Brain Research Reviews 39 (2002) 141–153

www.elsevier.com / locate / brainresrev

Review

Evolutionary divergence of the reptilian and the mammalian brains:

considerations on connectivity and development
Francisco Aboitiz a , *, Juan Montiel a , Daniver Morales b , Miguel Concha a,c
a
Programa de Morfologıa´ , Instituto de Ciencias Biomedicas
´ , Facultad de Medicina, Universidad de Chile, Santiago, Chile
b
Developmental Neurobiology Laboratory, The Rockefeller University, New York, NY, USA
c
Department of Anatomy and Developmental Biology, University College, London, UK

Accepted 27 June 2002

Abstract

The isocortex is a distinctive feature of the mammalian brain, with no clear counterpart in other amniotes. There have been long
controversies regarding possible homologues of this structure in reptiles and birds. The brains of the latter are characterized by the
presence of a structure termed dorsal ventricular ridge (DVR), which receives ascending auditory and visual projections, and has been
postulated to be homologous to parts of the mammalian isocortex (i.e., the auditory and the extrastriate visual cortices). Dissenting views,
now supported by molecular evidence, claim that the DVR originates from a region termed ventral pallium, while the isocortex may arise
mostly from the dorsal pallium (in mammals, the ventral pallium relates to the claustroamygdaloid complex). Although it is possible that
in mammals the embryonic ventral pallium contributes cells to the developing isocortex, there is no evidence yet supporting this
alternative. The possibility is raised that the expansion of the cerebral cortex in the origin of mammals was product of a generalized
dorsalizing influence in pallial development, at the expense of growth in ventral pallial regions. Importantly, the evidence suggests that
organization of sensory projections is significantly different between mammals and sauropsids. In reptiles and birds, some sensory
pathways project to the ventral pallium and others project to the dorsal pallium, while in mammals sensory projections end mainly in the
dorsal pallium. We suggest a scenario for the origin of the mammalian isocortex which relies on the development of associative circuits
between the olfactory, the dorsal and the hippocampal cortices in the earliest mammals.
 2002 Elsevier Science B.V. All rights reserved.

Theme: Other systems of the CNS

Topic: Comparative neuroanatomy

Keywords: Amygdala; Dorsal cortex; Dorsal ventricular ridge; Homology; Isocortex; Pallium; Regulatory genes; Ventral pallium

Contents

1. Introduction. the problem of isocortical origins .......................................................................................................................................... 142

2. The pallium of amniotes........................................................................................................................................................................... 143
3. Connectional and neurochemical comparisons: the recapitulation hypothesis................................................................................................ 143
4. Conflicting connectional evidence: the outgroup hypothesis ........................................................................................................................ 145
5. Developmental criteria ............................................................................................................................................................................. 145
5.1. Other components of the DVR ......................................................................................................................................................... 147
5.2. Dorsoventral gradients and their relation to the IT / VP ....................................................................................................................... 147
6. Different patterns of brain organization in reptiles and mammals ................................................................................................................ 148
7. A scenario for isocortical origins: olfaction, the hippocampus and the thalamofugal visual system................................................................. 149
7.1. Fossil brains ................................................................................................................................................................................... 149

*Corresponding author. Depto. de Psiquiatria, Facultad de Medicina, Pontificia Universidad Catolica de Chile, Marcoleta No. 387, 28 Piso, P.O. Box
114-D, Santiago 1, Chile. Fax: 156-2-665-1951.
E-mail address: faboitiz@med.puc.cl (F. Aboitiz).

0165-0173 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved.
PII: S0165-0173( 02 )00180-7
142 F. Aboitiz et al. / Brain Research Reviews 39 (2002) 141–153

8. Final comment ........................................................................................................................................................................................ 150

Acknowledgements ...................................................................................................................................................................................... 151
References................................................................................................................................................................................................... 151

1. Introduction. the problem of isocortical origins assumption that there are comparable components (homo-
logues) in the different taxa, despite their superficial
The mammalian isocortex (or neocortex) is a character dissimilarities. In order to understand the origin of the
unique to the brain of mammals in several respects. First, it mammalian isocortex, it is fundamental to determine
has undergone an enormous expansion, especially in the which ancestral structure(s) gave rise to it. Although
tangential domain [70]. Second, it has a six-layered obviously the ancestor is unavailable to study, there are
architecture which differs from the three-layered array of sister taxa (reptiles and birds) whose brains can be
simpler telencephalic laminar structures such as the hip- compared with those of mammals in order to infer the
pocampal formation, the olfactory cortex and the reptilian characteristics of the common ancestor. Commonly used
cortices [3,92]. On the other hand, the telencephalon of criteria for determining neural homology are connectivity
reptiles has a small, thin cortex and a prominent periven- [42,43,56], neurochemistry [74,75], topographical location
tricular structure named dorsal ventricular ridge (DVR), [1,2,34] and embryonic origins [4,40,66,67,87,90]. Un-
which receives many thalamic sensory projections (Fig. 1). fortunately, when dealing with the homologues of the
There have been important disagreements as to which isocortex, these different methodologies have led to di-
components of the non-mammalian telencephalon can be verging interpretations.
compared to the isocortex of mammals. This problem is In this paper we will address the issue of a possible
complicated by the intricate topography of the hemispheres correspondence between the reptilian dorsal cortex and the
in some vertebrate classes, and by the absence of a unified mammalian isocortex, and will review recent molecular
criterion to establish neural homology. Homology is a evidence supporting this interpretation. Then, the general
central problem to comparative anatomy, since the organization of the mammalian and reptilian brains will be
evolutionary considerations regarding the origin and di- discussed in light of these new findings, and we will
versification of any structure are usually based on the propose a scenario for the origin of the mammalian brain.

