptiles. They further argue that the intermediate layers of the
optic tectum of birds/reptiles, and of the superior colliculus of mammals, receive
somatosensory and auditory inputs in addition to visual ones, and can be used as
a reference to compare superficial and deep strata between birds and mammals.
Furthermore, they cite evidence that nuclei in the posterior thalamus of the rat
(which include the suprageniculate nucleus, the medial division of the geniculate
body, the posterior intralaminar nucleus, and the peripeduncular nucleus) project
upon the striatum and the claustroamygdaloid complex, in addition to specific
cortical areas (Doron and LeDoux 1999, 2000; Linke 1999).
As intense as it is, this controversy may not be crucial for the issue of neocor-
tical origins. The outgroup hypothesis was first proposed by assuming homology
between the mammalian LP/P and the avian/reptilian rotundus nucleus; the main
point is that the pallial projection of these nuclei reaches different, nonhomologous
targets in mammals and sauropsids (Aboitiz 1992a,b; 1995). Furthermore, recent
evidence indicates that at least the mammalian lateral posterior nucleus (a compo-
nent of the LP/P complex) projects heavily to the striatum, lateral amygdala, and
neocortex (but lacks connections with the dorsal claustrum; Guirado et al. 2005;
Doron and LeDoux 1999). In this context, in mammals including humans, there is
evidence for a subcortical, subconscious alarm system that bypasses the primary
visual cortex and includes activation of the superior colliculus, LP/P nucleus, and
the lateral amygdala (Shi and Davis 2001; Liddell et al. 2005). This pathway may
represent an evolutionarily ancient response system to threatening stimuli, and be
the heir of an ancestral collothalamic-ventral pallial or collothalamic-subpallial
pathway in early reptiles or amphibians. Thus, the mammalian projection from
LP to the striatum and amygdala may be likened to the rotundal projections to
the striatum and DVR in reptiles. In this way, if the LP/P and rotundus are indeed
homologues, the outgroup hypothesis would consider that the LP/P retained some
projections to the claustroamygdalar complex (equivalent to the ADVR) while
projecting additional inputs to the dorsal pallium. One possibility among others
would be that in the mammalian lineage, the equivalent to the sauropsidian nu-
cleus rotundus became fragmented and subdivided into several nuclei, including
the lateral posterior, the pulvinar and posterior/intralaminar complexes including
the suprageniculate nucleus. Thus, in mammals there would have been a separation
of two collothalamic pathways, one originating in cells of the deep collicular layers
and projecting to the mammalian suprageniculate nucleus, and the other origi-
nating from more superficial collicular cells and projecting to the LP/P complex.
In this way, the LP/P pathway might have retained many features of the original
tecto-rotundal-ventral pallial pathway, including the morphology of tectal effer-

ents and the presence of specific synaptic markers (Luksch et al. 1998; Dugas-Ford
and Ragsdale 2003), but adding a projection to the lateral neocortex. This process
would be entirely consistent with the concepts of neural pathway parcellation and
segregation in evolution (Ebbesson 1980, 1984; Krubitzer 1995, 2000), and if cor-
rect, it should be reflected in a common embryonic specification of these nuclei.
Furthermore, the development of new connections like the collothalamic–lateral
cortex projections is not an unusual feature of the mammalian brain, as can be
witnessed by the interhemispheric callosal tract and the corticospinal projection
(see Sect. 3.6.1).
The other main collothalamic pathway conveys auditory information, and is
commonly described as being relayed from the thalamic medial geniculate nucleus
to the DVR in reptiles and birds, and from the homologous nucleus to the auditory
cortex in mammals. However, in mammals thalamic auditory projections from
the medial geniculate body pars medialis also reach the lateral amygdala (LeDoux
et al. 1990, 1991; Turner and Herkenham 1991; Frost and Masterton 1992, 1994;
Doron and LeDoux 1999), and participate in the response to fearful stimuli, making
a rapid alarm system similar to that in the visual LP/P–lateral amygdala projection.
Furthermore, medial geniculate nucleus plasticity in fear conditioning is strongly
dependent on an intact basolateral amygdala (Maren et al. 2001). Therefore, the
two collothalamic pathways (visual and auditory) that project to the reptilian and
avian DVR, project to both the lateroventral neocortex and the lateral amygdala
of mammals, the latter connection subserving escape behaviors. Considering this
evidence, the lateral amygdala appears at least as an equally probable candidate
for homology with the reptilian DVR as the ventrolateral neocortex.
3.2.6
Summary
In nonmammals, there is no structure that clearly corresponds to the mammalian

neocortex. In the search for a homolog of this structure, one hypothesis asserts that
the avian anterior dorsal ventricular ridge corresponds to the lateroventral aspects
of the neocortex, receiving auditory and visual collothalamic projections, while the
avian Wulst (dorsal pallium) corresponds to the primary visual and somatosensory
cortices. Other evidence, based on work on reptiles, suggests that the reptilian
dorsal cortex has features of both the entorhinal cortex and the neocortex, and in
mammals there is evidence of collothalamic projections to the ventral pallium (the
claustroamygdalar system), which may be likened to the collothalamic projections
to the avian/reptilian DVR. Furthermore, the overall connectivity of ventral pallial
sectors such as the basolateral amygdala resembles the reptilian DVR more than
the neocortex.
Embryological Evidence 47
3.3
Embryological Evidence
3.3.1
Developmental Criteria for Homology
During embryogenesis, the DVR (especially its anterior part) develops from a po-
sition largely ventral and deep to the olfactory cortex. This was determined in early
embryological work on snakes (Warner 1946), lizards (von Hetzel 1974), Sphen-
odon (Hines 1923), crocodiles (Källén 1951), and turtles (Holmgren 1922; Källén
1951; Kirsche 1972), and more recently on birds (Striedter et al. 1998), establishing
that the DVR arises as a late proliferation process, after the migration of cells
belonging to lateral cortex has been completed. Later in development, the DVR
bulges into the ventricle, locating ventral to lateral cortex and immediately dorsal
to the corpus striatum (Ulinski 1983). Considering this early evidence, Northcutt
(1969) originally proposed that both the lateral cortex and the DVR of reptiles were
homologous as a whole with the mammalian lateral cortex and parts of the neocor-
tex (although he changed his view in subsequent writings, being more sympathetic
with the outgroup hypothesis; Northcutt and Kaas 1995; Northcutt 2003). Taking
a perhaps more radical position, Aboitiz (1992b, 1995) proposed that the DVR,
arising in a region that overlaps with the lateral cortex, consisted of late-produced
cells (late in relation to lateral cortex development), largely originating from a sim-
ilar embryonic region as the lateral cortex itself. Furthermore, much of the adult
avian and reptilian DVR would consist of late-produced cells that have no strict
homolog in the adult mammalian brain. This hypothesis is supported by the fact
that the amphibian lateral pallium receives not only olfactory projections but also
some inputs from the dorsal thalamus (Kicliter and Northcutt 1975), implying that
this structure is comparable to both the lateral and the ventral pallium of reptiles,
or that the amphibian lateral pallium also contains a ventral pallial component
(see also Moreno and González 2004; Moreno et al. 2004).
Considering this evidence, for the ADVR to be ancestral to the neocortex,
a massive migration of excitatory cells from the proliferative zone underneath the
lateral cortex (the region giving rise to the ADVR) toward the visual extrastriate
and auditory cortex would have to be demonstrated. However, to date evidence
suggests that in mammals these cortical areas arise from the cortical neuroep-
ithelium (Parnavelas 2000), while the neuroepithelial region corresponding to the
embryonic reptilian DVR produces ventral pallial components (Tole et al. 2005).
The migration of inhibitory interneurons from subcortical structures appears to
be a phylogenetically ancient character and may not be directly related to neo-
cortical origins, being possibly present also in agnathans (Marín and Rubenstein
2001; Meléndez-Ferro et al. 2002; Brox et al. 2003; Molnár et al. 2006).
Literally turning this issue around, Reiner (1993) and Butler (1994a) proposed
a topographic position of the DVR that is equivalent to that of lateral neocortex,
that is, between the dorsal and lateral cortices. Reiner (1993) asserted that the
dorsal pallial sector of stem amniotes possessed a lateral zone that was the fore-
runner of both DVR in sauropsids and lateral neocortex in mammals. In primitive
reptiles like Sphenodon, the DVR appears continuous with the dorsal cortex in its
anterior region, and in turtles this domain of continuity corresponds to the pal-
lial thickening (Ten Donkelaar 1998b; Ulinski 1990; Reiner and Northcutt 2000).
Nevertheless, Reiner (1993) did not mention the position of the lateral cortex,
which appears interposed between the DVR and the dorsal cortex through most
of their extent (Senn 1979; Ulinski 1990). Raising an additional hypothesis, Butler
(1994a) suggested homology between the DVR and the neocortex on the basis of
the presence of a subventricular zone (SVZ) in the two structures during develop-
ment, from which both the lateral neocortex of mammals and the DVR of reptiles
would emerge (Smart and Smart 1977; Yanes et al. 1987). We will come back to this
proposal in Sect. 3.5.1.
This problem has been recently clarified by studies of expression patterns of
regulatory homeobox-like genes in the embryonic forebrain, which have revealed
a conserved mosaic organization where the different compartments develop into
specific adult brain components (Gellon and McGinnis 1998; Moens et al. 1998;
Puelles and Rubenstein 1993; Seo et al. 1998). The embryonic lateral and medial
ganglionic eminences, located in the lateral subpallium and giving rise to the
corpus striatum and globus pallidus, express the marker genes Dlx1 and Dlx2
(Anderson et al. 1997b). The cerebral cortex arises mostly from the embryonic
pallium and is characterized by the expression of genes of the Emx and the Otx
families (Acámpora and Simeone 1999; Mallamaci et al. 1998; Pannese et al. 1998;
Puelles and Rubenstein 1993; Simeone et al. 1992). Smith Fernández et al. (1998)
identified for the first time what they termed an intermediate territory in the
equatorial region of the hemisphere, between the pallium and the subpallium
of amphibians, reptiles, birds, and mammals, which does not express either the
Emx1 or Dlx1 markers of the pallium and subpallium, respectively, but is largely
positive for the gene Pax6 (another pallial marker; Smith-Fernández et al. 1998).
More recent reports (Puelles et al. 1999, 2000) confirmed the existence of the
intermediate territory (which has been termed ventral pallium by these authors),
and extended the previous findings by showing that Pax6 and Tbr1 are expressed
in the whole pallium including the ventral pallium, but PAX6 appears mainly near
the ventricular zone and TBR1 has a more superficial activity. Thus, the medial,
the dorsal, and part of the lateral pallium express Emx1 and Tbr1 superficially
and Pax6 more internally, whereas the ventral pallium expresses Tbr1 superficially
and Pax6 deeply, but not Emx1. The presence of a ventral pallium has also been
confirmed in amphibians (Brox et al. 2002, 2004; Moreno and González 2004, 2006;
Moreno et al. 2004), indicating that it is an ancestral character and not a derived
feature of amniotes (reptiles, birds, and mammals).
In sauropsids, an important part of the DVR (more specifically, its anterior
component, including the neostriatum/nidopallium and ectostriatum/entopallial
nucleus of birds) and part of the lateral cortex develop from the Emx1-negative
ventral pallium, whereas in mammals, the basolateral amygdalar complex, part
of the claustral complex, the endopiriform nucleus, and parts of the lateral or
olfactory cortex – among other structures – were claimed to derive from this re-
gion (Puelles et al. 1999, 2000; Smith-Fernández et al. 1998; see Fig. 13). More
recently, Medina et al. (2004) described the anterior and posterior amygdalar ar-
eas and the amygdalo-hippocampal area as ventropallial structures. On the other
hand, the claustrum proper (formerly the dorsolateral claustrum), the posterior
endopiriform nucleus, the dorsal part of the piriform cortex, the basolateral amyg-
dalar nucleus, and the posterolateral cortical amygdalar area appear to belong to
the lateral pallium. As mentioned, two mammalian structures have recently been
proposed to correspond to the ADVR: the basolateral amygdala (Bruce and Neary
1995; Puelles et al. 1999; Smith Fernández et al. 1998) and the endopiriform nucleus
(Striedter 1997). Developmental evidence favors both the basolateral amygdala and
the endopiriform nucleus as comparable to the DVR (Smith Fernández et al. 1998;
Puelles et al. 1999). On the other hand, while some connectional evidence indi-
cates similarity between the ADVR and the basolateral amygdala (Bruce and Neary
1995), other evidence suggests similarity between the PDVR and the basolateral
amygdala (Martínez-García et al. 2002; Moreno and González 2004; Moreno et al.
2004; Novejarque et al. 2004), and the connections of the endopiriform nucleus
parallel quite closely those of the olfactory cortex (Behan and Haberly 1999). Ho-
mology of the DVR with the mammalian claustrum was originally questioned as
a first report communicated the absence of a claustrum in monotremes (Butler
et al. 2002), while a more recent report refuted this observation (Ashwell et al.
2004). Thus, although it seems clear that the reptilian ADVR derives from a ven-
tral pallial component, there are disagreements regarding the precise mammalian
homolog of this structure.
Smith-Fernández et al. (1998) argued that in reptiles and birds the ventral pal-
lium remains as a distinct neuroepithelial zone until late development, the period
in which it gives rise to most of the ADVR, which is in agreement with previous
embryological studies (Holmgren 1922; Källén 1951; Kirsche 1972). On the con-
trary, in mammals, this territory was described as producing only early-generated
components, becoming obliterated between the Emx1-positive and the Dlx1/2-
positive zones in later development (Smith-Fernández et al. 1998). In agreement
with this interpretation, Swanson (2000) and Künzle and Radtke-Schuller (2001)
suggest that the mammalian claustral complex has developmental timing similar
to early-produced cortical elements such as the mammalian subplate (an embry-
onic layer that develops before the definitive cerebral cortex in mammals); both
structures make up about the earliest pallial neurons. Although Puelles et al. (1999)
seem to disagree with the concept of the ventral pallium disappearing from the
neuroepithelial surface in mammals, they admit that this territory is considerably
compressed between the lateral pallium and the developing striatum.
To us, this evidence suggests that in mammals, some ventral pallial components
such as the claustrum consist of early produced components and may not be
directly comparable to those late-generated components of the reptilian – and
especially avian – highly developed DVR (Källén 1951). This agrees with the concept
Fig. 13 Embryonic telencephalic territories based on regulatory gene expression data. The
medial, dorsal and lateral pallia (violet) express the markers Emx1, Tbr1 and Pax6, while
the ventral pallium (yellow) expresses Tbr1 and Pax6 but not Emx1. The subpallium (green)
expresses Dlx genes. According to this data, the anterior dorsal ventricular ridge (ADVR)
and the avian nidopallium (N) derive mainly from the ventral pallium. a, vc, termination of
auditory and visual collothalamic pathways, respectively; vl, termination of visual lemniscal
pathways. STR, corpus striatum. (Modified from Aboitiz et al. 2003, with permission. Data
from Smith Fernández et al. 1998 and Puelles et al. 1999, 2000)
that in mammals there is no strict homology to the reptilian and avian ADVR, or
at least to a large part of it (Aboitiz 1992, 1995). In this way, much of the avian DVR
may consist of phylogenetically new cell groups, produced during late development,
a situation that is similar to what is observed in the mammalian neocortex, in which
superficial layers represent an evolutionary acquisition of the mammalian brain
(see Sect. 3.5.1). Nevertheless, connections from the collothalamic dorsal thalamus
to the ventral pallium are present in both reptiles and mammals, and therefore
may reflect a primitive character even if they do not reach exactly homolog regions
in each group.
Considering this evidence, Reiner (2000) modified his original proposal sug-
gesting that in the common ancestor to reptiles and mammals there was a structure
that diverged into the lateral isocortex of mammals and into the ADVR of reptiles.
This structure was either Emx1-negative and acquired Emx1 expression in mam-
mals, or, alternatively, was Emx1-positive and lost Emx1 expression in reptiles and
birds. A somewhat similar hypothesis was raised by Butler and Molnár (2002) and
Molnár and Butler (2002a,b), who proposed an alternative hypothesis by which the
ventrolateral neocortex, together with the mammalian claustrum and the pallial
amygdala, are field homologs of the sauropsidian ADVR, the former arising from
a duplication event in the ventrolateral pallium yielding a dorsal (cortical) and
a ventral (amygdaloclaustral) component. Again, difficulties with these interpre-
tations concern the ventral embryological origin of the DVR and the adult position
of the lateral cortex, which separates the DVR and the dorsal cortex through most
of their extent. The concept that the mammalian lateral cortex gained Emx1 ex-
pression (or that the DVR lost it) would need to be supported by embryological
tracing studies, indicating common embryonic origins of both structures. In this
context, Butler and Molnár (2002) reported the development of a DVR-like struc-
ture in the Pax6–/– mutant, indicating an evolutionarily atavic condition. However,
this mutant has been reported to develop a dysgenic ventral pallium (Tole et al.
2005), which is not entirely consistent with the development of a ventral pallial
DVR-like structure. In general, although these hypotheses may be consistent with
the concept of phylogenetic parcellation (Ebbesson 1980, 1984), they lack positive
evidence supporting them, such as a clear sign of ventral pallial origin of the lateral
neocortex. Furthermore, they might be impossible to refute, as any dorsal pallial
sign in these regions could be interpreted to result from the transformation of this
ventral pallial region into a dorsal pallial one.
Additional issues requiring further study concern the mammalian homologies
of the reptilian posterior DVR or avian archistriatum/arcopallium, and the hyper-
striatum ventrale/mesopallium (corresponding to the dorsolateral anterior DVR;
Guirado et al. 2000; Puelles et al. 2000) of birds. According to Smith-Fernández et al.
(1998), the reptilian posterior DVR and the avian archistriatum/arcopallium, or
at least part of these structures, express pallial markers and are comparable to the
corticomedial and central amygdala of mammals (Swanson and Petrovich 1998).
On the other hand, Puelles and colleagues (Puelles et al. 1999) argue that only
the posterior archistriatum/archipallium is pallial. The hyperstriatum ventrale or
mesopallium of birds expresses Emx1 during development, suggesting that it may

