Evolutionary divergence of the reptilian and the mammalian brains: considerations on connectivity and development

Brain Research Reviews 39 (2002) 141–153www.elsevier.com/ locate/brainresrev

Review

E volutionary divergence of the reptilian and the mammalian brains:considerations on connectivity and development

a , a b a,c*Francisco Aboitiz , Juan Montiel , Daniver Morales , Miguel Conchaa ´ ´Programa de Morfologıa, Instituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile

bDevelopmental Neurobiology Laboratory, The Rockefeller University, New York, NY, USAcDepartment 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 longcontroversies regarding possible homologues of this structure in reptiles and birds. The brains of the latter are characterized by thepresence of a structure termed dorsal ventricular ridge (DVR), which receives ascending auditory and visual projections, and has beenpostulated 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 arisemostly from the dorsal pallium (in mammals, the ventral pallium relates to the claustroamygdaloid complex). Although it is possible thatin mammals the embryonic ventral pallium contributes cells to the developing isocortex, there is no evidence yet supporting thisalternative. The possibility is raised that the expansion of the cerebral cortex in the origin of mammals was product of a generalizeddorsalizing influence in pallial development, at the expense of growth in ventral pallial regions. Importantly, the evidence suggests thatorganization of sensory projections is significantly different between mammals and sauropsids. In reptiles and birds, some sensorypathways project to the ventral pallium and others project to the dorsal pallium, while in mammals sensory projections end mainly in thedorsal pallium. We suggest a scenario for the origin of the mammalian isocortex which relies on the development of associative circuitsbetween 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 .......................................................................................................................................... 1422 . The pallium of amniotes........................................................................................................................................................................... 1433 . Connectional and neurochemical comparisons: the recapitulation hypothesis................................................................................................ 1434 . Conflicting connectional evidence: the outgroup hypothesis ........................................................................................................................ 1455 . Developmental criteria ............................................................................................................................................................................. 145

5 .1. Other components of the DVR ......................................................................................................................................................... 1475 .2. Dorsoventral gradients and their relation to the IT/VP ....................................................................................................................... 147

6 . Different patterns of brain organization in reptiles and mammals ................................................................................................................ 1487 . 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. Box114-D, Santiago 1, Chile. Fax:156-2-665-1951.

E-mail address: [email protected](F. Aboitiz).

0165-0173/02/$ – see front matter 2002 Elsevier Science B.V. All rights reserved.PI I : S0165-0173( 02 )00180-7

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8 . Final comment ........................................................................................................................................................................................ 150Acknowledgements ...................................................................................................................................................................................... 151References................................................................................................................................................................................................... 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 theunique to the brain of mammals in several respects. First, it mammalian isocortex, it is fundamental to determinehas undergone an enormous expansion, especially in the which ancestral structure(s) gave rise to it. Althoughtangential domain [70]. Second, it has a six-layered obviously the ancestor is unavailable to study, there arearchitecture which differs from the three-layered array of sister taxa (reptiles and birds) whose brains can besimpler telencephalic laminar structures such as the hip- compared with those of mammals in order to infer thepocampal formation, the olfactory cortex and the reptilian characteristics of the common ancestor. Commonly usedcortices [3,92]. On the other hand, the telencephalon of criteria for determining neural homology are connectivityreptiles has a small, thin cortex and a prominent periven- [42,43,56], neurochemistry [74,75], topographical locationtricular 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 theThere 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 possiblecomplicated by the intricate topography of the hemispheres correspondence between the reptilian dorsal cortex and thein some vertebrate classes, and by the absence of a unified mammalian isocortex, and will review recent molecularcriterion to establish neural homology. Homology is a evidence supporting this interpretation. Then, the generalcentral problem to comparative anatomy, since the organization of the mammalian and reptilian brains will beevolutionary considerations regarding the origin and di- discussed in light of these new findings, and we willversification 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 subpalliumis 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 onlyin turtles); STR, striatum. Medial is to the left.