Fig. 1. Coronal section of the cerebral hemispheres of a reptile and a mammal, indicating in gray the different components of the pallium. The subpallium
is shown in white. ADVR, anterior dorsal ventricular ridge; AM, amygdala (only part of which is pallial); CL, claustrum; DCx, dorsal cortex; DMCx,
dorsomedial cortex; HIP, hippocampus; ICx, isocortex; LCx, lateral cortex; MCx, medial cortex; OCx, olfactory cortex; PT, pallial thickening (present only
in turtles); STR, striatum. Medial is to the left.
 F. Aboitiz et al. / Brain Research Reviews 39 (2002) 141–153
Our main argument along this paper is that the evidence on
regulatory gene expression provides a notable example of
how molecular developmental biology may help to clarify
important issues in the evolution of the nervous system.
2. The pallium of amniotes
The reptilian pallium has a three-layered cortex, consist-
ing of a medial and a dorsomedial component (both
comparable to the mammalian hippocampal formation), a
dorsal cortex and a lateral or olfactory cortex [98] (Fig. 1).
In birds, there is a medial hippocampus and a lateral
olfactory cortex. The avian dorsal cortex is a relatively
complex, multilaminated structure called the Wulst. The
reptilian dorsal cortex and the Wulst of birds receive visual
projections as well as some somatosensory input [56].
Additionally, in reptiles and birds (together are called
sauropsida), many non-olfactory sensory projections termi-
nate in the dorsal ventricular ridge (DVR; Fig. 1), which
bulges into the lateral ventricle above the basal ganglia
[96,97]. The DVR is the most expansive telencephalic
component of reptiles and birds and is a main integratory
center in their brains. It consists of an anterior part
(ADVR) and a posterior or basal part (PDVR). The ADVR
(which in birds corresponds to the hyperstriatum ventrale,
neostriatum and ectostriatum) receives much of the sensory
input, and its output is directed mainly to the corpus
striatum and to the PDVR. The latter (corresponding to the
archistriatum in birds) has been compared to parts of the
mammalian amygdala and projects to the hypothalamus
[46,47,96].
On the other hand, the pallium of mammals mainly
consists of a hippocampal formation (archicortex), an
olfactory cortex (paleocortex) and an isocortex or neocor-
tex interposed between them. There is also a claus-
troamygdaloid complex that contains both pallial and
subpallial elements. The isocortex receives most of the
ascending sensory input from the thalamus and projects to
the hippocampus and to the amygdala, as well as sending
output to several lower brain centers including the corpus
striatum, thalamus, several brainstem nuclei and the spinal
cord. During development, the isocortex originates at least
in large part from the dorsal pallium [61,70,71] (see also
Ref. [4]). Recent studies indicate that additionally, cells
originating in the embryonic corpus striatum migrate
tangentially in a dorsal direction and become incorporated
into the isocortex and the hippocampus, mostly as
GABAergic interneurons [10,12,39]. Tangential migration
of inhibitory neurons from the subpallium has been
recently described in birds [20], which suggests that this
mechanism pre-dates the common ancestor of mammals
and sauropsids.
Which reptilian structures correspond to the mammalian
isocortex? One hypothesis—which has been termed the
recapitulation hypothesis [41–43,60,61]—postulates that
143
the isocortex has a dual origin, part of it deriving from the
reptilian dorsal cortex, and the other part deriving from the
DVR (especially the ADVR). An alternative hypothesis
suggests that the isocortex derives mostly from the re-
ptilian dorsal pallium, and has been called the outgroup
hypothesis [1,2,4,61,68,90]. Below, we will summarize
some of the evidence favouring each of the two possi-
bilities.
3. Connectional and neurochemical comparisons: the
recapitulation hypothesis
Before comparing the sensory systems of reptiles and
mammals, it will be useful to briefly discuss some aspects
of thalamic connectivity. Thalamic sensory nuclei have
been recently classified in two main classes: lem-
nothalamic and collothalamic [16,17]. Lemnothalamic
nuclei receive projections from lemniscal systems which
do not synapse in the midbrain (see Fig. 2). Examples of
lemniscal pathways are the somatosensory pathways that
use the spino-thalamic route, and the visual thalamofugal
pathway that goes directly from the retina to the dorsal
lateral geniculate nucleus. Collothalamic nuclei receive
sensory pathways that synapse in the midbrain colliculi
(optic tectum and torus semicircularis; Fig. 2). The most
prominent of the collicular pathways are the visual tec-
tofugal pathway, which originates in the retina and relays
in the optic tectum, projecting then to the thalamic nucleus
rotundus of sauropsids (‘R’ in Fig. 2) or the pulvinar
nucleus of mammals (‘P’ in Fig. 2); and the auditory
pathway, which synapses in the inferior colliculus / torus
semicircularis and in the thalamic medial geniculate body.
Lemnothalamic nuclei project to the dorsal cortex of
sauropsids and to dorsomedial aspects of the isocortex of
mammals (i.e., primary visual and somatosensory cortices),
while collothalamic nuclei project to the ADVR of saurop-
sids and to ventrolateral isocortical regions of mammals
(i.e., visual extrastriate and auditory cortices) [16,17].
On the basis of similarities in sensory projection sys-
tems, some investigators [43,56,60,85] proposed that the
dorsal cortex of reptiles is homologous to the primary
(striate) visual cortex, and to the somatosensory and motor
cortices of mammals since they all receive lemnothalamic
projections (see Fig. 1). Furthermore, as the auditory
radiation and the tectofugal visual pathway (both col-
lothalamic) end in the avian / reptilian ADVR, and in the
mammalian auditory and extrastriate visual cortices, the
DVR was considered to be homologous to the ventrolateral
isocortex [41–43,60,85]. The point of this hypothesis is
that the common ancestor to both reptiles and mammals
had a reptilian-like brain, perhaps already with a DVR or
with a primordial component which developed into a true
DVR in sauropsids, while in the line leading to mammals
this component was transformed into lateral isocortex [76].
144 F. Aboitiz et al. / Brain Research Reviews 39 (2002) 141–153

Fig. 2. Diagrams summarizing some visual projections in reptiles and in mammals, which illustrate the differences between collicular and lemniscal
sensory pathways. Visual projections originate in the retina (RET) and project in two separate pathways. The lemniscal pathway (in purple) is directed to
the dorsal lateral geniculate nucleus (G) in the lemnothalamus (LT), and from there to the dorsal cortex (DCx) of reptiles and to the primary visual cortex
(V1) of mammals. The collicular pathway (in red) projects to the optic tectum (or superior colliculus, OT) and from there to the reptilian anterior dorsal