derive from the dorsal or lateral pallium and not from the IT/VP. This structure has
recently been compared to the Emx1-positive dorsolateral ADVR of reptiles and to
the dorsolateral claustrum of mammals (Puelles et al. 2000; Guirado et al. 2000).
3.3.2
Dorsoventral Gradients and Expansion of the Dorsal Pallium
Considering the evidence reviewed in the above sections, we have argued that
the mammalian neocortex arose through the tangential expansion of the reptilian
dorsal pallium (Aboitiz 1992, 1993, 1995, 1999a,b). More recently (Aboitiz et al.
2003c), we proposed that a dorsalization mechanism, producing an increase in
proliferation of dorsal pallial sectors, would have generated the required telen-
cephalic expansion leading to the origin of the neocortex. Considering that much
evidence implies a strong similarity between the reptilian dorsal cortex and the
entorhinal/subicular cortex, one interesting possibility is that the dorsal cortex
expanded medially to become the entorhinal/subicular complex and laterally to
become the sensory neocortex (Powers 2003).
The dorsal hemisphere and the mammalian cerebral cortex are patterned by
virtue of several interacting signaling cascades. Genes of the Wnt family are essen-
tial for hippocampal development and are also expressed strongly in the caudome-
dial margin of the cortical pallium (Kim et al. 2001). Wnt receptors of the Frizzled
family are most concentrated in the isocortical neuroepithelium, while being sparse
or entirely absent in the more medial hippocampal neuroepithelium (Kim et al.
2001). Similarly, two Wnt inhibitors (secreted Frizzled-related proteins 1 and 3) are
expressed in opposing anterolateral to caudomedial gradients in the telencephalic
ventricular zone. In addition, the Emx2 gene, whose expression domain is similar
to that of Emx1 but includes subpallial sectors (Gulisano et al. 1996), has been found
to be arranged in a gradient with maximal concentrations in the posteromedial
isocortex and minimal concentrations in the anterolateral isocortex (Mallamaci
et al. 2000). Furthermore, the Pax6 gene is expressed in a gradient that is comple-
mentary to that of Emx2, being maximally expressed in the anterolateral isocortex
and minimally expressed in the posteromedial isocortex (Bishop et al. 2000).
The modulation of overall dorsoventral, frontocaudal, and/or mediolateral gra-
dients of expression of the above-mentioned regulatory genes may have profound
effects in the development of specific telencephalic components (Chapouton et al.
1999; Stoykova et al. 2000; Muzio et al. 2002; Grove et al. 1998; Monuki et al. 2001;
Shinozaki et al. 2002; Meyer et al. 2002, 2004; Shimogori et al. 2004; Tole et al.
2005). It is therefore possible that the expansion of the dorsal pallium in primitive
mammals occurred partly as a consequence of the enhancement of a dorsaliz-
ing signal in telencephalic development. Since the structure that expanded most in
mammalian evolution is the dorsal pallium (neocortex) rather than the medial pal-
lium, the lateral pallium, and the ventral pallium, there may be some yet unknown
genes exclusively determining the fate of this structure, which increased their do-
mains of expression and enhanced cell proliferation specifically in this region. In

particular, genes involved in the regional specification of the cortical proliferative
zone, such as Wnt3a, Neurogenin, and others, may have been fundamental in the
expansion of this structure (Monuki and Walsh 2001). In a way, the dorsal pallial
territory can be conceived as an interphase between different embryonic fields, one
corresponding to the medial pallium and determined by morphogens emanating
from the cortical hem (Gli3, Wnts, BMPs, and others; Grove et al. 1998), another
corresponding to more anterior regions including the lateral/ventral pallium and
olfactory structures from where FGFs are being produced (Shimogori et al. 2004),
and perhaps a third source expressing EGF factors and dependent on Pax6, located
along the ventrolateral pallium (the cortical antihem; Assimacopoulos et al. 2003).
The partly antagonistic interaction between these fields may have yielded an up-
and down-regulation of genes such as Wnts, Emx1/2, Lhx2, Pax6, Neurogenin, and
other genes generating a new territory produced by an increased rate of progenitor
cell proliferation in the ventricular zone (see Medina 2003). In this context, a recent
report indicates that transgenic mice expressing β-catenin in neural precursors de-
velop an enlarged cortical surface area, while maintaining a normal cortical depth
(Chenn and Walsh 2002). Another report indicates that ASPM, a gene essential for
mitosis in embryonic neuroblasts, is required for attaining a normal cortical size
(Bond et al. 2002). Perhaps these genes are downstream elements in the cascade
triggered by the interaction between these morphogenetic fields.
The expansion of the presumptive dorsal pallial territory may have produced
a ventrolateral displacement of the lateral pallium, which perhaps differentiated in
territory originally destined to the ventral pallium. In this way, through shifts in the
boundaries of the territories of regulatory gene expression, cells that initially differ-
entiated in one specific compartment may have acquired patterns of differentiation
of other telencephalic areas. The obliteration or compression of the ventral pal-
lium that has been described in the mammalian telencephalon (Smith-Fernández
et al. 1998) might result from tangential expansion of the expression domain of
Emx1 and related markers, from invasion of this territory by tangentially migrating
Emx1-positive cells, or simply from its elimination by cell exhaustion or cell death.
Of course, this may not be the whole story, because, in addition to the displacement
of pallial boundaries, there has also been an overall increase in brain size, which
possibly was largely produced by an increase in proliferative activity within the
dorsal pallium and other regions. On the other hand, the pallium of reptiles may
present an enlarged ventral pallium because of a ventralizing pallial influence that
maintains a restricted expression of Emx1 and other dorsal pallial genes.
3.3.3
Summary
Early developmental evidence indicated that the reptilian and avian DVR origi-
nates from a late-proliferative region located deep to the lateral cortex, in a position
topographically equivalent to that of the mammalian claustroamygdalar system.
Furthermore, more recent studies of gene expression patterns during development

indicate that the avian and reptilian DVR, as well as the mammalian claustrum
and amygdala, largely develop from the ventral or lateral pallial territory. During
development, the reptilian and avian proliferative zones giving rise to the DVR
continue producing neurons until late stages, while in mammals it appears that
ventral pallial neuronal production is restricted to earlier stages, producing a rel-
atively much smaller adult structure. Thus, large parts of the avian/reptilian DVR
may consist of cells newly acquired in the evolution of the reptilian lineage and
may not be strict homologs to any mammalian cells.
The mammalian neocortex derives from a Pax6, Tbr1, and Emx1-positive ter-
ritory in the dorsal hemisphere that greatly expands during development, as com-
pared to the equivalent zone of the reptilian brain. Thus, a dorsalization process
is proposed in which the region corresponding to the dorsal pallium increased
neuronal production in response to some morphogenetic activity or to a combi-
nation of activities, perhaps including Gli3, Wnts, Emxs, Lhx2, Pax6, FGFs, and
other factors derived from at least three signaling sources: the anterior forebrain,
the medially located cortical hem, and the lateral antihem. A second possibility is
that the neocortex expanded by either a massive migration of cells from the ven-
tral pallium into the dorsal cortex, somehow acquiring Emx1 expression during
development, or by a transformation of a ventral pallial region into a dorsal pallial
structure. Unfortunately, at this point there is no positive evidence indicative of
these processes. Therefore, we conclude that at this point, developmental evidence
favors homology between the mammalian neocortex and the dorsal pallium of
reptiles.
3.4
The Olfactory–Hippocampal Hypothesis
3.4.1
A Functional Interpretation of Dorsal Pallial Expansion in Mammalian Origins
If the neocortex arose from an expansion of a small field bordering the medial
pallium and the lateral pallium, the question of the adaptive benefit to develop this
structure arises. We consider that early neocortical expansion was largely due to
a strictly contingent situation that was not observed in early reptiles and relates
to the development of the sense of olfaction (see also Sagan 1977). In reptiles,
the dorsal cortex is an interface connecting the olfactory and the hippocampal
cortices and relaying dorsal thalamic input into the latter for visuospatial learning.
In early mammals, olfactory input may have been especially important for several
behaviors including learning. This condition produced an unusual development
of the olfactory–dorsal cortex–hippocampal networks, which resulted in an initial
expansion of the dorsal pallium. Subsequently, increasing lemnothalamic and col-
lothalamic projections were directed toward the dorsal pallium, thus contributing
to its further expansion.
The Olfactory–Hippocampal Hypothesis 55
As previously discussed, the reptilian medial and dorsal cortices receive multi-
modal sensory projections from the lateral anterior thalamic nucleus, and at least
visual projections from the lateral geniculate nucleus. However, the most important
sensory pathway is the collothalamic projection to the ventral pallial ADVR, carry-
ing visual, auditory and somatosensory input. In turn, the ADVR projects heavily
into the PDVR, which sends afferents to hypothalamic regions (Novejarque et al.
2004). Thus, in reptiles the ventral and dorsomedial pallia receive largely different
sensory pathways, and there is relatively little cross-talk between them. The situa-
tion is different in mammals. The lemnothalamic-receiving primary visual cortex
projects massively to the extrastriate cortical areas (which receive the collothala-
mic visual projection), and these, together with the auditory and somatosensory
cortical areas and the olfactory cortex, project (through a series of successive cor-
ticocortical projections) to the hippocampus (via the entorhinal cortex) and to
the amygdala, in order to process different types of mnemonic information (spa-
tial/episodic and emotional, respectively; Lynch 1986; Maren 1999). This implies
that in mammals there is a confluence of the lemnothalamic and collothalamic
processing pathways to a degree that is not observed in reptiles (Aboitiz 1992;
Aboitiz et al. 2003b,c; Butler 1994b). (Recall that in mammals there is also a rem-
nant of the collothalamic projection to the ventral pallium, which is important in
the generation of automatic emotional responses; Sect. 3.2.5.) Furthermore, the
direct dorsal thalamic input to the medial pallium in amphibians is weakened in
reptiles and disappears in both mammals and birds (Neary 1990; Ulinski 1990).
Thus, reptiles and amphibians have two parallel routes of dorsal thalamic input to
the medial pallium (via the dorsal pallium and directly from the thalamus), while
in mammals (and in birds) the main entrance of thalamic sensory input to the
medial pallium is via the dorsal pallium.
In addition to the thalamic sensory projections, in terrestrial vertebrates there
is an important olfactory input via the lateral pallium into the medial pallium. The
projections from both the lateral and dorsal pallium (receiving olfactory input)
into the medial pallium in amphibians may have served as precursors for the devel-
opment of olfactory–hippocampal circuits in amniotes (Ten Donkelaar 1998b,c).
In reptiles, there is a well-defined circuit connecting the medial (hippocampal), the
dorsal (receiving the lemnothalamic pathways), and the olfactory cortices (Lynch
1986; Ten Donkelaar 1998a).
There is evidence that in reptiles and probably in most other vertebrates, the
medial and the dorsal pallia participate in spatial learning (Rodríguez et al. 2002a,b;
see Sect. 3.2.4). Among reptiles, active foraging lizards tend to have larger medial
and dorsal cortices than species that hunt with a sit-and-wait strategy (Day et al.
1999). In addition, lesions in these regions impair spatial learning in these animals
(Day et al. 2001; Rodríguez et al. 2002a,b). The authors further argue that these
cortical areas may use nonspatial clues for spatial navigation, which is important
in relation to new concepts of hippocampal function described below.
In mammals, a classical understanding of hippocampal function is that this
structure creates a cartesian representation of space, in which the different places
and coordinates are mapped onto the structure itself (O’Keefe and Nadel 1978).
This concept was partly proposed on the basis of the discovery of place-cells in the
hippocampus of experimental animals, which are activated by specific positions
of the animal in a given space (O’Keefe and Dostrowsky 1971). However, the situa-
tion is slightly more complex, as evidence has shown that many hippocampal cells
fire in response to nonspatial determinants such as odors, and that the activity
of the cells depends on the behavioral state of the animal (see Eichenbaum 1999;
Eichenbaum et al. 1999). Hippocampal cells can recognize rewarded and nonre-
warded cues, spatial configurations of odors, differences between odors, or fire
at specific behavioral instances (Wiener et al. 1989; Wood et al. 1999, 2000). In
addition, it has been found that spatial and nonspatial (olfactory) information are
segregated in interleaved, oblique stripes along the hippocampus (Hampson et al.
1999). This structure has also been shown to be required for nonspatial olfactory
tasks, such as tests of transitive inference, higher-order sequential associations, or
the social transmission of food preferences (Galef 1990; Bunsey and Eichenbaum
1996; Dusek and Eichenbaum 1997; Alvarez et al. 2001; Ergorul and Eichenbaum
2006). In summary, there is substantial evidence that the mammalian hippocam-
pus participates in olfactory memory and in other memory processes in addition
to spatial mapping (Eichenbaum 1998, 2006).
Partly based on this evidence and on the finding that place cells are more
consistently controlled by local cues (see Eichenbaum et al. 1999), it has been
proposed that the representation of space in the hippocampus consists of the
specification of behaviorally relevant spots. These spots are identified by cues
such as odors and other (visual) characteristics of the environment, and include
a collection of independent representations of places, linked among them by the
behavioral context in which the animal explores its environment (Eichenbaum
1999, 2000a,b; Eichenbaum et al. 1999; Ergorul and Eichenbaum 2004). For these
authors, a fundamental function of the hippocampus is its participation in episodic
memory, that is, memory of the events that take place during a particular behavioral
action. Spatial memory emerges as consequence of the integration of successive
episodes during an exploration task and involves associations between different
sensory modalities, including vision and olfaction. This proposal could reconcile
the apparently discrepant findings that, in animals, the hippocampus participates
in spatial memory, whereas in humans, it participates in declarative memory.
Instead of spatial memory, Eichenbaum prefers to speak of a memory space,
which is an organized representation of memory episodes linked by their common
features (Eichenbaum 2000b; Eichenbaum et al. 1999; however, see alternative view
by O’Keefe 1999). We suggest that in the process of generating this memory space,
olfaction (which is an important sense used to investigate the environment by many
small mammals such as rodents and insectivores) may participate as a “glue” that
helps linking many of these spots, creating a cohesive map of the behaviorally
relevant points. In present-day mammals such as the rat, visual input is necessary
for the firing of a large number of hippocampal cells, while olfactory information
can be used to compensate for the lack of visuospatial information (Save et al.
The Olfactory–Hippocampal Hypothesis 57
2000). Therefore, visual information may have been progressively involved in the
associative hippocampal–olfactory networks during the origin of mammals, thus
triggering the expansion of the dorsal cortex. This is not to say that visual cues have
little importance in spatial or episodic learning in nonmammals, but rather that
the visual input to the mammalian hippocampus is more complex, so that more
accurate representations of both behavioral situations and their spatial context can
be made.
The olfactory–hippocampal–dorsal cortex circuit may have been put to use by
the first mammals to make relatively elaborate, largely olfactory-based representa-
tions of space, in which specific odors labeled particular places and routes (recall
that early mammals were presumably nocturnal and may not have been able to
rely on visual information as strongly as reptiles or laboratory mammals; Jerison
1973, 1990; Sagan 1977; Kemp 2005). Nevertheless, the contribution of the visual
system undoubtedly became necessary in the elaboration of more precise maps
of space, especially when mammals invaded diurnal niches after the decline of
dinosaurs. The dorsal cortex, receiving visual information from the thalamofugal
visual pathway, may have been an important element for associative learning in
the early mammalian brain, as it is now in reptiles (Aboitiz 1992a,b). Although
there is evidence for a strong conservatism in hippocampal general function and
in its participation in spatial learning (Salas et al. 2003; Colombo 2003), there
are also important differences in hippocampal connectivity between mammals
and reptiles (reviewed in Butler 1994a,b; Striedter 2005), which suggest that there
have been some changes in this overall conserved architecture, perhaps facili-
tating in mammals an expansion of associative functions and the elaboration of
more subtle forms of spatial and episodic memory. Electrophysiological evidence
indicates that the neuronal dynamics present in primitive olfactory–cortical cir-
cuits, including modulations of frequency, phase, and amplitude of oscillations
during olfactory processing are also observed in neocortical circuits, suggesting
that olfactory associative processing formed the basis for large-scale couplings
involving the expanding isocortex (Hermer-Vazquez and Hermer-Vazquez 2003).
Furthermore, these olfactory–hippocampal tangential circuits may have facilitated
the establishment of strong pallio-pallial connectivity that is related to slow-wave
sleep, a characteristic that is absent in reptiles and appears independently in mam-
mals and birds (Rattenborg 2006). Our point is that within a generally conserved
framework, early mammals made more use of olfactory–hippocampal associations
than other amniotes, and that this situation was related to the expansion of the
dorsal pallium, which received increasing dorsal thalamic input. Eventually, the
mammalian hippocampus received quite a strong thalamic sensory input via the
association areas of the neocortex and the entorhinal cortex, perhaps at the ex-
pense of the disappearance of direct thalamohippocampal projections. In a way, in
early mammaliaforms there may have been a stronger emphasis on hippocampal
function, which in part propelled dorsal pallial expansion.
In this context, a dorsalizing effect on dorsal pallial development as we have
suggested before, triggering an expansion of the dorsal cortex, may have been of
great benefit for the development of olfactory–hippocampal–cortical networks.