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Our main argument along this paper is that the evidence on the isocortex has a dual origin, part of it deriving from theregulatory gene expression provides a notable example of reptilian dorsal cortex, and the other part deriving from thehow molecular developmental biology may help to clarify DVR (especially the ADVR). An alternative hypothesisimportant issues in the evolution of the nervous system. suggests that the isocortex derives mostly from the re-

ptilian dorsal pallium, and has been called the outgrouphypothesis [1,2,4,61,68,90]. Below, we will summarize

2 . The pallium of amniotes some of the evidence favouring each of the two possi-bilities.

The reptilian pallium has a three-layered cortex, consist-ing of a medial and a dorsomedial component (bothcomparable to the mammalian hippocampal formation), adorsal cortex and a lateral or olfactory cortex [98] (Fig. 1). 3 . Connectional and neurochemical comparisons: theIn birds, there is a medial hippocampus and a lateral recapitulation hypothesisolfactory cortex. The avian dorsal cortex is a relativelycomplex, multilaminated structure called the Wulst. The Before comparing the sensory systems of reptiles andreptilian dorsal cortex and the Wulst of birds receive visual mammals, it will be useful to briefly discuss some aspectsprojections as well as some somatosensory input [56]. of thalamic connectivity. Thalamic sensory nuclei have

Additionally, in reptiles and birds (together are called been recently classified in two main classes: lem-sauropsida), many non-olfactory sensory projections termi- nothalamic and collothalamic [16,17]. Lemnothalamicnate in the dorsal ventricular ridge (DVR; Fig. 1), which nuclei receive projections from lemniscal systems whichbulges into the lateral ventricle above the basal ganglia do not synapse in the midbrain (see Fig. 2). Examples of[96,97]. The DVR is the most expansive telencephalic lemniscal pathways are the somatosensory pathways thatcomponent of reptiles and birds and is a main integratory use the spino-thalamic route, and the visual thalamofugalcenter in their brains. It consists of an anterior part pathway that goes directly from the retina to the dorsal(ADVR) and a posterior or basal part (PDVR). The ADVR lateral geniculate nucleus. Collothalamic nuclei receive(which in birds corresponds to the hyperstriatum ventrale, sensory pathways that synapse in the midbrain colliculineostriatum and ectostriatum) receives much of the sensory (optic tectum and torus semicircularis; Fig. 2). The mostinput, and its output is directed mainly to the corpus prominent of the collicular pathways are the visual tec-striatum and to the PDVR. The latter (corresponding to the tofugal pathway, which originates in the retina and relaysarchistriatum in birds) has been compared to parts of the in the optic tectum, projecting then to the thalamic nucleusmammalian amygdala and projects to the hypothalamus rotundus of sauropsids (‘R’ in Fig. 2) or the pulvinar[46,47,96]. nucleus of mammals (‘P’ in Fig. 2); and the auditory

On the other hand, the pallium of mammals mainly pathway, which synapses in the inferior colliculus/ torusconsists of a hippocampal formation (archicortex), an semicircularis and in the thalamic medial geniculate body.olfactory cortex (paleocortex) and an isocortex or neocor- Lemnothalamic nuclei project to the dorsal cortex oftex interposed between them. There is also a claus- sauropsids and to dorsomedial aspects of the isocortex oftroamygdaloid complex that contains both pallial and mammals (i.e., primary visual and somatosensory cortices),subpallial elements. The isocortex receives most of the while collothalamic nuclei project to the ADVR of saurop-ascending sensory input from the thalamus and projects to sids and to ventrolateral isocortical regions of mammalsthe hippocampus and to the amygdala, as well as sending (i.e., visual extrastriate and auditory cortices) [16,17].output to several lower brain centers including the corpus On the basis of similarities in sensory projection sys-striatum, thalamus, several brainstem nuclei and the spinal tems, some investigators [43,56,60,85] proposed that thecord. During development, the isocortex originates at least dorsal cortex of reptiles is homologous to the primaryin large part from the dorsal pallium [61,70,71] (see also (striate) visual cortex, and to the somatosensory and motorRef. [4]). Recent studies indicate that additionally, cells cortices of mammals since they all receive lemnothalamicoriginating in the embryonic corpus striatum migrate projections (see Fig. 1). Furthermore, as the auditorytangentially in a dorsal direction and become incorporated radiation and the tectofugal visual pathway (both col-into the isocortex and the hippocampus, mostly as lothalamic) end in the avian/ reptilian ADVR, and in theGABAergic interneurons [10,12,39]. Tangential migration mammalian auditory and extrastriate visual cortices, theof inhibitory neurons from the subpallium has been DVR was considered to be homologous to the ventrolateralrecently described in birds [20], which suggests that this isocortex [41–43,60,85]. The point of this hypothesis ismechanism pre-dates the common ancestor of mammals that the common ancestor to both reptiles and mammalsand sauropsids. had a reptilian-like brain, perhaps already with a DVR or