ventricular ridge (ADVR), via the nucleus rotundus (R) in the collothalamus (CT). In mammals, this pathway projects to the extrastriate visual cortex (Est,
in green), via the pulvinar nucleus (P). This nucleus has been classically considered to be homologous to (R), but some recent analyses [21,32] consider
that it is a derived character of mammals, with no clear homologue in sauropsids. The reptilian dorsal cortex (DCx) has connections with the M / DMCx. In
mammals, V1 exerts control over the ESt; all sensory isocortical areas indirectly project to the hippocampus (HIP). The reptilian posterior dorsal ventricular
ridge (PDVR) is related to parts of the mammalian amygdalar system and receives projections from the ADVR. In mammals, the collicular pathway
projects to the amygdala (AM) after a thalamic relay. DL, VM, dorsolateral and ventromedial components of the ADVR.
 F. Aboitiz et al. / Brain Research Reviews 39 (2002) 141–153
4. Conflicting connectional evidence: the outgroup
hypothesis
As mentioned, the outgroup hypothesis implies that the
isocortex arises mostly from the dorsal pallium, i.e., is
most likely homologue to the reptilian dorsal cortex. First,
we will briefly review some connectional evidence point-
ing to important differences between the reptilian ADVR
and the mammalian isocortex. For example, some authors
[14,21,32,68,73,105] have recently claimed that in terms of
overall connectivity, the ADVR is more similar to some
regions of the claustroamygdalar complex of mammals,
than to the ventrolateral isocortex. Both the ADVR and the
mammalian laterobasal amygdala receive collothalamic
projections, and both project to the ipsilateral cortex, the
corpus striatum and the subpallial amygdala. On the other
hand, the isocortex projects to many other brain regions
beside these. As a consequence, the thalamic nucleus
rotundus (‘R’ in Fig. 2) of sauropsids has been considered
by these authors to be more comparable to the intralaminar
nuclei of mammals (which receive collothalamic input and
project to the lateral amygdala) than to the mammalian
pulvinar (‘P’ in Fig. 2). There are two other important
differences in connectivity between the ventrolateral iso-
cortex and the ADVR, which need to be mentioned here.
The first is that the primary visual cortex of mammals
projects densely to the extrastriate visual cortex (especially
V2) [58,79], while in reptiles, projections from the dorsal
cortex to the ADVR are considered to be much weaker
[96,98]. Second, the mammalian isocortex projects re-
ciprocally to the entorhinal cortex and from there to the
hippocampus [36,80,100], while in reptiles few if any
connections have been reported from the ADVR to the
hippocampus [96–98]. Finally, despite the similarities in
sensory connectivity between the ventrolateral isocortex
and the ADVR, it is important to note that sensory
pathways may not always end in comparable structures. In
amphibians, collothalamic pathways terminate mainly in
the corpus striatum, which is clearly not homologue of
either the isocortex or the ADVR [16]. Therefore, only
some sets of connections are similar between the lateral
isocortex and the ADVR; and these that are similar (inputs
from collicular pathways) are reported to end mainly in the
subpallium of amphibians, which is not homologue of
either the ADVR or the isocortex.
Summarizing, the hypothesis of homology between the
lateral isocortex and the DVR (recapitulation hypothesis)
assumes that the sensory pathways associated to midbrain
colliculi end in the same targets in reptiles and mammals,
while the gross morphology of these targets (isocortex and
DVR) has diverged in these two taxa. On the other hand,
the alternative possibility of non-homology between iso-
cortex and DVR (outgroup hypothesis) implies that collicu-
lar pathways have changed their targets in the course of
reptilian and mammalian divergence. If this hypothesis is
correct, collothalamic projections to the dorsal pallium
145
(isocortex) either arose de novo in mammals, or existed in
the common ancestor to reptiles and mammals and were
subsequently lost in the dorsal cortex of sauropsids.
5. Developmental criteria
Another and long used homology criterion is develop-
mental origin. Many authors have argued that the general-
ized morphology and topographic relations are shown most
clearly in early developmental stages, which facilitates
cross-species comparisons [30,62,83,90]. This assumption
is valid in cases in which there is cross-species conservat-
ism of embryonic processes while adult morphology tends
to diverge. Alternatively, in cases of embryological di-
versity with adult conservatism, comparison of adult
structures and relations may provide a more accurate
diagnosis for homology [2,4]. In the case of the amniote
telencephalon, phylogenetic evidence points to a notable
conservation of early embryonic structure with adult
diversification [2,4,90], which puts weight on embryologi-
cal comparisons as a reliable homology criterion.
Studies indicate that during embryogenesis, the ADVR
develops from the lateral aspect of the pallium, in a
position deep (in the radial direction) and ventral to the
olfactory cortex [40,91]. On the other hand, most of the
isocortex is considered to originate from the dorsal pallium
(excepting the above-mentioned tangentially migrating
GABAergic cells that originate in the subpallium). This
evidence was initially claimed to support the hypothesis of
non-homology between the ADVR and the isocortex
[1,2,4,90]. Furthermore, studies of expression patterns of
regulatory homeobox-like genes in the embryonic fore-
brain have revealed a conserved mosaic organization in
which the different compartments develop into specific
brain components in the adult [31,57,65,84]. In the em-
bryonic mammalian telencephalon, distinct genetic
markers for pallial and for subpallial regions have been
detected. For instance, the corpus striatum (Fig. 3) arises
from the embryonic lateral and medial ganglionic emi-
nences, which are located in the lateral subpallium and
express the marker genes Dlx1 and Dlx2 [11]. The
cerebral cortex arises mostly from the embryonic pallium
and is characterized by the expression of genes of the Emx,
´
Otx and Pax families [8,51,64,65,86]. Smith Fernandez et
al. [87] confirmed these findings for amphibians, reptiles
and birds, showing that the amphibian dorsal pallium, the
reptilian dorsal cortex and the avian Wulst express the
same pallial markers as the isocortex. These authors also
identified for the first time an intermediate territory (IT;
see Fig. 3) in the equatorial region of the hemisphere,
located according to them between the pallium and the
subpallium of amphibians, reptiles, birds and mammals,
which does not express either the Emx1 or Dlx1 markers
but is largely positive for the gene Pax6 [87]. More recent
reports [66,67] have confirmed the existence of the IT
146 F. Aboitiz et al. / Brain Research Reviews 39 (2002) 141–153