This expansion may have permitted the invasion of collothalamic sensory routes
into the dorsal pallium, which were originally projected to the ventral pallium (or to
the subpallium, as in present-day amphibians; see also Northcutt 1969; Northcutt
and Kaas 1995). In addition, the auditory projection to the cerebral cortex instead
of to the ventral pallium may have benefited from the cortical representation of
space by developing a more elaborate sound localization system.
Thus, we postulate that a major innovation in the origin of the mammalian
brain has to do with the increasing confluence of the lemnothalamic and the
collothalamic pathways in the dorsal pallium, in order to process information
which, among other things, participated in spatial learning and episodic memory.
In this process, the hippocampus may have become a fundamental component in
which both types of sensory pathways converged. The lateral pallial basolateral
amygdala is an additional component in this process, which also received a strong
input from the dorsal pallium, in addition to the direct collothalamic projection.
In mammals, this structure establishes strong connections with the orbitofrontal
cortex and may have served as an additional element in these networks, establishing
an olfactory–amygdalar–hippocampal associative axis (McDonald 1991; Bota 2003;
see Aboitiz et al. 2003b,c).
3.4.2
Summary
In reptiles, the medial pallium or hippocampus receives ascending sensory pro-

jections from the thalamus and dorsal cortex, and olfactory projections via the
lateral cortex. There are some projections from the dorsal cortex into the ADVR,
but these are probably not as robust as the cortical projections to the mammalian
amygdala. It is possible that a somewhat similar situation existed in ancestral
mammal-like reptiles, in which there was a tangentially oriented, olfactory-related
network connecting the lateral, dorsal, and medial pallia, plus a dorsal thalamic
sensory projection to the dorsal and medial pallia. Early mammals presumably had
a well-developed sense of olfaction and may have used this skill to make behavioral
maps of their surroundings. The development of extensive olfactory-hippocampal
networks may have facilitated the expansion of the dorsal pallium, which began
to receive an extensive input from lemnothalamic projections but also from col-
lothalamic projections that were originally destined to the ventral pallium. This
permitted the strong confluence of the lemnothalamic and collothalamic sensory
systems, and perhaps contributed to the elaboration of more elaborate forms of
memory than simple spatial location in the hippocampus. Other sensory inputs
such as the auditory were possibly quite important in neocortical expansion as
well. Finally, a remnant of a collothalamic projection to the ventral pallium exists
in the dorsal thalamic projection to the mammalian amygdala.
Origin of Neocortical Lamination 59
3.5
Origin of Neocortical Lamination
3.5.1
Laminar Organization of the Neocortex
In the adult, the neocortex consists of six layers, the most superficial of them
(layer I) characterized for containing very few neuronal elements and many tan-
gentially oriented fibers; layers II and III contain small pyramidal cells and some
interneurons and establish associative contacts with neighboring regions. Layer
IV contains spiny stellate cells that receive thalamic afferents arriving radially
from the underlying white matter and send projections to superficial layers, and
layers V and VI contain projection neurons to different subcortical targets (layer
VI cells mostly send a reciprocal projection to the thalamus). The development of
this structure is a highly ordered process (Fig. 14). During corticogenesis, there
are successive waves of neuronal migration from the cortical neuroepithelium and
other regions. The first wave constitutes an embryonic preplate (PP) that, with
the posterior arrival of cortical plate (CP) neurons, will split into a superficial
marginal zone (MZ, future layer I), and a deeper subplate (SP). Eventually, most
cells from the MZ and SP die in late development or become highly diluted due
to telencephalic expansion. CP neurons arrange between the MZ and the SP and
will make the adult layers II–VI of the neocortex. These layers are generated in
an inside-out sequence in which early born neurons remain in deeper positions,
while neurons born later migrate past the earlier ones and locate more superficially
(Angevine and Sidman 1961; Rakic 1974).
Fig. 14 Laminar organization of the neocortex. There are several waves of cell migration
making up the distinct layers of the adult neocortex. Initially, a preplate is formed which
is later split into a superficial marginal zone (MZ) and a subplate (SP) by the arrival of
cells forming the cortical plate (CP). There, cells arrange in an inside-out gradient in which
early-produced cells locate in deep layers and late-produced cells locate in superficial layers.
Arrow points to progressively later generation times in the cortical plate
In early development, the MZ contains some pioneer neurons (PNs) and reelin-
positive Cajal-Retzius cells (Meyer et al. 1998, 1999), while the SP consists of PNs
plus sparsely distributed polymorphic neurons (Kostovic and Rakic 1990). PNs are
the first cells to arrive to the cortex and their axon, directed subcortically, serves as
a guide for growing thalamocortical axons (McConnell et al. 1989, 1994). Thalamic
and corticocortical axons arriving from the underlying white matter usually reach
the SP and remain there for some time before entering the developing CP. Cajal-
Retzius cells in the MZ help in radial glia maintenance and provide clues for radial-
migrating neurons that will form the CP (Soriano et al. 1997; Supèr et al. 1998a,b,
Xie et al. 2002). Thus, the MZ and SP participate in regulating cell proliferation,
neuronal migration, axonal growth, and thalamocortical synaptogenesis in the CP
(Alcántara et al. 2006; Kanold 2004; Marín-Padilla 1998; Xie et al. 2002; Alcántara
et al. 2006).
Neurons populate the PP and the developing cortex from several sources: one is
the subcortical ganglionic eminence (principally its medial ad caudal components),
which contributes PNs and GABAergic interneurons (Anderson et al. 1997a,b;
Bystron et al. 2005; Deng and Elberger 2001, 2003; Jiménez et al. 2002a,b; Kriegstein
and Noctor 2004; Lavdas et al. 1999; Marín and Rubenstein 2001, 2003; McConnell
et al. 1989; Morante-Oria et al. 2003; Nadarajah and Parnavelas 2002). A more
important source is the cortical neuroepithelium, providing excitatory, radially
migrating cells mostly to the SP and CP (Rakic 1995, 2000; Nadarajah et al. 2003;
Kriegstein and Noctor 2004; O’Leary and Borngasser 2006). Nevertheless, other
pallial regions contribute tangentially migrating, excitatory neurons to the PP (like
the dorsomedial cortical hem, providing Cajal-Retzius cells) and perhaps also to
the CP (Del Río et al. 1995; Meyer et al. 1998, 2002, 2004; Yang et al. 2000; Abraham
et al. 2004; Bielle et al. 2005).
3.5.2
Comparison of Mammalian Neocortex and Reptilian Cortex: Layer Homologies
Compared to the reptilian cortex, which has only a few neurons in its radial depth
(Ulinski 1990; Voogd et al. 1988), the mammalian neocortex is characterized by
its radial expansion, being organized in radial columns about 100 cells in depth
(Rockel et al. 1980; Rakic 1988). In mammals, neurons at different levels of the ra-
dial column belong to each of the six tangential laminae that make up this structure,
which in reptiles are no more than three. In this context, Marín-Padilla (1971, 1972,
1978, 1992, 1998) and Marín-Padilla and Marín-Padilla (1982) originally proposed
that the amphibian pallial cells and the reptilian cortical cells actually corresponded
to the mammalian embryonic preplate (especially the SP). His view was that the de-
velopmentally earliest cortical cells might be the best candidates for homology with
the ancestral reptilian cells. Thus, the entire CP (adult cortical layers II–VI), which
develops after the PP, might be considered a newly developed structure in mam-
malian evolution. Although sometimes viewed as an outdated recapitulationist
view, this interpretation is consistent with the heterochronic concept of hypermor-
phosis, in which additional stages are added at the end of embryonic development
(see Gould 1977; McKinney and McNamara 1991). A somewhat similar hypothesis
was provided by Ebner (1969) and Reiner (1991, 1993), who proposed that instead
of corresponding to the mammalian preplate, the reptilian cortex mostly corre-
sponds to the deep layers VI and V of the mammalian CP. Cells in the superficial
layers IV–II are connectionally, morphologically, and neurochemically different
from reptilian cells, and can be considered as a derived character of the mammalian
neocortex. Moreover, early-produced, deep-layer cortical neurons migrate radially
by translocation (a mode of migration independent of radial glia, in which the api-
cal process of the cell contacts the subpial layer, and the cell body is dragged toward
the surface while the apical process shortens), while late-produced, more super-
ficial neurons migrate to the cortex by locomoting along a radial glia that serves
as a substrate, a process that requires the action of the cyclin-dependent kinase
cdk5 and its activator p35 (Nadarajah et al. 2001). These differences in migratory
processes may reflect different phylogenetic origins in time (Aboitiz 1999a, 2001a).
Furthermore, other authors consider that much of the mammalian SP is not
ancestral; instead, this structure can be viewed as an embryonic acquisition of
the mammalian brain, since it is most complex in those areas that appear later
in mammalian evolution, and in mammals with more complex brains (Kostovic
and Rakic 1990). These authors proposed that the SP evolved as an embryonic
device to support the development of corticocortical connectivity. Other evidence
suggests the existence of a preplate-like structure in embryonic reptiles (Nacher
et al. 1996), which would imply that the preplate does not correspond to an adult
but to an embryonic ancestral structure. In this context, it is important to note that
in mammals, the difference between the embryonic SP and the deepest layers of
the adult cortical plate are not absolutely clear-cut, and that these structures may
be developmentally related. For example, the gene Tbr1 marks subplate neurons
and the earliest CP neurons; and mutations in this gene cause defects in both
the preplate and the deepest layer VI of isocortex (Hevner et al. 2001; Kolk et al.
2005), suggesting similarities in genetic organization between these structures. In
a similar line, in the rat and other mammals with a limited or moderate degree of
isocortical expansion, many subplate cells survive into adulthood, forming layer
VII (Reep 2000; Woo et al. 1991; Harman et al. 1995). Furthermore, some authors
claim that in marsupials there is no subplate; rather, the equivalent to the subplate
consists of the earliest generated layer VI cells that become incorporated into the
lower CP (Harman et al. 1995; Reep 2000). This would imply that an embryonic
subplate is not ancestral to mammals. Despite these controversies (some of which
we will intend to clarify below), it seems generally acknowledged at this point that
the superficial cortical layers represent a new acquisition of the mammalian brain.
We originally proposed that the Pax6 gene was involved in the evolutionary
origin of the isocortical superficial layers (see Aboitiz et al. 2001b, 2003), and that
this involvement consisted of the recruitment of the cortical subventricular zone
(SVZ) in the neurogenetic process. The SVZ is a proliferating compartment of
the cortical neuroepithelium that is located peripheral to the ventricular zone,
an earlier proliferative layer. Mutants for Pax6 exhibit cortical migration defects,
consisting of the inability to migrate and differentiate of superficial, late-generated
isocortical neurons belonging to layers IV to II, which are generated in the SVZ
(Caric et al. 1997; Fukuda et al. 2000). Furthermore, Pax6 promotes conversion
of ventricular zone to SVZ progenitors and stimulates neurogenesis (Heins et al.
2002; Scardigli et al. 2003). The genes Ngn1 and Ngn2 also regulate the transit of
cortical progenitors from the ventricular to the subventricular zones (Britz et al.
2006), but possibly in a Pax6-dependent manner (Scardigli et al. 2003). Further
evidence indicates that, while activation of the genes Ngn1 and Ngn2 is required to
specify the laminar characteristics of early-born cortical neurons, upper layer cor-
tical neurons are specified in an Ngn-independent manner, requiring instead the
synergistic activities of Pax6 and Tlx (Schuurmans et al. 2004). Recently, Molnár
et al. (2006) and Kriegstein et al. (2006) presented evidence indicating a progressive
development of the subventricular zone in large-brained mammals, its near ab-
sence in the reptilian embryonic dorsal cortex, and its parallel development in the
avian nidopallium, which supports the interpretation above. It will be of interest
to determine if there is a contribution of the subventricular zone and of the Pax6
gene and related ones to dorsal cortical development in reptiles.
In cortical development, the subventricular zone appears first in the lateral
aspect of the hemisphere, near the pallial-subpallial boundary, and in later
stages expands into more dorsal regions (Nieto et al. 2004; Zimmer et al. 2004).
Perhaps one possibility to reconcile the two hypotheses of lateral neocortical
origins (ventral pallial/DVR vs dorsal pallial; see Sects. 3.2 and 3.3) is that the
mammalian cortical subventricular zone originated in evolution as a consequence
of the propagation of a late-proliferating activity originally restricted to the
lateral aspect of the hemisphere. This event might be related to the enhanced
morphogenetic activity of the cortical antihem or a related source in the lateral
and ventral pallium, and to the consequent diffusion of some morphogenetic
signal(s) into more dorsal pallial regions. This wave inducing late proliferative
activity recruited neural precursors from the dorsal neuroepithelium and gave
rise to the neocortical subventricular zone. In this way, although originating in
the dorsal pallial region, cells from the subventricular zone could have arisen
as a consequence of the influence of a late-proliferating ventral or lateral pallial
proliferative activity. This possibility would be partly consistent with Butler’s
(1994a) proposal of the involvement of a subventricular zone in the origin of both
the reptilian DVR and the mammalian neocortex and could also help explain
the complex relation between cortical layering and the claustrum in the insula of
some basal insectivores (Künzle and Raddtke-Schuller 2001).
3.5.3
Is There a Preplate in Reptiles?
A conspicuous component of the mammalian PP are the superficially located