Which reptilian structures correspond to the mammalian with a primordial component which developed into a trueisocortex? One hypothesis—which has been termed the DVR in sauropsids, while in the line leading to mammalsrecapitulation hypothesis [41–43,60,61]—postulates that this component was transformed into lateral isocortex [76].

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Fig. 2. Diagrams summarizing some visual projections in reptiles and in mammals, which illustrate the differences between collicular and lemniscalsensory pathways. Visual projections originate in the retina (RET) and project in two separate pathways. The lemniscal pathway (in purple) is directed tothe 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 dorsalventricular 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] considerthat it is a derived character of mammals, with no clear homologue in sauropsids. The reptilian dorsal cortex (DCx) has connections with the M/DMCx. Inmammals,V1 exerts control over the ESt; all sensory isocortical areas indirectly project to the hippocampus (HIP). The reptilian posterior dorsal ventricularridge (PDVR) is related to parts of the mammalian amygdalar system and receives projections from the ADVR. In mammals, the collicular pathwayprojects to the amygdala (AM) after a thalamic relay. DL, VM, dorsolateral and ventromedial components of the ADVR.

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4 . Conflicting connectional evidence: the outgroup (isocortex) either arose de novo in mammals, or existed inhypothesis the common ancestor to reptiles and mammals and were

subsequently lost in the dorsal cortex of sauropsids.As mentioned, the outgroup hypothesis implies that the

isocortex arises mostly from the dorsal pallium, i.e., ismost likely homologue to the reptilian dorsal cortex. First, 5 . Developmental criteriawe will briefly review some connectional evidence point-ing to important differences between the reptilian ADVR Another and long used homology criterion is develop-and the mammalian isocortex. For example, some authors mental origin. Many authors have argued that the general-[14,21,32,68,73,105] have recently claimed that in terms of ized morphology and topographic relations are shown mostoverall connectivity, the ADVR is more similar to some clearly in early developmental stages, which facilitatesregions of the claustroamygdalar complex of mammals, cross-species comparisons [30,62,83,90]. This assumptionthan to the ventrolateral isocortex. Both the ADVR and the is valid in cases in which there is cross-species conservat-mammalian laterobasal amygdala receive collothalamic ism of embryonic processes while adult morphology tendsprojections, and both project to the ipsilateral cortex, the to diverge. Alternatively, in cases of embryological di-corpus striatum and the subpallial amygdala. On the other versity with adult conservatism, comparison of adulthand, the isocortex projects to many other brain regions structures and relations may provide a more accuratebeside these. As a consequence, the thalamic nucleus diagnosis for homology [2,4]. In the case of the amnioterotundus (‘R’ in Fig. 2) of sauropsids has been considered telencephalon, phylogenetic evidence points to a notableby these authors to be more comparable to the intralaminar conservation of early embryonic structure with adultnuclei of mammals (which receive collothalamic input and diversification [2,4,90], which puts weight on embryologi-project to the lateral amygdala) than to the mammalian cal comparisons as a reliable homology criterion.pulvinar (‘P’ in Fig. 2). There are two other important Studies indicate that during embryogenesis, the ADVRdifferences in connectivity between the ventrolateral iso- develops from the lateral aspect of the pallium, in acortex and the ADVR, which need to be mentioned here. position deep (in the radial direction) and ventral to theThe first is that the primary visual cortex of mammals olfactory cortex [40,91]. On the other hand, most of theprojects densely to the extrastriate visual cortex (especially isocortex is considered to originate from the dorsal palliumV2) [58,79], while in reptiles, projections from the dorsal (excepting the above-mentioned tangentially migratingcortex to the ADVR are considered to be much weaker GABAergic cells that originate in the subpallium). This[96,98]. Second, the mammalian isocortex projects re- evidence was initially claimed to support the hypothesis ofciprocally to the entorhinal cortex and from there to the non-homology between the ADVR and the isocortexhippocampus [36,80,100], while in reptiles few if any [1,2,4,90]. Furthermore, studies of expression patterns ofconnections have been reported from the ADVR to the regulatory homeobox-like genes in the embryonic fore-hippocampus [96–98]. Finally, despite the similarities in brain have revealed a conserved mosaic organization insensory connectivity between the ventrolateral isocortex which the different compartments develop into specificand the ADVR, it is important to note that sensory brain components in the adult [31,57,65,84]. In the em-pathways may not always end in comparable structures. In bryonic mammalian telencephalon, distinct geneticamphibians, collothalamic pathways terminate mainly in markers for pallial and for subpallial regions have beenthe corpus striatum, which is clearly not homologue of detected. For instance, the corpus striatum (Fig. 3) ariseseither the isocortex or the ADVR [16]. Therefore, only from the embryonic lateral and medial ganglionic emi-some sets of connections are similar between the lateral nences, which are located in the lateral subpallium andisocortex and the ADVR; and these that are similar (inputs express the marker genesDlx1 and Dlx2 [11]. Thefrom collicular pathways) are reported to end mainly in the cerebral cortex arises mostly from the embryonic palliumsubpallium of amphibians, which is not homologue of and is characterized by the expression of genes of theEmx,