Fig. 3. The cerebral hemispheres of reptiles, birds and mammals (only one hemisphere is shown; medial is to the left), indicating the pallium (dark grey),
which during development expresses the marker genes Emx1 /2, Otx1 /2, Pax6 and Tbr1, and gives rise to the Wulst (W) and hyperstriatum ventrale (HV)
of birds, and to cortical structures in reptiles and mammals. Light grey indicates the intermediate territory or ventral pallium (IT / VP), which is largely
negative for the genes Emx1 /2 and Otx1 /2, but positive for Pax6 and Tbr1. The IT / VP gives rise to the anterior dorsal ventricular ridge (ADVR) of
reptiles, to the neostriatum (N) of birds (which corresponds to a large part of the ADVR), and to the laterobasal amygdala and ventral claustrum (AM) of
mammals. The subpallium (white) expresses Dlx-type genes during embryogenesis and gives rise to the corpus striatum (STR) among other structures. In
each vertebrate class, the projection sites of the auditory pathway (a), and the collicular (vc) and lemniscal (vl) visual pathways are indicated. DCx, dorsal
cortex; ICx, isocortex, OCx, olfactory cortex. Based on Smith Fernandez´ et al. [87] and Puelles et al. [66].

(which has been named ventral pallium, VP, by these
authors), extending its definition by showing that, like
other pallial regions, the IT / VP also expresses the regula-
tory marker gene Tbr1.
Parts of the olfactory cortex, the olfactory bulbs, the
basolateral amygdalar complex, and the ventral claustrum
(among other regions) of mammals derive from the IT / VP
[67,87]. On the other hand, part of the lateral cortex, the
olfactory bulb and an important part of the reptilian ADVR
and of the avian neostriatum develop from the IT / VP (Fig.
3). This molecular evidence has been considered to
strongly support the early suggestions of non-homology
between the isocortex and the ADVR (outgroup hypoth-
esis) [1,2,4], and proposals of homology between the
reptilian ADVR and parts of the mammalian claus-
troamygdalar complex [14,34,90]. It is of interest to note
that Holmgren [34] originally named the sauropsidian
DVR and the mammalian claustroamygdaloid regions as
the ‘hypopallium’, which definitely agrees with the molec-
ular findings.
´
Smith Fernandez et al. [87] argued that in reptiles and
birds, the IT / VP remains as a distinct neuroepithelial zone
until late development, period in which it gives rise to
most of the ADVR. On the contrary, in mammals this
territory was described as producing only the above
mentioned early-generated components. In later embryonic
stages, the mammalian IT / VP is considered to be obliter-
ated between the Emx1 -positive and the Dlx1 /2 -positive
zones, disappearing from the neuroepithelial surface [87].
Somewhat in agreement with this, Swanson [94] has
proposed that the claustral complex of mammals (includ-
ing the basolateral amygdala, the claustrum, the endo-
piriform nucleus and isocortical layers 6b-7) is an early-
produced component, embryologically related to the sub-
plate or a subplate-like structure (see also Ref. [45]). If
these interpretations are true, most late-produced com-
ponents of the ADVR might not have a strict homologue in
the mammalian isocortex.
This evidence poses a serious challenge to the recapitu-
lation hypothesis of homology between the ventrolateral
isocortex and the ADVR [41–43], since it requires that in
mammals the IT / VP contributes cells to isocortical de-
velopment. However, the topographic location of the IT /
VP is such that the lateral (olfactory) cortex is interposed
between it and the isocortex. Thus, a massive tangential
migration of neurons from the IT / VP to the dorsal
pallium, producing the visual extrastriate and the auditory
cortices would be needed if the recapitulation hypothesis is
correct. The evidence that many isocortical GABAergic
cells originate in the subpallial corpus striatum and migrate
dorsally into the isocortex [10], raises the possibility that
some cells from the IT / VP also migrate to the dorsal
pallium. Just like cells from the ganglionic eminences that
migrate tangentially into the isocortex keep expressing
their Dlx1 subpallial marker [10,12], if cells from the
IT / VP migrate tangentially into the isocortex they might
 F. Aboitiz et al. / Brain Research Reviews 39 (2002) 141–153
maintain their molecular identity. This would make the
auditory and visual extrastriate cortices largely negative for
Emx1. However, recent studies indicate that Emx1 can be
considered as a marker of practically all pyramidal cells in
the cerebral cortex, and of most glutamate-containing
neurons in dissociated cortical cultures [19], something
that would be unexpected if the ventrolateral isocortex
(including auditory and visual extrastriate cortices) were
largely negative to this gene. Up to this point, no evidence
has been reported of a massive migration from the IT / VP
into the developing isocortex.
5.1. Other components of the DVR
The DVR is quite a complex structure which has many
intriguing components. We will discuss two of these, the
hyperstriatum ventrale of birds, and the posterior DVR,
which has been sometimes termed the ‘reptilian
amygdala’. The avian hyperstriatum ventrale (a structure
located ventral to the Wulst, which has been considered to
belong to the avian DVR), expresses Emx1 during de-
velopment (Fig. 3), suggesting that it may derive from the
dorsal or lateral pallium and not from the IT / VP [66,87].
In subsequent articles, Puelles et al. [67] and Guirado et al.
[32] subdivide the reptilian ADVR into dorsolateral and
ventromedial moieties (Fig. 2). These components would
correspond to the hyperstriatum (which is Emx1 positive)
and the neostriatum (Emx1 negative) of birds, respectively.
These authors further argue that the hyperstriatum / dorsola-
teral component of the avian / reptilian ADVR (Emx1
positive) might correspond to the mammalian dorsolateral
claustrum, the dorsal endopiriform nucleus and the ba-
somedial amygdala (and perhaps some elements of the
lateral isocortex). On the other hand, the neostriatum /
ventromedial component of the ADVR (Emx1 negative)
corresponds to the ventromedial claustrum, ventral endo-
piriform nucleus and laterobasal amygdala of mammals.
One additional issue concerns the homologies between
parts of the mammalian amygdalar complex and the
reptilian PDVR / avian archistriatum. Some authors [54,95]
divide the amygdala into pallial (cortical and basolateral
amygdala) and subpallial (central and medial amygdala)
moieties. According to Smith Fernandez ´ et al. [87], the
reptilian PDVR and the avian archistriatum express pallial
markers and are comparable to the corticomedial and
central amygdala of mammals, while Puelles et al. [66]
argue that only the posterior archistriatum is pallial. An
additional interpretation, based on hodological studies, is
that the reptilian PDVR is homologue to the mammalian
laterobasal amygdala [46]. Dubbeldam [23] claims that the
avian archistriatum consists of a sensorimotor moiety that
receives projections from the ADVR, and an ‘amygdalar’
moiety. Perhaps further embryological studies will help
clarify the compartmentalization and homologies of the
mammalian amygdala and the reptilian PDVR / avian ar-
chistriatum.
147
5.2. Dorsoventral gradients and their relation to the IT /
VP
In this context, it is important to note that the regulation
of distinct transcription factors may produce overall effects
in the dorsoventral patterning of the hemispheres. For
example, in Nkx2.1 loss of function mutants, a dorsaliza-
tion of the basal ganglia is observed, in which the striatum
is enlarged at the expense of the development of the more
ventral pallidum [93]. On the other hand, in the Pax6
mutant, a ventralization of the developing basal ganglia is
observed in which the medial ganglionic eminence ex-
pands into the territory of the more dorsally located lateral
ganglionic eminence, which results in underdevelopment
of the striatum [89]. In this mutant, there is also a dorsal
displacement of the limits of expression for marker genes
such as Emx1, Tbr1, Shh, Dlx1, Nkx2.1 and others,
producing malformations in the claustrum, endopiriform
nucleus, insular cortex and piriform / lateral cortex. Finally,
the isocortex is also severely disrupted, presumably due to
failure of differentiation and migration of cortical
progenitors, especially late-produced neurons in the ven-
trolateral pallium [28,89]. Another observation is that the
Pax6 2 / 2 mutant develops a dorsal ventricular ridge-like
structure in the lateral pallium [18], which according to the
authors may consist of cells that failed to migrate to the
lateral isocortex and other regions. However, this DVR-
like structure may derive of subpallial components and of
components originating in the dorsal, lateral and ventral
pallium (all positive to Pax6 and dependent on this gene
for migration). If this is the case, it may not be strictly
comparable to the sauropsidian DVR, which originates
mostly from the ventral pallium.
The above evidence may suggest that in the evolution of
the vertebrate pallium, expansion of the domains of
expression of regulatory genes, produced by overall dor-
salizing or ventralizing factors, may have had a key
influence in the origin of new brain architectures such as
that of mammals. For example, it is possible that in the
origin of the isocortex, the IT / VP was dwarfed as a
consequence of some dorsalizing influence that enhanced
Emx1 expression and was concomitant with the emergence
and expansion of the isocortex. Nevertheless, only a
change in boundaries may not be sufficient for the expan-
sion of the mammalian isocortex. Substantial increases in
cell proliferation within the territory destined to the dorsal
pallium were probably required to produce the enormous
growth of this structure in early and late mammalian
evolution.
In an argumentation in favor of homology between the
mammalian isocortex and the reptilian ADVR, Reiner [76]
has proposed that the structure ancestral to both ADVR
and ventrolateral isocortex was either Emx1 negative and
acquired Emx1 expression in the origin of mammals, or it
was Emx1 positive and lost Emx1 expression in the
evolution of reptiles and birds. In our view, shifts in the
148 F. Aboitiz et al. / Brain Research Reviews 39 (2002) 141–153
boundaries of distinct telencephalic territories could cer-
tainly happen, with the result that cell groups that were
initially destined to one compartment become incorporated
into another, without need of tangential migration of its
cellular constituents. However, in most reptiles the topog-
raphic relation between the IT / VP and the isocortex is
such that the lateral cortex is interposed between them
[1,2,66,67], so that a mere shift in gene expression
boundaries may perhaps not be sufficient to transform the
IT / VP into an isocortical area. The only exception to this
situation may be the turtle dorsal cortex, which develops a
structure called pallial thickening (Fig. 1), located deep to
the olfactory cortex, and topographically between the
dorsal cortex and the ADVR. Although definitely not an
IT / VP derivative [87], the pallial thickening deserves
further embryological studies. It is possible that the pallial