reelin-positive Cajal-Retzius cells. Reelin-positive neurons have been observed in
the MZ of the developing cortex of turtles, lizards, and crocodiles; at lower levels,
reelin expression has also been detected below the developing cortex of turtles and
lizards and in the ventricular zone of crocodiles (Bar et al. 2000; Bernier et al. 2000;
Goffinet et al. 1999; Pérez-García et al. 2001; Tissir et al. 2003). In crocodiles, these
neurons were found to co-express p73 (Tissir et al. 2003), which is a marker of
reelin-positive Cajal-Retzius cells that derive from the cortical hem in the medial
hemisphere (Meyer et al. 2002). Considering that in the mammalian dentate gyrus,
one of the roles of reelin is to guide growing entorhinal axons (Förster et al. 2006b),
it is possible that the ancestral function of this molecule in early amniotes was to
attract dorsal cortex axons into the medial cortex. This would explain the origin
of most Cajal-Retzius cells from the cortical hem in the dorsomedial aspect of
the telencephalon. Interestingly, a recent report showed that HAR1F, an RNA gene
co-expressed with reelin in Cajal-Retzius cells, has been the subject of intense
selection during human evolution (Pollard et al. 2006).
In mammals, both the level of reelin expression per cell and the number of
reelin-positive neurons in the marginal zone are much higher than in reptiles,
indicating that with the appearance of the neocortex there has been a unique
amplification of reelin expression in Cajal-Retzius cells (Bar and Goffinet 2000;
Bar et al. 2000). Furthermore, the levels of reelin expression seem to correlate
with the degree of cortical columnarity in different reptilian species (Bar and
Goffinet 2000; Bar et al. 2000; Meyer et al. 2002). It is possible that in mammals,
the increase of reelin expression occurred in the context of controlling the final
stages of cortical migration and layer positioning (Aboitiz 1999; Aboitiz et al. 2001,
2003c). Nevertheless, the fact that in reptiles reelin is expressed in the marginal
zone and in other regions below the cortex suggests that this protein may have
other functions besides controlling the end stages of neuronal migration.
In the developing reptilian cortex, some authors argue for the presence of an
incipient PP that is split by the arrival of the CP (Bernier et al. 1999; Goffinet et al.
1999; Supèr et al. 1998b; Tissir et al. 2003). In our view, this preplate-like structure
might consist in large part of Cajal-Retzius-like cells and subpallial, tangentially
migrating cells, but it is not clear that it contains radial-migrating excitatory ele-
ments. Early migration of subpallial, inhibitory neurons into the pallium has been
suggested in amphibians (Brox et al. 2003), birds (Cobos et al. 2001a), and rep-
tiles. In the developing lizard brain, Nacher et al. (1996) described the presence of
somatostatin-positive cells appearing first in the inner plexiform layer and later in
the outer plexiform layer of the medial and dorsal cortices. Cordery and Molnár
(1999) observed cells positive for neuropeptide Y, scattered in all regions of the
ventral pallium of the turtle. Finally, some early tangentially migrating neurons
observed in the mammalian intermediate zone may perhaps correspond to tan-
gential neurons traveling in the reptilian intermediate zone (Cordery and Molnár
1999; Bar et al. 2000). Therefore, although in reptiles there may be early tangen-
tially migrating neurons, some of which are perhaps comparable to interneurons
of the mammalian preplate and SP, it is possible that the latter are more complex
in terms of cell numbers and types.
Summarizing, many elements forming the reptilian preplate-like structure arise

from tangential migration from subpallial regions (and presumably from the corti-
cal hem); these might correspond to some tangentially migrated cells in the mam-
malian PP. Nevertheless, the mammalian SP also contains an important population
of glutamatergic, excitatory cells whose development has been poorly character-
ized (Finney et al. 1998; Hanganu et al. 2001, 2002). In this context, a recent report
has described an important radial contribution to the PP and SP, presumably con-
sisting of excitatory cells (O’Leary and Borngasser 2006). According to Harman
et al. (1995), SP neurons (excitatory) derive from the earliest CP neurons. One
possibility is that, in placental mammal evolution, SP excitatory neurons may have
originated from the CP itself, being generated in progressively earlier developmen-
tal stages to support the development and connectivity of the later-appearing true
CP cells (Kostovic and Rakic 1990; Harman et al. 1995; Aboitiz et al. 2005).
3.5.4
Origin of the Inside-out Developmental Gradient
Another characteristic of the mammalian cortex is the inside-out developmental

gradient of lamination, in which late-produced, radial migrating neurons move
past the layers of neurons produced earlier. This pattern is common to all mam-
malian cortical regions, including the hippocampus (Petrone et al. 2003), but
is found only in the mammalian cortex. In reptiles, the cortex develops in an
outside-in pattern, with younger cells locating below the older ones (Goffinet et al.
1986). Furthermore, the synaptic organization of the mammalian neocortex dif-
fers dramatically from other cortical structures such as the olfactory cortex and
the hippocampal formation, and from the reptilian cortex. In the neocortex of
advanced mammals, thalamocortical and corticocortical axons travel predomi-
nantly via the white matter below the cortex and penetrate the cortex upwards, in
a radial direction to make synapses in layer IV (Rakic 1988). On the other hand, in
the reptilian cortex and in archicortical and paleocortical mammalian structures,
afferents (cortical and thalamic) run tangentially in the superficial MZ, synapsing
in series a number of apical dendrites from pyramidal cells (Supèr et al. 1998a,b).
The mammalian inside-out developmental gradient has been proposed to result
from a developmental strategy oriented to gain synaptic contacts between the
phylogenetically new late-born neurons during radial cortical expansion, and the
cortical afferents (from both the thalamus and other cortical regions) located in the
MZ. In order to establish such contacts, late-born neurons had to migrate past the
layers of early-born neurons (Aboitiz 1999, 2001; see Fig. 15). This is consistent with
the hypothesis that some glutamatergic Cajal-Retzius cells may attract migrating
neuroblasts through the CP, thus contributing to generate the inside-out gradient
(Del Río et al. 1995; Alcántara et al. 2006). Another interpretation is that the shift
of thalamic afferents from the superficial layer I to the subcortical white matter
released a barrier that permitted the expansion of the cortex in an inside-out
manner (Supèr and Uylings 2001). This hypothesis links the processes of preplate
Fig.15 This diagram depicts a possible sequence in the acquisition of laminar characteristics
of the neocortex. In reptiles, with an outside-in neurogenetic gradient (arrow upwards)
afferents follow the pioneer neurons (red diamonds) in the superficial marginal zone, above
the cortex (ovals). In the hippocampus, there is already an inside-out gradient (arrow
downwards) but afferents and pioneer neurons are still located superficially. In Erinaceus,
axons enter the cortical plate from below but may run obliquely and end in the marginal
zone. Finally, in the primary sensory cortex of advanced mammals, most pioneer neurons
locate in the subplate, and axons enter the cortex radially, synapsing with neurons in layer IV
splitting into a MZ above and a SP (containing PNs that guide thalamic axons) below
the developing CP, with the origin of the inside-out neurogenetic gradient (this
link is supported by recent developmental evidence; Rakic et al. 2006). However,
it leaves wanting an adaptive explanation of these changes (Aboitiz et al. 2003b).
In addition, comparative evidence suggests that inside-out lamination and the
change from superficial to deep position of afferents are dissociable to some
extent. The mammalian hippocampus has an inside-out laminar pattern while
its afferents are still organized superficially in layer I, suggesting that the inside-
out lamination pattern originated before the rerouting of afferents (Aboitiz et al.
2003c). Furthermore, in the neocortex of small-brained insectivores, axons initially
enter the cortical plate in a radial direction, but then follow an oblique course, reach
the superficial layer I and run tangentially in it for a long distance (Valverde et al.
1986; Supèr et al. 1998a,b), indicating that the superficial, tangential arrangement
of thalamic afferents remained an important feature after the origin of inside-out
cortical lamination.
Considering that early-produced cortical plate cells may represent an ancestral
phenotype, while late-produced cells are considered to be an evolutionary acqui-
sition, we have suggested that the cdk5/p35 pathway, which assists late-produced
neurons while migrating along the radial glia (Nadarajah et al. 2001; see Sect. 3.5.2),
is somehow related to the migration of the phylogenetically new cell types of the
mammalian isocortex and to the origin of the inside-out neurogenetic gradient
of the isocortex (Aboitiz 1999a, 2001; Aboitiz et al. 2001a,b). More specifically,
although cdk5 is required for locomotion along the radial glia, its activator p35 is
important for migrating neurons to cross the previously produced layers of cells
inside the CP. Cells in isocortical layer V might represent an intermediate condition
between the ancestral phenotypes and the new ones, as they originate in the deep
ventricular zone instead of the subventricular zone, and are morphologically and
neurochemically reptilian-like; but like younger cells, they seem to be more depen-
dent on cdk5 than cells of layer VI to cross the subplate and other cortical layers.
Again, the study of cdk5/p35 expression in the developing cortex of reptiles may
provide substantial information on isocortical evolution. “Additionally, reelin may
have contributed to the inverted layering by arresting migration and detaching
neurons from the radial glia, thus permitting late-born neurons to use the latter
to migrate past early-born neurons. If reelin fails as in the reeler mutant, neurons
stack in a roughly outside-in gradient, maintaining abnormal attachments to the
radial glia (Caviness 1976; Pinto-Lord et al. 1982).”
3.5.5
Pioneer Neurons and the Transition from a Tangential to a Radial Synaptic Organization
in the Neocortex
The transition from a tangential to a radial organization of cortical inputs in neo-

cortical origins implies that afferents (thalamocortical and corticocortical) have
been gradually displaced from a superficial, tangential position to a deep, white
matter position with a radial entrance to the cortex (Fig. 15). It is conceivable that
ancestrally, the pioneer neurons that guide thalamocortical and corticocortical
axons migrated mostly through the superficial MZ, attracting axons superficially,
while in isocortical evolution there has been a gradual shift in the position of
pioneer neurons to a subplate position that becomes located underneath the cor-
tical plate. In this way, more and more afferents were progressively dragged below
the cortex instead of above it in the MZ. In support of this view, data from our
laboratory shows the existence of PN in the MZ of the developing reptilian cor-
tex, which are followed by growing thalamocortical afferents (Montiel et al. 2004;
Aboitiz et al. 2005). Additional evidence indicates that in embryonic turtles, there
are early migrating cells within the lateral forebrain bundle and striatum, project-
ing their axons to the thalamus (Cordery and Molnár, 1999). This suggests that
a PN-guidance axis also exists in reptilian telencephalic development. Consistent
with the concept of a gradual shift in the location of pioneer neurons and the su-
perficial arrangement of some cortical afferents in primitive mammals (Valverde
et al. 1986), a higher proportion of PNs is left in the subplate of humans than in the
subplate of rodents, where many PNs remain in the MZ (Meyer et al. 1998, 2000).
In addition, in some mutant mice such as the reeler and the SRK, the SP is mal-
positioned above the CP. This might be due to abnormal cell-to-cell attachments
among SP cells, which act as a barrier imoending CP cells to migrate past them. In
these mutants, axons tend to follow in the anomalously superficial superplate and
then descend into the cortical plate to establish synapses with the corresponding
cells, suggesting that axons have followed the pioneer neurons that are superfi-
cially malpositioned (Caviness 1976; Caviness et al. 1988; Molnár 1998; Molnár
and Cordery 1999; Higashi et al. 2005). Moreover, like the normal SP, the reeler
superplate expresses neurocan, which serves as a guide for thalamocortical axonal
growth (Li et al. 2005b). In addition, in prenatally irradiated mice, in which the
subplate is partially destroyed, thalamocortical axons traverse the CP obliquely to
run up to the marginal zone, somewhat resembling more primitive arrangements
(Li et al. 2005a). Likewise, cdk5 and p35 mutants apparently show defects in pre-
plate splitting and an alteration of the trajectory of thalamic axons, which may be
a consequence of a misplacement of PNs (Rakic et al. 2006). Overall, this evidence
may indicate that the reelin and cdk5/p35 signaling systems were also involved in
the repositioning of PNs during neocortical evolution.
3.5.6
Summary
The neocortex evolves from a three-layered, tangentially organized ancestral cor-