´either the ADVR or the isocortex. Otx and Pax families [8,51,64,65,86]. Smith Fernandez etSummarizing, the hypothesis of homology between the al. [87] confirmed these findings for amphibians, reptiles

lateral isocortex and the DVR (recapitulation hypothesis) and birds, showing that the amphibian dorsal pallium, theassumes that the sensory pathways associated to midbrain reptilian dorsal cortex and the avian Wulst express thecolliculi end in the same targets in reptiles and mammals, same pallial markers as the isocortex. These authors alsowhile the gross morphology of these targets (isocortex and identified for the first time an intermediate territory (IT;DVR) has diverged in these two taxa. On the other hand, see Fig. 3) in the equatorial region of the hemisphere,the alternative possibility of non-homology between iso- located according to them between the pallium and thecortex and DVR (outgroup hypothesis) implies that collicu- subpallium of amphibians, reptiles, birds and mammals,lar pathways have changed their targets in the course of which does not express either theEmx1 or Dlx1 markersreptilian and mammalian divergence. If this hypothesis is but is largely positive for the genePax6 [87]. More recentcorrect, collothalamic projections to the dorsal pallium reports [66,67] have confirmed the existence of the IT

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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 genesEmx1/2, Otx1/2, Pax6 andTbr1, 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 largelynegative for the genesEmx1/2 and Otx1/2, but positive forPax6 and Tbr1. The IT/VP gives rise to the anterior dorsal ventricular ridge (ADVR) ofreptiles, to the neostriatum (N) of birds (which corresponds to a large part of the ADVR), and to the laterobasal amygdala and ventral claustrum (AM) ofmammals. The subpallium (white) expressesDlx-type genes during embryogenesis and gives rise to the corpus striatum (STR) among other structures. Ineach 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 zones, disappearing from the neuroepithelial surface [87].authors), extending its definition by showing that, like Somewhat in agreement with this, Swanson [94] hasother pallial regions, the IT/VP also expresses the regula- proposed that the claustral complex of mammals (includ-tory marker geneTbr1. ing the basolateral amygdala, the claustrum, the endo-