thickening is a derived character of turtles, which may be
supported by recent phylogenetic analyses indicating that
turtles are a rather modified group of diapsid reptiles, and
unrelated to ancestral reptiles [52,77,106].
6. Different patterns of brain organization in reptiles
and mammals
As opposed to sauropsids, in which lemniscal and
collicular sensory pathways are largely (but not totally)
separated in the dorsal cortex and the ADVR, in the
mammalian isocortex there is a strong confluence of the
lemniscal and collicular pathways, especially in the case of
the visual pathways. This suggests different patterns of
brain organization in mammals and in reptiles / birds (Fig.
2).
In reptiles and birds, the collicular pathways are appar-
ently more important to perception and anatomically more
robust than the lemniscal projections [97,98]. In reptiles,
the dorsal cortex (receiving lemnothalamic projections) is
strongly connected with the medial / dorsomedial (hip-
pocampal) and the lateral (olfactory) cortices. The ADVR,
which receives most collothalamic projections, is con-
nected primarily to the PDVR (comparable to parts of the
mammalian amygdalar complex). In turtles and lizards,
projections from the dorsal cortex and medial cortex into
the ventromedial (Emx1 negative) ADVR are sparse, but
the pallial thickening (related to the dorsal cortex) and the
rostrolateral (somatosensory) dorsal cortex are reciprocally
connected to the dorsolateral ADVR (Emx1 positive) [32].
Therefore, some integration or convergence of lem-
nothalamic and collothalamic pathways may occur in the
dorsolateral ADVR (Fig. 2). Both the ventromedial ADVR
and the dorsolateral ADVR project to the PDVR, in which
convergence of different sensory modalities may occur, as
it also happens in the mammalian amygdala. The PDVR
projects to hypothalamic nuclei, perhaps modulating social
and aggressive behavior and visceral responses [46].
Summarizing, in the telencephalon of reptiles and birds
two relatively separate systems exist for processing sen-
sory information: one receiving mainly olfactory and
lemnothalamic information, which is connected with the
hippocampus, and the other, receiving mainly col-
lothalamic information (and some lemnothalamic infor-
mation), which is more related to the amygdalar system
(see Fig. 2).
In many mammals, the primary visual cortex (with
lemnothalamic input) projects heavily into extrastriate
areas (especially V2), and these to higher-order visual
cortices. Since extrastriate and higher-order visual areas
also receive collicular input (via the pulvinar nucleus),
there is an important degree of convergence between
lemniscal and collicular pathways (Fig. 2). Both pathways
eventually route their information to the hippocampus and
amygdala. Although there are some species differences in
hippocampal connectivity, most species show similar
overall patterns of connections [99]. In the rat and in the
monkey, nearly all areas in the neocortical mantle (visual,
auditory and somatosensory) are bidirectionally connected
to the subiculum and entorhinal cortex, which route
information into the hippocampus [9,15,48,63,80,102,103].
Likewise, in most mammals studied, visual, auditory and
somatosensory information is transmitted to the mam-
malian amygdala by a series of modality-specific cortico-
cortical pathways [55]. These two structures, the hip-
pocampus and the amygdala, process different types of
mnemonic information (spatial and emotional, respective-
ly) [50,53]. Thus, the mammalian hippocampus may
receive a much heavier sensory projection than is the case
in reptiles and birds, who may rely more on amygdalar
components (PDVR / archistriatum) than on the former to
process certain types of mnemonic information. For exam-
ple, although the hippocampus of sauropsids is known to
be involved in spatial memory as it is in mammals [78], in
birds not all forms of spatial memory depend on the
hippocampus. In homing pigeons, hippocampal lesions
disrupt certain types of spatial learning such as using the
sun compass directional information, while the capacity to
learn on the basis of landmark beacons remains spared
[29].
7. A scenario for isocortical origins: olfaction, the
hippocampus and the thalamofugal visual system
The reviewed evidence provides important insights into
the developmental mechanisms leading to the evolutionary
emergence of the isocortex. However, an equally important
question (but more difficult to address) concerns the
functional context in which these transformations took
place. In other words, we might ask what are the be-
havioral correlates of the expansion of the dorsal pallium
and the lemnothalamic visual pathway in early mammals,
and of the IT / VP and the collothalamic visual pathway in
sauropsids. We postulate that the divergent evolution of the
brains of reptiles and mammals was related to emphasis on
different strategies for processing sensory information.
 F. Aboitiz et al. / Brain Research Reviews 39 (2002) 141–153
In an attempt to shed some light on this problem, we
suggest below that the mammalian isocortex originated in
the dorsal pallium by virtue of the relations of the dorsal
cortex with the medial / dorsomedial cortex (hippocampus)
and the olfactory cortex (Fig. 2), and their participation in
hippocampal episodic and spatial memory [1]. Briefly, in
early mammals spatial memory may have strongly de-
pended on nonspatial clues like olfaction to develop maps
of space. For example, odors may permit to recognize
specific places and routes made by the animal in its daily
routine. Thus, the circuit connecting olfactory cortex and
hippocampus may have been quite important for the
behavior of early mammals. With the colonization of
diurnal niches after the demise of dinosaurs, the visual
system perhaps became also important for spatial memory.
In this condition, the dorsal cortex of early mammals,
originally receiving visual and somatosensory lem-
nothalamic input, may have become progressively in-
volved in associative networks for hippocampal memory.
This may have triggered the expansion of the dorsal cortex
into an isocortex, which also begun to receive collicular
visual and auditory information to participate in associative
networks with other sensory modalities.
This proposal is partly based on Lynch’s [50] original
hypothesis of the origin of the isocortex, and assumes that
the development of olfaction was a key event in early
mammalian evolution. It has been repeatedly proposed that
in ancestral mammals, olfaction was an important sensory
modality [37,38,44]. Endocasts of mesozoic mammals
indicate relatively large olfactory bulbs and perhaps an
elevated rhinal fissure [38], suggesting a large olfactory
cortex in relation to the rest of the pallium. Likewise, in
small-brained insectivores and in some marsupials, olfac-
tory-related structures occupy a much larger proportion of
the volume of the brain than is the case in larger-brained
species with a well-developed isocortex [25,26,88,101]. In
the subsequent evolution of early and late mammals,
olfactory and limbic (including hippocampal) structures
scale together but in large part separately of the isocortex
[88], perhaps indicating that the latter has become largely
independent of limbic components for certain types of
sensory and motor processing.
The olfactory cortex is heavily connected with the
hippocampal cortex in both reptiles and mammals. In
reptiles, there is a circuit interconnecting the medial
(hippocampal) cortex, the dorsal cortex (receiving the
lemnothalamic pathways) and the olfactory cortex [50,96].
Furthermore, there is evidence that the medial and dorsal
cortices of reptiles participate in spatial navigation, and
these structures have been recently found to use nonspatial
clues in tasks of spatial orientation [22]. Although it has
long been considered that the mammalian hippocampus
encodes mainly visual spatial memory [13,72], recent
findings indicate that it also represents olfactory infor-
mation [24,59,104], and that there is an interleaved segre-
gation of spatial and nonspatial information along the
length of this structure [33]. This suggests that nonspatial
149
cues (like odors) may be used in the elaboration of spatial
maps in the mammalian and reptilian hippocampi, and
possibly in mammalian ancestors. Furthermore, more than
being strictly involved in spatial memory, the hippocampus
has been recently considered to be crucial for storing
episodic memory, that is, the remembrance of behaviorally
relevant events and sequences of events, from which
spatial maps and other forms of memory emerge [27].
Therefore, these olfactive–hippocampal networks may
have participated in rather broad aspects of memory
formation beside purely spatial memory.
We postulate that the lateral, dorsal, and medial cortices
were put to use by the first mammals to make relatively
elaborate, largely olfactory-based representations of space
and other behaviorally relevant items, in which specific
odors labeled particular objects, places and routes. As-
sociative networks between the dorsal cortex and the
olfactory system, via the hippocampus, may have become
increasingly important in these animals to develop mul-
tisensorial maps of space. Eventually, the contribution of
the visual system became undoubtedly necessary in the
elaboration of more precise maps of space. The dorsal
cortex, receiving visual information from the thalamofugal
visual pathway, may have thus become an important
sensory processing system in the early mammalian brain
[1]. Other parts of the isocortex (visual extrastriate and
auditory) may have originated from an expansion of the
dorsal cortex to accommodate the incoming mesencephalic
inputs that became increasingly involved in associative
interactions with the primary visual cortex, and with the
olfactory system through the hippocampus.
The early involvement of the primary visual cortex in
processing spatial information implies that it developed at
least a crude spatial representation of the visual field. The
visual cortex of reptiles has a rather poor visuotopic
organization, due to its tangential synaptic organization
[1,3,4,96,98]. In these animals, visual topographic infor-
mation is mostly processed in the optic tectum. The
development of a columnar organization of the isocortex,
associated with the increase in cellular depth and the
acquisition of an inside-out neurogenetic gradient during
development allowed the establishment of more sophisti-
cated retinotopic maps in the primary visual cortex [1,3,5–
7]. This permitted the latter to drive the activity of other
cortical areas that begun to receive visuotopically orga-
nized tectofugal projections. In addition, the auditory
projection to the cerebral cortex may have benefited from
the cortical representation of space through the elaboration
of a more sophisticated sound localization system (see Ref.
[1], and below).
7.1. Fossil brains
Endocast information indicates that early mammal-like
reptiles (therapsids) had narrow, tubular hemispheres with
no signs of telencephalic expansion [35,44,69]. Increase in
brain size, resulting from a generalized growth of the
150 F. Aboitiz et al. / Brain Research Reviews 39 (2002) 141–153