tex into a six-layered, radially organized structure. First, there was possibly a radial
expansion of the primitive mammalian cortex, producing late-born, phylogenet-
ically new neurons, possibly by the contribution of an expanded subventricular
proliferative zone and the action of the Pax6 gene. This process may have been
triggered by the influence of a spreading morphogenetic activity emanating from
the cortical antihem or a related lateral or ventral pallial source. Subsequently,
the inside-out neurogenetic gradient was produced in order to maximize synaptic
contacts between the new, late-born neurons and the superficially located cortical
afferents. In this process, the cdk5 signaling cascade may have been fundamental
in the acquisition of new mechanisms of radial migration, and the cdk5 activator
p35 was especially important in permitting late-born neurons to cross the barrier
formed by previously migrated cells. In addition, an important increase in the ex-
pression of reelin by Cajal-Retzius cells permitted the preservation of a neuron-free
marginal zone by arresting below it, and contributed to the inverted lamination
by detaching neurons from the radial glia. Finally, and partly due to the enormous
tangential expansion of the neocortex, a shortcut for thalamocortical axons was
found via the subcortical white matter. This was possible by virtue of the change
in position of the pioneer neurons that guide thalamocortical axons from a super-
ficial position in the marginal zone to a deeper position in the subplate. Signaling
systems involved in neocortical lamination, such as reelin and cdk5/p35, are also
related to preplate splitting. This suggests that there is an important evolutionary
link between these processes, although they are dissociable to some extent. There
are natural conditions in which, despite an inside-out laminar organization, affer-
ents tend to synapse in the superficial marginal zone, indicating that many pioneer
neurons remain in a superficial position.
3.6
Expansion of the Neocortex
3.6.1
Multiplication of Cortical Areas
After the neocortex acquired its basic laminar structure and its main visual, au-
ditory, and somatosensory inputs, it began a progressive tangential expansion in
several mammalian lineages, leading to the multiplication of sensory and motor
areas receiving distinct thalamic inputs. Thus, while some small-brained mam-
mals may have less than 20 distinct cortical areas, in macaques there may be more
than 50 (Northcutt and Kaas 1995; Catania et al. 1999; Van Essen et al. 1992). Al-
though Brodmann (1909) counted roughly the same number of areas in the human
brain, it is quite likely that this number is an underestimation (Wallace et al. 2002;
Striedter 2005). Possibly, the last common ancestor of extant mammals already had
a primary and a secondary visual area, an auditory area, a primary and a supple-
mentary somatosensory area, and a motor area that probably overlapped to some
extent with the somatosensory area (Northcutt and Kaas 1995). These areas have
been found in all mammals studied, and therefore are likely to have been present
in their common ancestor. Across species, the increase in the number of so-called
higher-order cortical areas that receive input from these primary areas (although
corticocortical connections are largely reciprocal) is related to the tangential ex-
pansion of the neocortex. Although increase in total cortical surface also produces
some increase in the size of each area, this does not account for the full expansion
of the cortical mantle (Changizi 2001; Changizi and Shimojo 2005). Tangential
cortical expansion has occurred several times in mammals (for example, primates
and carnivores, the most well-studied orders), producing a proliferation of distinct
cortical areas, many of them being largely unimodal but several being polymodal,
integrating different types of inputs. Some similarities have been observed in the
organization of these higher-level sensory areas between primates and carnivores
(Payne 1993), but it is not clear if these represent true homology or parallelism.
The addition of new cortical areas in phylogeny has been proposed to result
from the parcellation of initially overlapping inputs into distinct cortical fields
(Ebbesson 1980, 1984). Similarly, Krubitzer (1995, 2000) and Krubitzer and Kahn
(2003) proposed that new cortical areas emerged from the selective aggregation of
modular heterogeneities within phylogenetically more ancient areas. One such ex-
ample could be the overlap between the somatosensory and motor areas observed
in some marsupials, which become segregated in placental mammals (Lende 1963).
Another, not alternative possibility is that the addition of new cortical areas results
from the expansion of the morphogenetic fields generated by distinct signaling
sources during cortical development. Disbalances in FGF, EMX, or PAX6 signaling
during corticogenesis may have profound effects in the relative extension of occip-
ital vs frontal areas (Bishop et al. 2000, 2002; Muzio and Mallamaci 2005; Zhou et al.
2001; Mallamaci et al. 2000; Grove and Fukuchi-Shigomori 2003). This situation
can be likened to the expansion of distinct cortical fields in different species: for
Expansion of the Neocortex 69
example, in rodents there is an enlargement of the vibrissae somatosensory rep-

resentation; the star-nosed mole has an extremely elaborated nose representation;
in echolocating bats the auditory areas occupy a large extension of the neocortex;
and in the platypus the somatosensory representation of the electrosensory beak
is enormous (Catania 1999; Krubitzer and Kahn 2003; Striedter 2005). Thus, the
modulation of distinct morphogenetic signals may produce the expansion or re-
duction of specific areas, thus providing a plausible target for natural selection to
act upon.
But how does this process result in the addition of new areas? It is quite likely that
cortical expansion has a fundamental role in this process (Changizi 2001; Changizi
and Shimojo 2005; Striedter 2005). If there is an expansion of the cortical field,
the morphogen sources become increasingly separated, leaving a large territory
with very low morphogen activity. One possibility is that additional signaling
sources have been selected between these regions, in order to preserve cortical
connectivity or as a direct demand for processing capacity (Allman et al. 1971;
Allman 1999; Striedter 2005). An interesting point is that neighboring areas sharing
a sensory modality usually have mirror-image topographic representations of
the periphery, and are thus joined either at the midline representation or at the
peripheral representation of the sensory surface. If the anteriorizing signal FGF8 is
ectopically placed in the occipital cortex of a normal developing mouse, a second
vibrissae representation develops, caudal to the original, which is organized in
a mirror-image manner with respect to the normal area (Fukuchi-Shigomori and
Grove 2001). Thus, the appearance of new signaling sources might partly produce
the mirror-image organization of the different sensory areas of the neocortex. One
possible signaling source of this type is area MT of primates, which emerges quite
early in cortical development (Rosa 2002; Bourne and Rosa 2006). This area has
been proposed to act as a source of morphogens that organize the arrangement of
visual cortical areas between it and the primary visual area. It is not clear if there
is a homolog of MT in nonprimates; if there was not, this putative signaling center
would be an acquisition of the primate brain.
Finally, the mammalian neocortex is also unique in terms of its extrinsic con-
nectivity: the neocortex sends a robust projection to the brainstem and also to the
spinal cord, largely but not exclusively from the motor cortex; and there are also
strong projections from the neocortex to the contralateral hemisphere. The corti-
cospinal tract permits direct cortical control of the spinal motor neuron pool. In
a first study, it was found that corticospinal axons penetrate deeper into the spinal
laminae (approaching the motoneuron somata more closely), and the length of the
corticospinal tract is longer (reaching lower levels of the spinal cord) in animals
with higher manual dexterity such as primates (Heffner and Masterton 1975).
However, after removing the phylogenetic effects, only tract length was corre-
lated with dexterity, while laminar penetration had no effect in dexterity (Iwaniuk
et al. 1999). For example, the armadillo is an interesting case, with a high laminar
penetration but a quite short corticospinal tract and little dexterity. There is also
a relation between cortical size and the development of the corticospinal tract,
indicating that dexterity is not the only factor involved in its growth (Nudo and
Masterton 1990a,b; Striedter 2005). Nevertheless, considering a fixed brain size,
animals with higher dexterity tend to have an increased length of the corticospinal
tract. Furthermore, the large-brained ungulates and cetaceans have been omitted
from these analyses, which could become important exceptions to the dependency
of this tract on brain size.
Interhemispheric connections are also a feature of mammalian brains. We
(Aboitiz and Montiel 2003; Aboitiz et al. 2003a) have proposed that these fibers
originated in early mammals as a consequence of the development of precise topo-
graphic maps of the sensory surfaces (visual, somatosensory, and also the tonotopic
representations of the auditory cortices). In these conditions, each hemisphere
contained a topographic map of the contralateral sensory field, there being no
continuity between them at the midline. Thus, interhemispheric fibers may have
served as a bridge between the two hemi-representations at the midline, restoring
the continuity of the sensory field (Lepore et al. 1985, 1986; Ptito 2003). In the
case of audition, the connection between the hemispheres may have contributed
to the spatial location of sounds at an additional, cortical level (sound localiza-
tion mechanisms are already present at brainstem levels). In reptiles, topographic
sensory representations are largely localized in the optic tectum, which has a well-
developed tectal commissure to serve the midline fusion process, but mammals
had to develop a similar system when the neocortex acquired topographic maps
of the sensory surface. Speed of communication between the hemispheres may
have been crucial at these early processing levels, which is consistent with the fact
that primary and secondary sensory areas have the largest and faster-conducting
callosal fibers (with the largest fibers communicating auditory areas; Aboitiz et al.
1992). In many marsupials, interhemispheric connections make a long turn via the
anterior commissure, but in some larger-brained marsupials, interhemispheric
axons take a shortcut via the fasciculus aberrans running via the internal capsule
to the anterior commissure. In placental mammals, interhemispheric fibers run
via the massive corpus callosum, which develops dorsal to the hippocampal com-
missure, thus minimizing axonal distance and signal transmission time between
the hemispheres (Shang et al. 1997). During development, callosal axons cross the
midline via the formation of a glial wedge that establishes a sort of bridge between
the hemispheres (Shu and Richards 2001). Furthermore, the molecular control
of this process is based on an ancient mechanism consisting on the orchestrated
action of genes such as Robo and Slit, which are related to midline axonal crossing
in both vertebrates and invertebrates (T Shu et al. 2003). Thus, while the develop-
ment of a glial structure allowing callosal axon passage across the midline may be
a novelty of early placental mammals, the molecular mechanisms involved were
probably co-opted from pre-existing devices.
Discussion 71
3.6.2
Summary
Early mammals presumably had at least two visual, two somatosensory/motor,

and one auditory cortical areas. Neocortical expansion has resulted in the increase
in area sizes but more importantly in the proliferation of new cortical areas. Hy-
potheses to explain the addition of new cortical areas relate to the segregation of
initially heterogeneous cortical areas in a trend to increase connectional speci-
ficity and processing speed, and to the addition of new sources of morphogenetic
activity as the brain expands. Other characteristics of the neocortex are the devel-
opment of corticospinal axons, which permit direct cortical control over the spinal
motoneurons and an increase in manual dexterity, as well as interhemispheric
connections, which in placental mammals course via the corpus callosum. The
latter may have originated as a consequence of the development of topographic
sensory representation in the mammalian cerebral cortex, making it possible to
establish a continuity between the two hemirepresentations of the sensory surfaces
that are located in separate hemispheres.
4
Discussion
4.1
An Overview
We have attempted to provide an overview of both vertebrate brain development

and evolution in order to illustrate the correspondence between developmental
and evolutionary processes, and the notorious conservatism in neuronal develop-
mental programs that can be observed in distinct phylogenetic groups. We could
obviously not cover all aspects of the “evo-devo” of brain development, and there
are many neural systems that had to be left aside. Nevertheless, we believe we have
succeeded in providing a broad scenario for the origin and continuous evolution
of the vertebrate brain, emphasizing the dorsal pallium and later the mammalian
neocortex, which is the structure of most interest to us, mammals.
4.1.1
Early Neuronal Differentiation
Embryonic neural specification, in which epidermal cells are prevented from ac-
quiring neural fates by autosecretion of BMP proteins, is paralleled with the evi-
dence on the earliest nervous systems as basiepidermal neural nets derived from
the proliferating ectoderm. Furthermore, the delamination from a proliferating
epithelium and the participation of bHLH factors in early neuronal differentia-
tion seem to be common mechanisms in a wide variety of animals (Ross et al.
2003). Likewise, the aggregation of ciliated cells (receptors) may have also been
Discussion 71
3.6.2
Summary
Early mammals presumably had at least two visual, two somatosensory/motor,

and one auditory cortical areas. Neocortical expansion has resulted in the increase
in area sizes but more importantly in the proliferation of new cortical areas. Hy-
potheses to explain the addition of new cortical areas relate to the segregation of
initially heterogeneous cortical areas in a trend to increase connectional speci-
ficity and processing speed, and to the addition of new sources of morphogenetic
activity as the brain expands. Other characteristics of the neocortex are the devel-
opment of corticospinal axons, which permit direct cortical control over the spinal
motoneurons and an increase in manual dexterity, as well as interhemispheric
connections, which in placental mammals course via the corpus callosum. The
latter may have originated as a consequence of the development of topographic
sensory representation in the mammalian cerebral cortex, making it possible to
establish a continuity between the two hemirepresentations of the sensory surfaces
that are located in separate hemispheres.
4
Discussion
4.1
An Overview
We have attempted to provide an overview of both vertebrate brain development

and evolution in order to illustrate the correspondence between developmental
and evolutionary processes, and the notorious conservatism in neuronal develop-
mental programs that can be observed in distinct phylogenetic groups. We could
obviously not cover all aspects of the “evo-devo” of brain development, and there
are many neural systems that had to be left aside. Nevertheless, we believe we have
succeeded in providing a broad scenario for the origin and continuous evolution
of the vertebrate brain, emphasizing the dorsal pallium and later the mammalian
neocortex, which is the structure of most interest to us, mammals.
4.1.1
Early Neuronal Differentiation
Embryonic neural specification, in which epidermal cells are prevented from ac-
quiring neural fates by autosecretion of BMP proteins, is paralleled with the evi-
dence on the earliest nervous systems as basiepidermal neural nets derived from
the proliferating ectoderm. Furthermore, the delamination from a proliferating
epithelium and the participation of bHLH factors in early neuronal differentia-
tion seem to be common mechanisms in a wide variety of animals (Ross et al.
2003). Likewise, the aggregation of ciliated cells (receptors) may have also been
72 Discussion
a relatively common mechanism in primitive metazoans, which in chordates led

to the process of neurulation producing a CNS consisting of a hollow neural tube.
Apparently there were two main components making up this early neural tube:
a rostral component, related to the hemichordate larval apical organ and other cili-
ated structures, and a caudal component, corresponding to other ciliated elements.
In modern vertebrates, different inducing signals are required for both compo-
nents, the more caudal depending on the notochord and axial mesoderm (secreting
Noggin, Chordin, and Follistatin), and the more anterior parts depending on the
visceral anterior endoderm (secreting Cerberus and Dickkopf among other signals;
Wilson and Rubenstein 2000; Martindale 2005). In sessile urochordates and some
larval hemichordates, only cephalic markers are present, while the rest of the body
and nervous system is apparently lacking, indicating a developmental separation
between head-related and trunk-related neural tissues.
The process of CNS condensation is directed dorsally in vertebrates, but in
arthropods and other animals it is directed ventrally (De Robertis and Sasai 1996).
The body organization of arthropods and vertebrates is an upside-down version
one of the other, in both morphological and genetic terms. One interpretation of
this inverted organization is that at some point, deuterostome ancestors began to
swim upside-down. However, recent evidence shows a more complicated picture,
in which hemichordates have a protostome-like dorsoventral organization but also
bear a basiepidermal net with small signs of condensation; therefore CNS con-
densation appears to be a late evolutionary event in deuterostomes and may have
occurred independently of CNS condensation in protostomes (Lowe et al. 2003).
4.1.2
Patterning
Anterior–posterior patterning is a highly conserved process in phylogeny, as quite

similar genetic mechanisms are involved in animals as different as vertebrates
and Drosophila (Pearson et al. 2005). They particularly depend on genes of the
homeobox cluster and related genes, which serve to determine an anteroposterior
axis despite great morphological divergences. The origin of vertebrates is marked
by a double duplication of the Hox cluster, which includes the Dlx genes located
anterior to them (García-Fernández 2005). Vertebrates are characterized by the
differentiation of tissues surrounding the neural plate (epidermal placodes and
the neural crest) and by the neural tissue neighboring the placodal region, that
develops as the telencephalic hemispheres. In this process, Dlx genes play a crucial
role determining the limits of the placode/neural crest tissue. Noticeably, the
molecular networks involved in the specification of the preplacodal region and
the individual placodes are quite similar to those observed in Drosophila for the
specification of sensory structures from imaginal disks. For example, the lens
and nasal placode precursors arise from a common territory; however, in later
development, cells tend to segregate and then converge into specific placodes. The
Dlx5 and Pax6 genes are initially co-expressed in the future lens and olfactory cells,
An Overview 73
encircling the presumptive forebrain. Nevertheless, in later stages Dlx5 transcripts

segregate in the olfactory placode and PAX6 segregates in the lens (Bhattacharyya
et al. 2004). These events closely resemble the separation of eye and antennal
primordia from a common imaginal disk in Drosophila, where there is antagonistic
expression of the Distalless (Dll) and eyeless genes (homologs to Dlxs and Pax6 in
vertebrates, respectively).
Later in vertebrate development, Dlxs appear expressed in the ventral forebrain
and in the presumptive subpallium of the hemispheres (T. Luo et al. 2001a,b).
Placodes are essential for the differentiation of paired sensory organs (Whitlock
2004), and it is possible that ancestrally, sensory organs were all located in the
anterior brain vesicle as they are in larval urochordates and perhaps in cephalo-
chordates. In this context, cephalic neurulation may have been closely associated
with the condensation and invagination of sensory components (in Drosophila
a similar process may consist of the formation of imaginal disks, which depends
on the gene Dll; Panganiban 2000). Of particular interest to us is the anterior neu-
ral ridge (Couly and Le Douarin 1985), which secretes FGFs and in the cephalic
region acts as a promoter of ventral and anterior fates (Lupo et al. 2006). The
olfactory and the hypothalamic placodes originate in association with this region.
The olfactory placode participates in forebrain and telencephalic differentiation
by inducing the formation of an olfactory bulb and the telencephalic vesicles (De
Carlos et al. 1995). Thus, we suggest that the development of the olfactory sense
in early vertebrate ancestors was associated with the origin of a dorsal forebrain
structure receiving these inputs, which differentiated as an olfactory bulb and the
cerebral hemispheres. Modern agnathans partly retain this ancestral condition in
which the cerebral hemisphere is dominated by olfactory input. Nevertheless, they
also have ascending dorsal thalamic input, which may have been present in the
early dorsal forebrain. In gnathostomes, thalamic sensory inputs tend to displace
olfactory inputs from the medial pallium, restricting the latter afferents to the
lateral pallium. In amniotes, some thalamic inputs begin to deviate to the dorsal
and ventral pallium, and in birds and mammals they become practically absent
from the medial pallium (Wicht and Northcutt 1998).
The forebrain, midbrain, and hindbrain can be subdivided into a series of
transverse segments termed neuromeres (prosomeres in the forebrain), which
appear to be highly conserved in different species. An organizational scheme,
termed the prosomeric model, has been proposed as a topographic framework
for brain organization in different vertebrates (Puelles and Rubenstein 1999, 2003)
According to this model, the vertebrate telencephalon (consisting of a medial,
a dorsal, a lateral, and a ventral pallium, plus a subpallium) is located dorsal to the
presumptive hypothalamic region. Posterior to them are the prethalamus, dorsal
thalamus, and other structures. A slightly different interpretation is that the medial
pallium really consists of a more posterior component than the rest of the forebrain
(Kimura et al. 2005).
The patterning of the cerebral hemispheres depends on several signaling sources
(Sur and Rubenstein 2005). On one hand, there are the anterior signals derived from
74 Discussion
the anterior neural ridge, secreting FGF8, which is later expressed in the dorsal
aspect of the frontal hemisphere; caudally, there is the telencephalic roof plate,
secreting several factors (BMPs, Wnts) that induce other factors (Emxs, Pax6),
which in some instances cooperate but in others (as in the cerebral cortex) they
antagonize each other. These factors trigger development of the medial pallium
and the dorsal pallium at the border between the FGF and the BMP/Wnt signaling
fields. An additional morphogenetic center is the antihem, located in the lateral
pallium. The dorsal pallium is quite a narrow strip of tissue in most nonmammals,
but expands significantly with the origin of the mammalian neocortex.
4.1.3
Diversification of the Hemispheres and Neocortical Origins
The cerebral hemispheres of vertebrates have diversified enormously, having in-

creased in size and complexity independently in each phylogenetic group. In car-
tilaginous fish, there is an expansion of the central nucleus, while in teleosts, with
an everted brain, the area dorsalis is the largest. Amphibians have quite simple
brains, perhaps secondarily reduced; while in reptiles and birds a ventral pallial
component termed the dorsal ventricular ridge (DVR) becomes the most promi-
nent telencephalic structure. Mammals are characterized by the expansion of the
neocortex. Which brain component is ancestral to the mammalian neocortex?
This has been considered to be one of the thorniest problems in comparative
neuroanatomy (Northcutt 2003). Early studies of sensory connectivity proposed
that parts of the neocortex (the lateral neocortex, receiving visual extrastriate
and auditory inputs) was comparable to the avian and reptilian DVR by virtue
of receiving similar sensory inputs from sensory pathways that are relayed in
the mesencephalon (collothalamic). This was challenged by noting that the to-
pographic position and developmental origins of the DVR did not correspond to
the position and origin of the lateral neocortex, which was presumably of dorsal
pallial origin (Aboitiz 1992, 1993, 1995). Subsequent authors proposed homology
between the DVR and mammalian components like the basolateral amygdala or
the dorsal claustrum, but there is no agreement as to which precise component
corresponds to the DVR (Bruce and Neary 1995; Striedter 1997). Furthermore,
developmental and genetic evidence confirmed the ventral pallial identity of the
reptilian DVR (Pax6-positive, Emx1-negative), and the dorsal pallial identity of
the mammalian neocortex (Pax6-positive, Emx1-positive; Smith-Fernández et al.
1998; Puelles et al. 1999, 2000). The growth of the dorsal pallium in primitive
mammaliaforms may have resulted from the increased activity and interaction
of genes related to the developmental expansion of this structure, such as Wnts,
Emxs, Lhx2, and Pax6, depending on morphogenetic activity emanating from the
medial pallium; from FGF8 and other factors emanating from the anterior fore-
brain, and from factors derived from the lateral pallial antihem (Monuki et al. 2002;
Assimacopoulos et al. 2003; Sur and Rubenstein 2005). Thus, the dorsal pallium,
from being a small territory bordering the lateral/ventral pallium and the medial
An Overview 75
pallium in nonmammals, expanded into a prominent cortical sheet by virtue of

the interaction between these different morphogenetic sources.
4.1.4
Olfaction, the Hippocampus and the Amygdala
The expansion of the dorsal pallium in early mammals may have related to the
development of extensive networks connecting the olfactory cortex and hippocam-
pus. These circuits are present in amphibians and reptiles, but in early mammals
the sense of olfaction acquired great relevance owing to their presumed nocturnal
habits (Jerison, 1973; Sagan, 1977; Lynch, 1986; Kemp 2005). Likewise, there was
a noticeable development of the auditory apparatus, making it possible to localize
sound sources in the dark. Although primitive cynodonts and mammal-like rep-
tiles had quite a narrow braincase with no signs of telencephalic expansion, the
acquisition of the mammalian grade (marked by the detachment of the inner ear
ossicles from the inner jaw) roughly coincides with a dramatic increase in brain size
(Kielan-Jaworowska et al. 2004). This may have been related to the growth of the
dorsal pallium, which began to receive an increasing number of sensory afferents,
both lemnothalamic and collothalamic. These inputs were then relayed to both the
hippocampus and the amygdala (Aboitiz et al. 2003, 2003c). This situation con-
trasts with that observed in reptiles, in which the bulk of collothalamic projections
is sent directly to the ventral pallial DVR, with little interaction with the medial
pallium. Nevertheless, in mammals a direct connection from the collothalamus
to the amygdala persists and operates as a fast-response system in situations of
alarming stimuli. This system relates to emotional responses to threatening stimuli
and to the response to stressful events.
4.1.5
Cortical Lamination
A distinct feature of the mammalian neocortex is its lamination. As opposed to

the reptilian cortex, consisting of only three thin tangential layers, the mammalian
neocortex consists of six layers. Embryologically, the neocortex first develops
a transient structure termed the preplate, which is later split into a marginal zone
(future layer I) and a subplate by the arrival of the cells making up the true cortical
plate (layers II–VI). Neurons in the cortical plate migrate in an inside-out gradient,
late-generated cells locating above cells that are produced early, the former having
to migrate radially past the layers of older cells. In reptiles, however, lamination
occurs according to an outside-in gradient in which late-born neurons locate below
early-born neurons. Furthermore, thalamic axons enter the neocortex radially,
from the underlying white matter, while in reptiles they arrange tangentially in the
superficial marginal zone.
Marín-Padilla (1971) originally proposed that the reptilian cortex corresponded
to the early-appearing mammalian subplate, but there are some discrepant facts
76 Discussion
such as the apparent absence of a subplate proper in some marsupials (the subplate
appears to be included in the deepest cortical plate layers; Harman et al. 1995; Reep
2000). Perhaps more parsimonious, but in the same line, is the interpretation that
the deepest cortical plate cells correspond to the cells of the reptilian dorsal cortex.
More superficial, later-appearing and phylogenetically newer cortical neurons are
produced in the subventricular zone instead of the ventricular zone and depend on
Pax6 for their differentiation (Schuurmans et al. 2004). Thus, we proposed that this
gene along with others were fundamental in the acquisition of the superficial layers
of the neocortex, which derived mostly from the proliferative subventricular zone
(Aboitiz et al. 2003c). Thus, a fundamental event in neocortical origins consisted
of the differentiation of a subventricular zone in the cortical neuroepithelium,
which was probably associated with both the tangential and radial expansion of
the dorsal pallium. This proliferating zone originates in the lateral aspect of the
hemisphere, and in reptiles and birds it may have been related to the development
of the DVR, since it was restricted to ventral pallial sectors.
Another curious neocortical feature is its inside-out neurogenetic gradient. We
suggested that this was a strategy for these late-produced neurons to establish
synaptic contacts with the thalamic and cortical afferents that were located super-
ficially in layer I. The hippocampus resembles this primitive condition, in which the
developmental gradient is inside-out, and the afferents are located superficially in
layer I. In the development of the inside-out gradient, the signaling pathway of the
cyclin-dependent kinase 5 (cdk5) was possibly of special importance; in particular,
its activator p35 may have been crucial for neurons to be able to cross the layers
of previously migrated cells (Chae et al. 1997). Furthermore, the protein reelin,
secreted by Cajal-Retzius cells in the marginal zone, may have contributed to this
organization by permitting the generation of a cell-free layer I, which these neu-
rons, with increased migratory capacity, tended to penetrate. In addition, reelin is
hypothesized to block neural-glia, and perhaps neuron-to-neuron, attachments,
mechanism that may have provided interneuronal space for cortical plate neurons
to cross the subplate and layers of older neurons (this does not exclude other de-
velopmental functions for reelin). As the neocortex expanded tangentially, some
axons begun to enter the cortex via the underlying white matter, instead of run-
ning in the superficial marginal zone as they do in the reptilian cortex. This new
position served as a shortcut to access the dorsal pallium. Intermediate forms are
seen in primitive mammals, where axons penetrate the cortex from the underlying
white matter but later cross to the marginal zone to run tangentially along it for
some distance. In this process, the position of pioneer neurons, migrating from the
subpallium and directing the growth of thalamocortical axons, gradually shifted
from an ancestral position in the superficial marginal zone to a deeper position
below the cortical plate, in the mammalian subplate. Genes and signaling pathways
involved in the generation of the inside-out cortical lamination such as reelin and
cdk5/p35 may have been co-opted for the redistribution of pioneer neurons.
Issues with Evolutionary Theory 77
4.1.6
Tangential Expansion and the Origin of New Areas
Finally, the cortical sheet expands dramatically in some mammals with the conse-
quent increase in number of cortical areas. Most mammals share at least two
visual areas (striate, lemnothalamic-receiving, and extrastriate, collothalamic-
receiving), an auditory (collothalamic) area, and a somatosensory/motor (lem-
nothalamic) area. However, in large-brained mammals the number of areas may
exceed 50. The origin of new areas has been explained on the basis of segregation of
heterogeneous inputs to one region and the consequent homogeneization of these
fields; and on the appearance of new signaling centers that trigger the differenti-
ation of new cortical regions (Krubitzer 1995, 2000; Allman 1999; Krubitzer and
Kahn 2003; Striedter 2005). Both mechanisms may be valid; for example in mar-
supials there is significant overlap between the somatosensory and motor areas,
while in placental mammals these regions are well separated; in addition, it has
been postulated that the primate visual area MT is a signaling center that patterns
the organization of other visual areas (Rosa 2002). The isocortex is also notorious
for its connectivity: it develops a long corticospinal tract, related to increasing
voluntary control of the spinal cord, and interhemispheric connections, which we
proposed to be originally related to the fusion of the two hemirepresentations
of the sensory surfaces in each hemisphere at the midline (Aboitiz and Montiel
2003). Auditory interhemispheric connections are among the fastest-conducting
of all and may have participated in the localization of sound sources.
Provided this synopsis of the subjects dealt with in this article, we will now
turn into some more general issues that bear relation with theoretical concepts of
evolutionary biology and comparative morphology.
4.2
Issues with Evolutionary Theory
4.2.1
Genetic Conservatism Versus Morphological Diversity
One of our goals was to establish a continuity from the origin of the vertebrate
central nervous system to the appearance and diversification of the mammalian
cerebral cortex. In doing this, it became apparent that there have been key inno-
vations such as the grouping of ciliated sensory receptors in both the imaginal
disks of Drosophila and in the neural tube of vertebrates, and the delamination
process by which neurons segregate from the proliferating epithelium, which are
shared by many metazoans and may reflect common developmental mechanisms.
These correspondences may reflect a common origin or a different origin starting
from a shared ancestral developmental schedule. Considering the morphological
dissimilarities in the different taxa (for example, that neurulation appears to be
a late event in the history of protostomes; Lowe et al. 2003, 2006), we tend to prefer
78 Discussion
the hypothesis that there was a common developmental schedule prior to the diver-
sification of protostomes and deuterostomes, which became involved in different
morphogenetic processes in the different lineages. One particularly good example
of this situation is the role of the Pax6 gene in eye development; mutations in this
gene produce defects in eye development in Drosophila, mouse, and humans (Quir-
ing et al. 1994). Furthermore, if the mouse Pax6 gene is expressed ectopically in
Drosophila, it triggers the development of eye structures in regions such as wings
or legs (Halder et al. 1995). The Pax6 gene has been involved in photoreceptor
development in a variety of animals and is likely to have had a role in the original
specification of photoreceptors (Gehring 1996; Glardon et al. 1997; Pineda et al.
2000). However, the morphogenetic processes giving rise to the different types
of eye were acquired independently in the history of each lineage (for example,
arthropods and insects, mollusks and vertebrates), with Pax6 being a crucial el-
ement in all of them, perhaps owing to its early participation in photoreceptor
specification.
This situation is somehow reminiscent of the old discussion about whether all
animals could be described according to a common body plan or instead each phy-
lum was characterized by a unique body structure. This controversy dates from
at least two centuries ago, clearly exemplified by the Cuvier-Geoffroy debate of
pre-Darwinian times, in which Etienne Geoffroy Saint-Hilarie defended the unity
of composition doctrine, while Georges Cuvier posited four basic plans of animal
organization: vertebrates, articulates, mollusks, and radiates (Appel 1987). Since
1830, it became widely accepted that separate phyla are indeed characterized by
their unique body plans, thus supporting Cuvier’s position, which interpreted mor-
phology from a functional viewpoint (although being antievolutionist in the sense
that it rejected Lamarck’s transformism). In light of recent evidence, showing the
striking conservation of regulatory genes such as the Dlx/Hox cluster and other
genes that are essential for the formation of the body plan in most known phyla,
these ideas may be reconciled by considering an ancestral genetic patterning device
that generated different morphogenetic mechanisms in each lineage (Slack et al.
1993). Thus, although vertebrate brains share molecular patterning mechanisms
with Drosophila and other animals, the morphogenetic processes in which they
participate have diverged in each phylum, making a specific morphological orga-
nization for vertebrates, another for arthropods, another for mollusks and so on.
4.2.2
Development as a Clue to Evolution
Another issue is that developmental processes may yield clues about how evolution-
ary changes occurred. Although Haeckel’s concept that ontogeny recapitulates phy-
logeny is usually seen as an outdated preformist conception, evidence has shown
an important concordance between developmental events and evolutionary tran-
sitions. In this sense, we should consider the developmental process not as strictly
recapitulating earlier adult phylogenetic stages as considered by Haeckel, but rather
as the sequential acquisition of embryonic characters that were acquired during