Fig. 4. Endocasts of mammal-like reptiles and primitive mammals, indicating the progressive increase in brain size. Note that in Morganucodon, expansion
of the posterior part of the hemisphere can be observed. More advanced mammals like Triconodon show a more complete expansion of the hemispheres.
Based on Rowe [81,82]. Dates in millions of years ago: Probaignognathus, about 235 MYA; Therioherpeton, about 215 MYA; Morganucodon, about 205
MYA; Triconodon, about 155 MYA; Didelphys, about 65 MYA to present.

isocortex, occurs in more recent fossil mammals like
Hadrocodium and Triconodon [49,81,82] (Fig. 4). The full
enlargement of the brain coincides with the detachment of
the auditory bones from the mandible to form the mam-
malian middle ear [49,81,82], and perhaps with the de-
velopment of auditory projections into the isocortex. In
this sense, expansion of the brain, which may be attributed
to cortical growth and to invasion of the collicular sensory
pathways into the isocortex, was related to the develop-
ment of higher auditory acuity, perhaps in relation to more
sophisticated spatial representation of sound sources. Inter-
estingly, Morganucodon, a primitive mammaliaform from
the early Jurassic, and taxonomically intermediate between
the above forms and smaller-brained, more primitive
therapsids, shows only partial expansion of the brain. In
this species, widening of the occipital parts of the hemi-
spheres can be observed [81,82] (Fig. 4), perhaps evidenc-
ing early expansion of the dorsal cortex.
8. Final comment
We have reviewed developmental evidence for a sepa-
rate origin of the mammalian isocortex and the reptilian
DVR. The latter appears to be related to ventral pallial
structures of mammals such as the basolateral amygdala
and / or the endopiriform nucleus (ventral claustrum), while
the isocortex originates largely from the dorsal pallium.
Connectional evidence indicating similarity of sensory
input in the reptilian ADVR and the mammalian auditory
and extrastriate isocortex is weakened by other hodological
evidence that suggests different interpretations. One im-
portant assumption held by several workers has been that
the modern reptilian brain represents a stage somewhat
comparable to that of the ancestral mammals. On the other
hand, the developmental evidence suggests to us that the
reptilian and mammalian brains may have diverged very
early in their organization. It is possible that the origin of
the mammalian isocortex was partly a developmental
consequence of a generalized dorsalizing tendency which
led to the expansion of the dorsal cortex, while the
evolution of the sauropsidian pallium may have been
dominated by the action of some ventralizing factor,
leading to the expansion of the IT / VP.
The above proposals have been complemented with a
scenario describing the origin of the isocortex from the
dorsal pallium based on the relations of this structure and
the hippocampus and olfactory cortex. In our view, the
 F. Aboitiz et al. / Brain Research Reviews 39 (2002) 141–153
main significance of these scenarios is that they provide an
evolutionary framework which may guide future studies of
the embryology and structure of the cerebral cortex.
Furthermore, it is important to stress the point that the
developmental and functional approaches to evolutionary
problems are complementary rather than alternative; these
address different but equally important questions. Finally,
a similar scenario for the evolutionary development of the
reptilian DVR is still needed. In sauropsids, mesencephalic
sensory pathways remain as the main processors of topog-
raphically organized exteroceptive information, as it may
be in lower vertebrates. Thus, the advent in early mammals
of an olfactory-based brain and as a consequence, of a
dominant, topographically organized visual lemnothalamic
projection, may be considered a fundamental innovation in
vertebrate brain evolution, which drove the collicular
pathways out of their ancestral route to the telencephalon.
Acknowledgements
Supported by FONDECYT Grant 1970294 and by a gift
from EMEC S.A. and ENAEX S.A. to Francisco Aboitiz.
We wish to acknowledge Alexander Vargas for interesting
discussions. Claudia Andrade provided secretarial help.
References
[1] F. Aboitiz, The evolutionary origin of the mammalian cerebral
cortex, Biol. Res. 25 (1992) 41–49.
[2] F. Aboitiz, Homology in the evolution of the cerebral hemispheres:
the case of reptilian dorsal ventricular ridge and its possible
correspondence with mammalian neocortex, J. Hirnforsch. 4 (1995)
461–472.
[3] F. Aboitiz, Evolution of isocortical organization. A tentative
scenario including roles of reelin, p35 / cdk5 and the subplate zone,
Cereb. Cortex 9 (1999) 655–661.
[4] F. Aboitiz, Comparative development of the mammalian isocortex
and the reptilian dorsal ventricular ridge. Evolutionary considera-
tions, Cereb.Cortex 9 (1999) 783–791.
[5] F. Aboitiz, The origin of isocortical development, Trends Neurosci.
24 (2001) 202–203.
[6] F. Aboitiz, D. Morales, J. Montiel, The inverted neurogenetic
gradient of the mammalian isocortex. Development and evolution,
Brain Res. Rev. 38 (2001) 129–139.
´
[7] F. Aboitiz, J. Montiel, J. Lopez, An hypothesis of the early
evolution of the development of the isocortex, Brain Res. Bull. 57
(2002) 481–483.
´
[8] D. Acampora, A. Simeone, Understanding the roles of Otx1 and
Otx2 in the control of brain morphogenesis, Trends Neurosci. 22
(1999) 116–122.
[9] J.P. Aggleton, S.D. Vann, C.J. Oswald, M. Good, Identifying cortical
inputs to the rat hippocampus that subserve allocentric spatial
processes: a simple problem with a complex answer, Hippocampus
10 (2000) 466–474.
[10] S.A. Anderson, D.D. Eisenstat, L. Shi, J.L.R. Rubenstein, Inter-
neuron migration from basal forebrain to neocortex: dependence on
Dlx genes, Science 278 (1997) 474–476.
[11] S.A. Anderson, M. Qiu, A. Bulfone, D.D. Eisenstat, J. Meneses, R.
Pedersen, J.L.R. Rubenstein, Mutations of the homeobox genes
151
Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and dif-
ferentiation of late born striatal neurons, Neuron 19 (1997) 27–37.
[12] S. Anderson, M. Mione, K. Yun, J.L.R. Rubenstein, Differential
origins of neocortical projection and local circuit neurons: role of
Dlx genes in neocortical interneuronogenesis, Cereb. Cortex 9
(1999) 646–654.
[13] P.J. Best, A.M. White, Hippocampal cellular activity: a brief history
of space, Proc. Natl. Acad. Sci. USA 95 (1998) 2717–2719.
[14] L.L. Bruce, T.J. Neary, The limbic system of tetrapods: a compara-
tive analysis of cortical and amygdalar populations, Brain Behav.
Evol. 46 (1995) 224–234.
[15] ´ The hippocampo-neocortical dialogue, Cereb. Cortex 6
G. Buzsaki,
(1996) 81–92.
[16] A.B. Butler, The evolution of the dorsal pallium in the telencephalon
of amniotes: cladistic analysis and a new hypothesis, Brain. Res.
Brain Res. Rev. 19 (1994) 66–101.
[17] A.B. Butler, The evolution of the dorsal thalamus of jawed
vertebrates, including mammals: cladistic analysis and a new
hypothesis, Brain. Res. Rev. 19 (1994) 29–65.
[18] ´ Development and evolution of the collopal-
A.B. Butler, Z. Molnar,
liumin amniotes: a new hypothesis of field homology, Brain Res.
Bull. 57 (2002) 475–479.
[19] C.H. Chan, L.N. Godinho, D. Thomaidou, S.S. Tan, M. Gulisano,
J.G. Parnavelas, Emx1 is a marker for pyramidal neurons in the