the phylogenetic history, as proposed by Von Baer’s biogenetic law (see Gould
1977). Naturally, there are distortions of this process that may generate profound
evolutionary changes, most of them occurring through the process of heterochrony
in which the developmental timing of specific events is delayed or anticipated. In
the case of the lamination of the mammalian cerebral cortex, we have proposed
that a main heterochronic process has been the mechanism of hypermorphosis, in
which development is lengthened and additional stages are added to the end of it,
generating a mosaic of phylogenetically new and phylogenetically old structures
(Gould 1977). The expansion of morphogenetic fields such as the dorsal pallium in
mammals, giving rise to the neocortical mantle, has been proposed to result from
increased cell proliferation owing to the action of several morphogens and their
receptors, thus in a way adding new stages to the developmental program. An espe-
cially interesting finding in this context is that many brain structures that appear
late in development also tend to increase more in size (see Finlay and Darlington
1995; Finlay et al. 2001). In this way, the telencephalic vesicles and the pallium of ver-
tebrates are both among the latest developing and the more expanding and diversi-
fied brain structures. In general, telencephalic evolution has been characterized by
increasing growth of specific structures (the telencephalic vesicles and then the ex-
pansion of different components within them, such as the central pallial nucleus of
sharks, the area dorsomedialis in bony fish, the dorsal ventricular ridge in reptiles
and the neocortex in mammals; Northcutt 1981). In these cases, in which terminal
stages are added in a rough sequence, concomitant with continuous growth, it is
possible to track the evolutionary sequence with at least some confidence.
Nevertheless, morphology is complicated in its essence. There are always ex-
ceptions to these general rules, which have led to profound disagreements in
the interpretations of brain evolution. Fortunately, the phylogenetically conserved
gene expression patterns during development have appeared as important ele-
ments that can disambiguate the origin of several structures and, in our view, have
helped to clarify the origin of several structures such as the mammalian neocortex.
In this context, even if it may require further elaboration, the prosomeric model
proposed by Puelles and collaborators (Puelles and Rubenstein 2003) has come
as a fundamental reference for comparative studies. Although many criticisms
have been raised concerning this model, it is undoubtedly one of the first serious
attempts to make a comprehensive framework for vertebrate brain organization.
4.2.3
Developmental Processes and Homology Criteria
Perhaps the most basic issue in comparative biology relates to the concept of
homology. In order to determine the ancestry of a given structure, a criterion
for homology must be established. The modern concept of homology specifies
identity between two structures, each present in one of two different species,
which is established in the context of the hypothesis of a common ancestor that
80 Discussion
had the same character. Thus, homology is a hypothesis of evolutionary continuity

through a common ancestor (Northcutt 1996b). However, the original definition of
homology was pre-evolutionary and made reference to the distinction between real
or apparent similitude between organs (Owen 1837; see Aboitiz 1988, 1989, 1995;
Panchen 1994). Thus, homologous organs were the same organ under all its variety
of forms in different species (i.e., vertebrate arms and wings), while analogous or-
gans were those that looked similar and had comparable functions, but were not the
same (i.e., vertebrate and insect wings). Criteria to establish homology were strictly
comparative and were based on topographic position in the body (assuming a com-
mon overall architectural plan in the anatomy of different species), embryological
origins, or general similarity (there is even a concept of serial homology between
organs of the same animal, as in the case of paired limbs; Aboitiz 1995). With the
advent of evolutionary theory, homology came to imply common ancestry (Aboitiz
1988, 1995). However, the criteria for establishing homology remain strictly com-
parative, in which homology is no more proved than before Darwinian times (how-
ever, more accurate evidence is now available, allowing more educated guesses).
Two main approaches have been used to determine phylogenetic homology.
One of these is the comparison between adult structures and the other is the com-
parison of the embryonic primordia that give rise to these structures (Russel 1916;
Garstang 1922; Northcutt 1990a, 1996b; Striedter and Northcutt 1991; Striedter
1997; see also Aboitiz 1995; Aboitiz et al. 2003c). None of these is infallible, as
there are examples of undoubtedly homologous adult organs deriving from quite
different embryonic components and cases of strikingly similar adult structures
that have been acquired independently in evolution (De Beer 1971; Striedter and
Northcutt 1991). A particularly conflicting case is when two structures derive from
the same embryonic field but have undergone different evolutionary histories as
adult structures. Some authors use the term “field homology” to describe these
events (Butler and Molnár 2002; Puelles and Medina 2002), while others are clearly
not in concordance with this concept (Northcutt 1999, 2003). In Norhcutt’s terms
(2003), even if two structures arise from the same germinal compartments, they
are not necessarily homologous; they must also possess homologous stages in
their development, indicating a common history of transformations. For this rea-
son, we prefer to use the concept of embryonic homology to specify homologous
embryonic structures that give rise to nonhomologous adult structures in two
species, while the term “adult homology” indicates direct homology between the
respective adult organs (Aboitiz et al. 2003b,c). In any case, the question remains
as to whether embryonic or adult structure are better criteria for determining
the phylogenetic continuity of two structures. In our view, there are two extreme
possibilities: if phylogenetic evidence points to adult conservation with embryonic
diversity, adult comparisons may be a better criterion for homology, while if in
phylogeny there is adult diversity and embryonic conservation, embryonic com-
parisons should be considered a stronger criterion for homology (Aboitiz 1995). In
the case of the vertebrate telencephalon, the evidence reviewed points to a notice-
able conservatism in early developmental processes and topographic arrangement,
while there is also good evidence for dramatic divergence in brain structure during
late development (Northcutt 1981, 1984, 1990b, 2002; Striedter 2005).
One particularly controversial case of homology is the origin of the neocortex.
Hypotheses based on adult connectivity have pointed to homology between the
lateral neocortex and the reptilian DVR, while other hypotheses (based on to-
pography, developmental patterns and on adult connectivity, Aboitiz 1992, 1995;
Bruce and Neary 1995) have proposed homology with the reptilian dorsal pallium.
We conclude that the reptilian/avian DVR and the mammalian neocortex have
different developmental origins and are not likely to be homologs. Nevertheless,
according to Northcutt (2003) even if these structures had a similar developmental
origin, a differentiated DVR should prove to be ancestral to the neocortex to be con-
sidered its homolog. Fossil evidence indicates that early mammal-like reptiles had
quite a simple telencephalon with no signs of expansion, indicating that reptilian
and mammalian brains underwent independent histories of brain development.
4.2.4
Development, Adaptation, and Behavior
Finally, a purely developmental perspective is left wanting of a functional interpre-

tation of brain organization and evolution. The adaptationist paradigm affirms that
most important evolutionary changes have been the result of adaptations to specific
circumstances. Other evolutionists do not seem to agree with pan-adaptationist
interpretations and propose an active role of developmental processes and their
variations in determining the evolutionary trajectories (Arthur 2004). In our view,
this disagreement is in principle easy to solve. The proper Darwinian concept of
descent with modification (Darwin 1859) implies that natural selection may act
only on the available variability; it cannot create anything. Thus, genetic and devel-
opmental processes clearly set a frame in which selection is able to work. The point
is that, via the accumulation of small changes (cumulative selection; see Dawkins
1997), major evolutionary transformations may take place. Therefore, the problem
may be restated in terms of how much genetic and developmental variability is
available for a given evolutionary transformation; this is an empirical question and
does not invalidate the action of selective processes.
Perhaps the point of more controversy relates to the possibility that evolutionary
changes may have been abrupt, produced by dramatic reorganizations of the de-
velopmental program (Arthur 2004). A common argument against the gradualistic
interpretation is that natural selection exists but produces only small changes like
the variations in beak length in Darwin’s finches, which vary according to feeding
habits (Weiner 1995). Major evolutionary transformations would require other
kinds of mechanisms (Gould 1977; Arthur 2004). As mentioned, Darwin did not
differentiate between small or large changes; he considered that major transforma-
tions could take place through the successive accumulation of small changes. In this
context, Dawkins (2003) argues that the argument of micro vs. macro evolution is
misleading: it is as if, when looking at a tree we considered that the small buds could
82 Discussion
not give rise to big branches because they look so different. The possibility of major
changes occurring through the accumulation of small changes is logically possible,
and although for practical reasons has not been demonstrated, there is no evidence
against it. This does not mean that in some instances there may be some discon-
tinuous changes, such as polyploidy, as it occurs in several plant species or some
homeotic transformations of body parts. For example, most mammals (including
the giraffe) have a fixed number of cervical vertebrae (seven). However, in birds the
number of cervical vertebrae is highly variable (Carroll 1988), and the addition or
deletion of vertebrae must have occurred by discontinuous events (one individual
may be born with one extra vertebra but not half of it). Something similar may hap-
pen with frameshift events in which the identity of some body parts or segments
have been displaced caudally or rostrally (Wagner and Chiu 2001). But these are rel-
atively simple developmental changes, involving the number or relative position of
already formed organs. In our opinion, the evolution of biologically complex struc-
tures such as the eye, in which the development of different tissues must be tightly
coordinated in order to produce an elaborate optic device, is unlikely to have arisen
in a single or a few steps. Rather, phylogenetic evidence strongly indicates a series
of intermediate steps prior to the acquisition of complex eyes such as those of
insects, cephalopods, or vertebrates (Dawkins 1997). For example, in the evolution
of the mollusk eye, small improvements in image formation took place (gradual
increase in curvature, forming either a concave or a convex light-receiving surface,
and eventually, the gradual narrowing of the pupil and the formation of a lens in
concave eyes). Likewise, the origin of the mammalian cerebral cortex, although it is
a structure at first sight radically different from comparable structures in reptiles,
can be explained by a series of changes in region-specifying genes and neuronal
migration-controlling genes. Theories invoking macromutations producing the
whole diverse array of structural characteristics of the neocortex, i.e., its inverted
lamination, radial organization, tangential expansion and proliferation of sensory
areas, are still in lack of serious supporting evidence. Another issue refers to the
origin of the vertebrate brain. While Northcutt (2005) argues for a practically si-
multaneous origin of the different vertebrate characters, Butler (2006) claims for
a serial transformation in which telencephalic origin was the latest event. In our
view, this may have been a continuous but rapidly changing scenario, in which
acquisition of one character facilitated the development of new characters and so
on (Sect. 3.2.4). In this context, a major discontinuity in the origin of vertebrates
is evidenced by the double duplication of the Dlx-Hox cluster (Digregorio et al.
1995; Stock et al. 1996). Although the genetic duplication events were most likely
discrete (but possibly appearing in more than one individual), this does not imply
that morphological change occurred equally suddenly. Rather, it is quite likely that
in a first instance, this mutation had no major phenotypic consequences. In fact, re-
cent evidence indicates that mammalian Hox genes, despite being present in larger
numbers than other vertebrates, are in many cases redundant in function and the
loss of redundancy does not imply major phenotypic changes (García-Fernández
2005; Tvrdik and Capecchi 2006). After genetic duplication, genes may have started
Final Comments 83
to diverge, acquiring complementary functions, which may have facilitated the