cerebral cortex, Cereb. Cortex 11 (2001) 1191–1198.
[20] ´
I. Cobos, L. Puelles, S. Martınez, The avian telencephalic subpal-
lium originates inhibitory neurons that invade tangentially the
pallium (dorsal ventricular ridge and cortical areas), Dev. Biol. 239
(2001) 30–45.
[21] ´
J.C. Davila, S. Guirado, L. Puelles, Expression of calcium-binding
proteins in the diencephalon of the lizard Psammodromus algirus, J.
Comp. Neurol. 427 (2000) 67–92.
[22] L.B. Day, D. Crews, W. Wilczynski, Effects of medial and dorsal
cortex lesions on spatial memory in lizards, Behav. Brain Res. 118
(2001) 27–42.
[23] J.L. Dubbeldam, Birds, in: R. Nieuwenhuys, H.J. Ten Donkelaar, C.
Nicholson (Eds.), The Central Nervous System of Vertebrates, Vol.
3, Springer, Berlin, 1998, pp. 1525–1636.
[24] J.A. Dusek, H. Eichenbaum, The hippocampus and transverse
patterning guided by olfactory cues, Behav. Neurosci. 112 (1998)
762–771.
[25] B.L. Finlay, R.B. Darlington, Linked regularities in the development
and evolution of mammalian brains, Science 268 (1995) 1578–
1584.
[26] B. L Finlay, M.N. Hersman, R.B. Darlington, Patterns of vertebrate
neurogenesis and the paths of vertebrate evolution, Brain Behav.
Evol. 52 (1998) 232–242.
[27] N.J. Fortin, K.L. Agster, H.B. Eichenbaum, Critical role of the
hippocampus in memory for sequences of events, Nat. Neurosci. 5
(2002) 458–462.
[28] T. Fukuda, H. Kawano, N. Osumi, K. Eto, K. Kawamura, His-
togenesis of the cerebral cortex in rat fetuses with a mutation in the
Pax-6 gene, Dev. Brain Res. 120 (2000) 65–75.
[29] A. Gagliardo, M. Mazzotto, V.P. Bingman, Hippocampal lesion
effects on learning strategies in homing pigeons, Proc. R. Soc.
London B 263 (1996) 529–534.
[30] W. Garstang, The theory of recapitulation: a critical re-statement of
the biogenetic law, J. Linn. Soc. (Zool.) London 35 (1922) 81–101.
[31] G. Gellon, W. McGinnis, Shaping animal body plans in development
and evolution by modulation of Hox expression patterns, BioEssays
20 (1998) 116–125.
[32] ´
S. Guirado, J.C. Davila, M.A. Real, L. Medina, Light and electron
microscopic evidence for projections from the thalamic nucleus
rotundus to targets in the basal ganglia, the dorsal ventricular ridge,
and the amygdaloid complex in a lizard, J. Comp. Neurol. 424
(2000) 216–232.
[33] R. E Hampson, J.D. Simeral, S.A. Deadwyler, Distribution of spatial
and nonspatial information in dorsal hippocampus, Nature 402
(1999) 610–614.
152 F. Aboitiz et al. / Brain Research Reviews 39 (2002) 141–153
[34] N. Holmgren, Points of view concerning forebrain morphology in
higher vertebrates, Acta Zool. 6 (1925) 413–477.
[35] J.A. Hopson, Paleoneurology, in: C.C. Gans, R.G. Northcutt, P.S.
Ulinski (Eds.), Biology of the Reptilia, Vol. 4, Academic Press, New
York, 1979, pp. 39–146.
[36] R. Insausti, Comparative anatomy of the entorhinal cortex and
hippocampus in mammals, Hippocampus 3 (1993) 19–26.
[37] H.J. Jerison, in: Evolution of the Brain and Intelligence, Academic
Press, New York, 1973, 482 pp.
[38] H.J. Jerison, Fossil evidence on the evolution of the neocortex, in:
E.G. Jones, A. Peters (Eds.), Cereb. Cortex, Vol. 8A, Plenum, New
York, 1990, pp. 285–309.
´
[39] D. Jimenez, ´
L.M. Lopez-Mascaraque, F. Valverde, J.A. De Carlos,
Tangential migration in neocortical development, Dev. Biol. 244
(2002) 155–169.
¨ ´ On the ontogeny of the reptilian forebrain. Nuclear
[40] B. Kallen,
structures and ventricular sulci, J. Comp. Neurol. 95 (1951) 307–
347.
[41] H.J. Karten, The ascending auditory pathway in the pigeon
(Columba livia). II. Telencephalic projections of the nucleus
ovoidalis thalami, Brain Res. 11 (1968) 134–153.
[42] H.J. Karten, The organization of the avian telencephalon and some
speculations on the phylogeny of the amniote telencephalon, Ann.
NY Acad. Sci. 167 (1969) 164–179.
[43] H.J. Karten, Evolutionary developmental biology meets the brain:
the origins of mammalian neocortex, Proc. Natl. Acad. Sci. USA 94
(1997) 2800–2804.
[44] T.S. Kemp, in: Mammal-Like Reptiles and the Origin of Mammals,
Academic Press, 1982, 363 pp.
[45] H. Kunzle, S. Raddtke-Schuller, Cortical connections of the claus-
trum and subjacent cell groups in the hedgehog tenrec, Anat.
Embryol. 203 (2001) 403–415.
´
[46] E. Lanuza, M. Belekhova, A. Martınez-Marcos, C. Font, F. Mar-
´ ´ Identification of the reptilian basolateral amygdala:an
tınez-Garcıa,
anatomical investigation of the afferents to the posterior dorsal
ventricular ridge of the lizard Podarcis hispanica, Eur. J. Neurosci.
10 (1998) 3517–3534.
´
[47] E. Lanuza, A. Martınez-Marcos, ´ ´ What is the
F. Martınez-Garcıa,
amygdala? A comparative approach, Trends Neurosci. 22 (1999)
207.
[48] P. Lavenex, D.G. Amaral, Hippocampal-neocortical interaction: a
hierarchy of associativity, Hippocampus 10 (2000) 420–430.
[49] Z.X. Luo, A.W. Crompton, A.L. Sun, A new mammalia form from
the early jurassic and evolution of mammalian characteristics,
Science 292 (2001) 1535–1540.
[50] G. Lynch, in: Synapses, Circuits, and the Beginnings of Memory,
MIT Press, Cambridge, MA, 1986, 122 pp.
[51] A. Mallamaci, R. Iannone, P. Briata, L. Pintonello, S. Mercurio, E.
Boncinelli, G. Corte, EMX2 protein in the developing mouse brain
and olfactory area, Mech. Dev. 77 (1998) 165–172.
[52] H. Mannen, S.S.L. Li, Molecular evidence for a clade of turtles,
Mol. Phylogenet. Evol. 13 (1999) 144–148.
[53] S. Maren, Long-term potentiation in the amygdala: a mechanism for
emotional learning and memory, Trends Neurosci. 22 (1999) 561–
566.
´
[54] F. Martınez-Garcıa,´ A. Martınez-Marcos,
´ E. Lanuza, The pallial
amygdala of amniote vertebrates: evolution of the concept, evolution
of the structure, Brain Res. Bull. 57 (2002) 463–469.
[55] A.J. McDonald, Cortical pathways to the mammalian amygdala,
Progr. Neurobiol. 55 (1998) 257–332.
[56] L. Medina, A. Reiner, Do birds possess homologues of mammalian
primary visual, somatosensory and motor cortices?, Trends Neuro-
sci. 23 (2000) 1–12.
[57] C.B. Moens, S.P. Cordes, M.W. Giorgianni, G.S. Barsh, C.B.
Kimmel, Equivalence in the genetic control of hindbrain segmenta-
tion in fish and mouse, Development 125 (1998) 381–391.
[58] V.M. Montero, Retinotopy of cortical connections between the
striate cortex and extrastriate visual areas in the rat, Exp. Brain Res.
94 (1993) 1–15.
[59] C.E. Myers, M.A. Gluck, Cortico-hippocampal representations in
simultaneous odor discrimination: a computational interpretation of
Eichenbaum, Mathews and Cohen (1989), Behav. Neurosci. 110
(1996) 685–706.
[60] W.H.J. Nauta, H.J. Karten, A general profile of the vertebrate brain,
with sidelights on the ancestry of the cerebral cortex, in: F.O.
Schmitt (Ed.), The Neurosciences, Second Study Program, Roc-
kefeller University Press, New York, USA, 1970, pp. 7–26.
[61] R.G. Northcutt, J.H. Kaas, The emergence and evolution of mam-
malian neocortex, Trends Neurosci. 18 (1995) 373–379.
[62] R.G. Northcutt, The origin of craniates: neural crest, neurogenic
placodes, and homeobox genes, Israel J. Zool. (suppl.) 42 (1996)
273–313.
[63] S.M. O’Mara, S. Commins, M. Anderson, J. Gigg, The subiculum: a
review of form, physiology and function, Prog. Neurobiol. 64
(2001) 129–155.
[64] M. Pannese, G. Lupo, B. Kablar, E. Boncinelli, G. Barsacchi, R.
Vignali, The Xenopus Emx genes identify presumptive dorsal
telencephalon and are induced by head organizer signals, Mech.
Dev. 73 (1998) 73–83.