gradual acquisition of novel morphological characters (Taylor and Raes 2004;
Schubert et al. 2006).
In morphological adaptation, a fundamental element is function and behav-
ior. Although developmental variability determines the possible morphological
variations, function, or behavior, determines which of these variants serves the
individual better. In other words, if the ancestors of giraffes had not browsed in
the highest branches, no selective trend toward increasing their necks would have
ever started. Thus, behavior and functions that are critical for survival determine
the direction of natural selection by favoring those structural variations that better
serve them (see Aboitiz 1990). This view has been sometimes dismissed for being
considered a form of neo-Lamarckism, because it implies that function precedes
form. However, it is fully consistent with modern genetic concepts and does not
imply the inheritance of acquired characteristics. It only affirms that, among the in-
dependently arising developmental variants, those that fit a function that is critical
for survival better will become selected. It is in this context that we have intended
to provide a behavioral scenario for brain evolution, associating the evolution-
ary events to behavioral changes. Obviously, there can be no swimming behavior
without a swimming apparatus, but swimming may have appeared as a co-option
of structures initially serving a different function. Once this new function was
acquired and became useful for survival, a selective trend may have been initiated
in which more efficient structures were selected, leading to increased swimming
behavior and so on, in a mutually reinforcing loop between structure and func-
tion. In the cases of the origin of the cerebral hemispheres and of the mammalian
neocortex, we have proposed that one particular sensory function (olfaction) was
of particular importance. Again, a primitive chemosensory system must have pre-
existed in the ancestors of both groups, but the relevance of this modality for the
behavior of the first vertebrates and the first mammals was probably a triggering
event for brain expansion (this is not to exclude other sensory systems such as
audition in the case of mammals). This led to an expansion of other sensory ca-
pacities and the elaboration of a more diverse behavioral repertoire, from which
new evolutionary trends emerged, producing the vertebrate and the mammalian
radiations in each case.
4.3
Final Comments
There has been a renewed interest in the study of the relation between development
and evolution, which promises to yield a wealth of interesting evidence that may
dramatically change many of our current conceptions. Although this interest has
been focused on many systems, we consider that the case of the central nervous
system may be a particularly enlightening example of this relation. This is not
only for the selfish reason that in our brains resides the capacity to be thinking
beings, but also because this is probably one of the systems in which the relations
84 Discussion
between form and function acquire their most elaborate expression. Thus, interdis-
ciplinary approaches including physiology, development, behavior, and genetics
may become especially fruitful to unveil these complex interactions. More than
trying to confirm and make known our own views, our intention here has been to
provide a series of working hypotheses that may motivate other workers to pursue
experimental and theoretical work on these lines.
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Subject Index
Acanthostega 27 cartilaginous 26
adenohypophysis (adenohypohysea) cartilaginous fishes 25, 31
16 Casineria 27
ADll (AmphiDll) 17, 22 catenin 53
agnathans 24, 28, 73 cdk5 (cyclin-dependant kinase 5) 61,
amniotes 27 65
amphibians 31, 32 central prosencephalic complex 29
amphioxus 8, 9, 12 central prosencephalic nucleus 79
amygdala 6, 33, 51 cephalochordates 8, 9, 13, 15, 17, 21
– basolateral 43, 48, 49, 58 Cerberus 14, 72
– lateral 43, 45, 46 cerebellum 37
– striatal 43 chordates 8, 11, 15
anapsid 27 Chordin 10, 12, 13, 72
anterior commissure 70 cilia (ciliated) 12–14, 20, 71
anterior neural ridge 19, 73 claustroamygdalar complex 6
anterior thalamic nucleus 42, 55 claustroamygdaloid complex 33, 39
anterior visceral endoderm 14 claustrum 45, 49, 51, 62
antihem 74 cnidarians 7, 13
apical organ 13, 72 CNS condensation 9–11
apical pole 12 collothalamic 31, 40, 44, 55, 58
Archaeothyris 28 conodonts 15, 25
arcopallium 33, 40, 51 corpus callosum 37, 70
area dorsomedialis 79 cortex
area MT 69 – dorsal 32, 38, 39, 41, 43, 57
auditory area 68 – dorsomedial 32, 39, 43
– lateral 32, 38, 39, 47
bHLH (basic helix-loop-helix) 71 – medial 32, 38, 42, 43
bilaterian 7 cortical plate (CP) 59, 61, 63, 64, 76
biogenetic law 1, 79 corticospinal tract 29, 69, 77
blastopore 8 corticostriatal sulcus 4
blastula 18 ctenophorans 13
BMP (BMP4) 10, 12, 14, 53, 74 ctenophores 7
bony fish 25, 26, 32 cyclostomes 25, 31
Brain factor (BF1) 22 cynodonts 35, 36
branchial skeleton 16, 24
Branchiostoma see amphioxus deuterostome 11
Burguess Shale 15 deuterostomes 8, 15
developmental evolutionary genetics
Cajal-Retzius cells 60, 63, 64 see evo-devo
114 Subject Index
diapsid 27 Haikouichthys 15
Dickkopf 14, 72 HAR1F 63
dipleurula 14 Hatscheck’s pit 20
Dlx (Dlx1, Dlx2) 4, 17, 21, 48–50, 72 hem
dorsal ventricular ridge see DVR – cortical 6, 63
dpp (decapentaplegic) 10 hemichordate 14, 72
Drosophila 2, 4, 10, 12, 72, 77, 78 hemichordates 8, 11, 12, 18
DVR 28, 33, 39, 47, 48, 74, 79, 81 hippocampal 6
– anterior (ADVR) 33, 44, 49–51, 55 hippocampus 33, 39, 43, 55, 64
– posterior (PDVR) 33 homeobox see Hox
homeothermy 37
ear ossicles 35 homology 3, 38, 44, 51
echinoderms 8, 14 Hox 2, 4, 22, 48, 72
Eitenascidia 17 Hylonomus 27, 28
ems (empty spiracles) 4 hypermorphosis 79
EMX 68 hyperpallium 33
Emx (Emx1, Emx2) 4, 48–50, 52 hypophyseal duct 26
encephalization 36 hypophyseal placode 14
endocasts 35 hypothalamus 16, 19, 31
endopiriform nucleus 49
entopallial nucleus 40 Ichthyostega 27
entorhinal cortex 39, 42, 43, 57 imaginal disks 72
episodic memory 56, 58 inside-out 76
evo-devo 1–3 insula 62
eye interhemispheric connections 70, 77
– evolution 82 interneurons 6, 59, 60
– medial 18 inversion
– paired 21, 25 – dorsoventral 10
eye development 78
Joseph cells 18
fasciculus aberrans 70
FGF (FGF8) 19, 68, 69, 74 lamprey 25
Follistatin 10, 13, 72 lateral posterior and pulvinar complex
Frizzled 14, 52 43–45
lemnothalamic 31, 40, 55, 58
ganglionic eminences 6, 48, 60 locomotion 61
gastrula 2, 7 LP/P nucleus 45
gastrulation 8 lungfishes 32
geniculate nucleus
– lateral 41, 42, 55 macro evolution 81
– medial 46 marginal zone (MZ) 59, 63–66
Gli3 53 mesencephalon 5
glial wedge 70 mesomere 3
gnathostome 31 mesopallium 33, 51
gnathostomes 24, 73 migration
Gobiconodon 35, 37 – radial 61, 63
– tangential 63
Hadrocodium 35, 37 monorhins 25
hagfish 25, 30 Morganucodon 35
Haikouella 15, 21 motor area 68
Subject Index 115
Myllokunmingia 15 place cells 56

myxinoids 25, 29 placodes (PL) 21, 72
polyploidy 82
neocortex 28, 33, 39, 81 poriferans 7
neural crest (NC) 21, 72 preplate (PP) 64
neural gland 19 prosencephalon (prosencephalic) 5
neurocan 67 prosomeres (prosomeric) 3, 4, 73
neuroepithelium 47, 62 prosomeric model 4, 73, 79
Neurogenin (Ngn) 10, 20, 53, 62 Protoclepsydrops 28
neurohypophyseal duct 19 protostomes 8, 11
neuromeres 3, 73 pulvinar 40
neuropeptide Y 63 pyramidal cells 59
neurulation 4, 10, 12, 77
nidopallium 33, 40, 50 radial glia 61
Noggin 10, 13, 72 radiates 7
notochord 8, 24 recapitulation hypothesis 39
nucleus rotundus 40, 43, 45 reeler 66
reelin 60, 63
ocellus 18 Repenomanus 37
Oikopleura 15 Repenonamus 35
olfactores 15 reptiles 32
olfactory bulb 16, 28, 29, 73 rhombencephalon 5
olfactory cortex 6, 39, 47, 49, 55, 64 rhombomeres (rhombomeric) 3
olfactory placode 14, 21 Robo (Roundabout) 70
optic tectum 29, 40, 44, 70
organs of Hesse 18 sarcopterygian 26
ostracoderms 25 septum 28
otolith 18 Sinoconodon 35
out-group hypothesis 39, 47 sleep 57
Slit 70
p35 61, 65 sog (short gastrulation) 10
p73 63 somatosensory area 68
paedomorphosis 32 spatial learning 55, 58
Paleothyris 27 spatial memory 56
pallial Sphenodon 47, 48
– dorsal 57 striatum 28, 33
pallial thickening 39, 41 subpallium 4, 28
pallium 31, 48 subplate (SP) 61, 65, 67, 75, 76
– dorsal 4, 6, 42, 43, 52, 58 substantia nigra 29
– lateral 6, 30, 33, 54 subventricular zone 6, 48, 61, 62, 76
– medial 6, 30, 32, 54 superior colliculus 40, 44
– ventral 6, 30, 33, 47, 48, 52 synapsid 28, 35
parcellation 68
Pax 18 Tbr (T-brain) 14, 22, 48, 50, 61
PAX6 68, 73 telencephalon impar 30, 31
Pax6 20, 48, 50, 52, 53, 62, 78 tetrapods 30
pharyngula 2, 3 thalamus
Pikaia 15 – dorsal 28, 30, 42, 47
pineal organ 18 therapsids 35
pioneer neurons (PN) 60, 65, 67 tornaria 14
116 Subject Index
Transcendental Anatomy 2 Westlothiana 27

translocation 61 WNT 14
Triconodon 35, 37 Wnt (Wnt3, Wnt3a) 52, 53, 74
Tulerpeton 27 Wulst 32
tunicates see urochordates
Xenoturbella 8
urochordates 8, 12, 15, 17, 21 Yunnanozoon 15
ventricular zone 6, 32, 76 Zic 18

vibrissae 69 zona limitans intrathalamica 29
visual area 42, 68 zootype 2

Origin of Vertebrate Telencephalon

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Origin of Vertebrate Telencephalon

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Reviews and critical articles covering the entire ﬁeld of normal anatomy (cytology,

histology, cyto- and histochemistry, electron microscopy, macroscopy, experimental

Manuscripts should be addressed to

Prof. Dr. F. BECK, Howard Florey Institute, University of Melbourne,

Prof. Dr. F. CLASCÁ, Department of Anatomy, Histology and Neurobiology,

Prof. Dr. H.-W. KORF, Zentrum der Morphologie, Universität Frankfurt,

Prof. Dr. R. PUTZ, Anatomische Anstalt der Universität München,

Prof. Dr. Dr. h.c. Y. SANO, Department of Anatomy,

Origin and Evolution

Juan Montiel, Dr.

2 Evolution of the Vertebrate Nervous System and Telencephalon . . . . . . . . . . 7

3 Origin of the Mammalian Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

3.4.1 A Functional Interpretation of Dorsal Pallial Expansion

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

circumstances. This perspective considered adaptation as a constant, universal

or pallial-subpallial boundary in the ventricle at the equatorial level of the vesicle

Fig. 2 Main components of the developing mammalian telencephalon. The telencephalic

This section discusses the vertebrate brain in a phylogenetic framework. We will

Metazoans (multicellular animals) are subdivided into poriferans (sponges), ra-

This section discusses the vertebrate brain in a phylogenetic framework. We will

Metazoans (multicellular animals) are subdivided into poriferans (sponges), ra-

waste is expelled (Martindale 2005). Thus, the endodermal opening (comparable to

Fig. 3 Phylogenetic relations of deuterostomes. According to the most recent phylogenetic

epidermal cells is to become neuronal, and this is blocked by the expression of

a centralized nervous system. Despite their general protostome-like dorsoventral

Fig. 5 Garstang’s proposal of transformation of a hemichordate larva into a primitive

plate (mostly consisting of the prospective hypothalamus and telencephalon) is

early event in animal evolution. Importantly, even if urochordates may be phylo-

There is developmental evidence suggesting a close relation between the vertebrate

nerves, but apparently they collect mostly mechanosensitive information (Wicht

The origin of vertebrates is marked by the appearance of differentiated tissues de-

Fig. 7 Gene expression patterns in the anterior brain of hemichordates, urochordates,

markers that suggest a close relation between the olfactory/hypophyseal placode

Vertebrates – or craniates – are divided into agnathans (jawless vertebrates) and

iforms or brachiopterygians) bear lobed ﬁns and vascularized lungs (Nieuwenhuys

Agnathans already possess a differentiated telencephalon, although its organiza-

The ﬁrst vertebrates (agnathans) were free-living animals with well-developed

etal parts of the hemispheres can be observed (Kielan-Jaworowska et al. 2004;

Unfortunately, when intending to identify structures homologous to the isocortex,

Butler (1994a,b) classiﬁed dorsal thalamic nuclei as either lemnothalamic or

isocortex, has been long considered to be homologous to the reptilian or avian

of the nucleus rotundus. More speciﬁcally, the mouse suprageniculate nucleus

tecto-rotundal-ventral pallial pathway, including the morphology of tectal effer-

In nonmammals, there is no structure that clearly corresponds to the mammalian

mesopallium of birds expresses Emx1 during development, suggesting that it may

mains of expression and enhanced cell proliferation speciﬁcally in this region. In

Furthermore, more recent studies of gene expression patterns during development

great beneﬁt for the development of olfactory–hippocampal–cortical networks.

In reptiles, the medial pallium or hippocampus receives ascending sensory pro-

A conspicuous component of the mammalian PP are the superﬁcially located

Summarizing, many elements forming the reptilian preplate-like structure arise

Another characteristic of the mammalian cortex is the inside-out developmental

The transition from a tangential to a radial organization of cortical inputs in neo-

The neocortex evolves from a three-layered, tangentially organized ancestral cor-

example, in rodents there is an enlargement of the vibrissae somatosensory rep-

Early mammals presumably had at least two visual, two somatosensory/motor,

We have attempted to provide an overview of both vertebrate brain development

Early mammals presumably had at least two visual, two somatosensory/motor,

We have attempted to provide an overview of both vertebrate brain development