[65] L. Puelles, J.L.R. Rubenstein, Expression patterns of homeobox and
other putative regulatory genes in the embryonic mouse forebrain
suggests neuromeric organization, Trends Neurosci. 16 (1993) 472–
479.
[66] L. Puelles, E. Kuwana, E. Puelles, J.L.R. Rubenstein, Comparison of
the mammalian and avian telencephalon from the perspective of
gene expression data, Eur. J. Morphol. 37 (1999) 139–150.
[67] L. Puelles, E. Kuwana, E. Puelles, A. Bulfone, K. Shimamura, J.
Keleher, S. Smiga, J.L.R. Rubenstein, Pallial and subpallial deriva-
tives in the embryonic chick and mouse telencephalon, traced by the
expression of the genes Dlx-2, Emx-1, Nkx-2.1, Pax-6 and Tbr-1, J.
Comp. Neurol. 424 (2000) 409–438.
[68] L. Puelles, Thoughts on the development, structure and evolution of
the mammalian and avian telencephalic pallium, Phil. Trans. R. Soc.
London B Biol. Sci. 356 (2001) 1583–1598.
[69] J. Quiroga, The brain of the mammal-like reptile Probainognathus
jenseni (Therapsida, Cynodontia), A correlative paleo-neurological
approach to the neocortex at the reptile-mammal transition, J.
Hirnforsch. 21 (1980) 299–336.
[70] P. Rakic, Specification of cerebral cortical areas, Science 241 (1988)
170–176.
[71] P. Rakic, A small step for the cell, a giant leap for mankind: a
hypothesis of neocortical expansion during evolution, Trends Neuro-
sci. 18 (1995) 383–388.
[72] J.N.P. Rawlins, Neurobiology. A place for space and smells, Nature
397 (1999) 561–563.
[73] ´
C. Redies, M. Ast, S. Nakagawa, M. Takeichi, M. Martınez-de-la-
Torre, L. Puelles, Morphologic fate of diencephalic prosomeres and
their subdivisions revealed by mapping cadherin expression, J.
Comp. Neurol. 421 (2000) 481–514.
[74] A. Reiner, A comparison of neurotransmitter-specific and neuro-
peptide-specific neuronal cell types present in the dorsal cortex of
reptiles with those present in the isocortex of mammals, Brain.
Behav. Evol. 38 (1991) 53–91.
[75] A. Reiner, Neurotransmitter organization and connections of turtle
cortex: implications for the evolution of mammalian isocortex,
Comp. Biochem. Physiol. Comp. Physiol. 104 (4) (1993) 735–748.
[76] A. Reiner, A hypothesis as to the organization of cerebral cortex in
the common amniote ancestor of modern reptiles and mammals,
Novartis Found. Symp. 228 (2000) 83–108.
[77] O. Rieppel, R.R. Reisz, The origin and early evolution of turtles,
Annu. Rev. Ecol. Syst. 30 (1999) 1–22.
[78] ´
F. Rodrıguez, ´
J.C. Lopez, ´
J.P. Vargas, Y. Gomez, C. Broglio, C.
Salas, Conservation of spatial memory function in the pallial
forebrain of reptiles and ray-finned fishes, J. Neurosci. 22 (2002)
2894–2903.
 F. Aboitiz et al. / Brain Research Reviews 39 (2002) 141–153
[79] M.G.P. Rosa, L.A. Krubitzer, The evolution of visual cortex: where
is V2?, Trends Neurosci. 22 (1999) 242–248.
[80] D.L. Rosene, G.W. Van Hoesen, The hippocampal formation of the
primate brain, in: E.G. Jones, A. Peters (Eds.), Cerebral Cortex, Vol.
6, Plenum, New York, 1987, pp. 345–350.
[81] T. Rowe, Coevolution of the mammalian middle ear and neocortex,
Science 273 (1996) 651–654.
[82] T. Rowe, Brain heterochrony and origin of the mammalian middle
ear, Mem. Calif. Acad. Sci. 20 (1996) 71–95.
[83] E.S. Russel, in: Form and Function: A Contribution to the History of
Animal Morphology, University of Chicago Press, Chicago, IL,
1916, 383 pp.; Reprinted 1982.
˚
[84] H.C. Seo, B.O. Sætre, B. Havik, S. Ellingse, A. Fjose, The zebrafish
Pax3 and Pax7 homologues are highly conserved, encode multiple
isoforms and show dynamic segment-like expression in the develop-
ing brain, Mech. Dev. 70 (1998) 49–63.
[85] T. Shimizu, H.J. Karten, Multiple origins of neocortex: contributions
of the dorsal ventricular ridge, in: H.P. Zeigler, J.H. Bischof (Eds.),
Vision, Brain and Behavior in Birds, MIT Press, Cambridge, MA,
1993, pp. 75–86.
[86] A. Simeone, M. Gulisano, D. Acampora, A. Stornaiuolo, M.
Rambaldi, E. Boncinelli, Two vertebrate homeobox genes related to
the Drosophila empty spiracles gene are expressed in the embryonic
cerebral cortex, EMBO J. 11 (1992) 2541–2550.
´
[87] A. Smith Fernandez, ´
C. Pieau, J. Reperant, E. Boncinelli, M.
Wassef, Expression of the Emx-1 and Dlx-1 homeobox genes define
three molecularly distinct domains in the telencephalon of mouse,
chick, turtle and frog embryos: implications for the evolution of
telencephalic subdivisions in amniotes, Development 125 (1998)
2099–2111.
[88] H. Stephan, Evolutionary trends in limbic structures, Neurosci.
Biobehav. Rev. 7 (1983) 367–374.
[89] A. Stoykova, D. Treichel, M. Hallonet, P. Gruss, Pax 6 modulates
the dorsoventral patterning of the mammalian telencephalon, J.
Neurosci. 20 (2000) 8042–8050.
[90] G.F. Striedter, The telencephalon of tetrapods in evolution, Brain
Behav. Evol. 49 (1997) 179–213.
[91] G.F. Striedter, A. Marchant, S. Beydler, The ‘neostriatum’ develops
as part of the lateral pallium in birds, J. Neurosci. 18 (1998)
5839–5849.
` E. Soriano, H.B.M. Uylings, The functions of the preplate
[92] H. Super,
in development and evolution of the neocortex and hippocampus,
Brain Res. Brain Res. Rev. 27 (1998) 40–64.
153
[93] L. Sussel, O. Marın,´ S. Kimura, J.L. Rubenstein, Loss of Nkx 2.1
homeobox gene function results in a ventral to dorsal molecular
respecification within the basal telencephalon: evidence for a
transformation of the pallidum into striatum, Development 126
(1999) 3359–3370.
[94] L.W. Swanson, Cerebral hemisphere regulation for motivated be-
havior, Brain Res. 886 (2000) 113–164.
[95] L.W. Swanson, G.D. Petrovich, What is the amygdala?, Trends
Neurosci. 21 (1998) 323–331.
[96] H.J. Ten Donkelaar, Reptiles, in: R. Nieuwenhuys, H.J. Ten
Donkelaar, C. Nicholson (Eds.), The Central Nervous System of
Vertebrates, Vol. 2, Springer, Berlin, 1998, pp. 1316–1524.
[97] P.S. Ulinski, in: Dorsal Ventricular Ridge: A Treatise on Brain
Organization in Reptiles and Birds, Wiley, New York, 1983, 284 pp.
[98] P.S. Ulinski, The cerebral cortex of reptiles, in: E.G. Jones, A. Peters
(Eds.), Cerebral Cortex, Vol. 8A, Plenum, New York, 1990, pp.
217–265.
[99] T. Van Groen, I. Kadish, J.M. Wyss, Species differences in the
projections from the entorhinal cortex to the hippocampus, Brain
Res. Bull. 57 (2002) 553–556.
[100] G.W. Van Hoesen, The parahippocampal gyrus. New observations
regarding its cortical connections in the monkey, Trends Neurosci.
10 (1982) 345–350.
[101] J. Voogd, R. Nieuwenhuys, P.A.M. Van Dongen, Mammals, in: R.
Nieuwenhuys, H.J. Ten Donkelaar, C. Nicholson (Eds.), The
Central Nervous System of Vertebrates, Vol. 3, Springer, Berlin,
1998, pp. 1638–2097.
[102] M.P. Witter, Organization of the entorhinal-hippocampal system: a
review of current anatomical data, Hippocampus 3 (1993) 33–44.
[103] M.P. Witter, P.A. Naber, T. Van Haeften, W.C. Machielsen, S.A.
Rombouts, F. Barkhof, P. Scheltens, F.H. Lopes da Silva, Cortico-
hippocampal communication by way of parallel parahippocampal-
subicular pathways, Hippocampus 10 (2000) 398–410.
[104] E.R. Wood, P.A. Dudchenko, H. Eichenbaum, The global record of
memory in hippocampal neuronal activity, Nature 397 (1999)
613–616.
[105] M.S. Yoon, L. Puelles, C. Redies, Formation of cadherin-express-
ing brain nuclei in diencephalic and alar plate divisions, J. Comp.
Neurol. 421 (2000) 461–480.
[106] R. Zardoya, A. Meyer, The evolutionary position of turtles revised,
Naturwissenschaften 88 (2001) 193–200.