Parts of the olfactory cortex, the olfactory bulbs, the piriform nucleus and isocortical layers 6b-7) is an early-basolateral amygdalar complex, and the ventral claustrum produced component, embryologically related to the sub-(among other regions) of mammals derive from the IT/VP plate or a subplate-like structure (see also Ref. [45]). If[67,87]. On the other hand, part of the lateral cortex, the these interpretations are true, most late-produced com-olfactory bulb and an important part of the reptilian ADVR ponents of the ADVR might not have a strict homologue inand of the avian neostriatum develop from the IT/VP (Fig. the mammalian isocortex.3). This molecular evidence has been considered to This evidence poses a serious challenge to the recapitu-strongly support the early suggestions of non-homology lation hypothesis of homology between the ventrolateralbetween the isocortex and the ADVR (outgroup hypoth- isocortex and the ADVR [41–43], since it requires that inesis) [1,2,4], and proposals of homology between the mammals the IT/VP contributes cells to isocortical de-reptilian ADVR and parts of the mammalian claus- velopment. However, the topographic location of the IT/troamygdalar complex [14,34,90]. It is of interest to note VP is such that the lateral (olfactory) cortex is interposedthat Holmgren [34] originally named the sauropsidian between it and the isocortex. Thus, a massive tangentialDVR and the mammalian claustroamygdaloid regions as migration of neurons from the IT/VP to the dorsalthe ‘hypopallium’, which definitely agrees with the molec- pallium, producing the visual extrastriate and the auditoryular findings. cortices would be needed if the recapitulation hypothesis is

´Smith Fernandez et al. [87] argued that in reptiles and correct. The evidence that many isocortical GABAergicbirds, the IT/VP remains as a distinct neuroepithelial zone cells originate in the subpallial corpus striatum and migrateuntil late development, period in which it gives rise to dorsally into the isocortex [10], raises the possibility thatmost of the ADVR. On the contrary, in mammals this some cells from the IT/VP also migrate to the dorsalterritory was described as producing only the above pallium. Just like cells from the ganglionic eminences thatmentioned early-generated components. In later embryonic migrate tangentially into the isocortex keep expressingstages, the mammalian IT/VP is considered to be obliter- theirDlx1 subpallial marker [10,12], if cells from theated between theEmx1-positive and theDlx1/2-positive IT/VP migrate tangentially into the isocortex they might

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maintain their molecular identity. This would make the 5 .2. Dorsoventral gradients and their relation to the IT /auditory and visual extrastriate cortices largely negative for VPEmx1. However, recent studies indicate thatEmx1 can beconsidered as a marker of practically all pyramidal cells in In this context, it is important to note that the regulationthe cerebral cortex, and of most glutamate-containing of distinct transcription factors may produce overall effectsneurons in dissociated cortical cultures [19], something in the dorsoventral patterning of the hemispheres. Forthat would be unexpected if the ventrolateral isocortex example, inNkx2.1 loss of function mutants, a dorsaliza-(including auditory and visual extrastriate cortices) were tion of the basal ganglia is observed, in which the striatumlargely negative to this gene. Up to this point, no evidence is enlarged at the expense of the development of the morehas been reported of a massive migration from the IT/VP ventral pallidum [93]. On the other hand, in thePax6into the developing isocortex. mutant, a ventralization of the developing basal ganglia is

observed in which the medial ganglionic eminence ex-5 .1. Other components of the DVR pands into the territory of the more dorsally located lateral

ganglionic eminence, which results in underdevelopmentThe DVR is quite a complex structure which has many of the striatum [89]. In this mutant, there is also a dorsal

intriguing components. We will discuss two of these, the displacement of the limits of expression for marker geneshyperstriatum ventrale of birds, and the posterior DVR, such asEmx1, Tbr1, Shh, Dlx1, Nkx2.1 and others,which has been sometimes termed the ‘reptilian producing malformations in the claustrum, endopiriformamygdala’. The avian hyperstriatum ventrale (a structure nucleus, insular cortex and piriform/ lateral cortex. Finally,located ventral to the Wulst, which has been considered to the isocortex is also severely disrupted, presumably due tobelong to the avian DVR), expressesEmx1 during de- failure of differentiation and migration of corticalvelopment (Fig. 3), suggesting that it may derive from the progenitors, especially late-produced neurons in the ven-dorsal or lateral pallium and not from the IT/VP [66,87]. trolateral pallium [28,89]. Another observation is that theIn subsequent articles, Puelles et al. [67] and Guirado et al.Pax6 2 /2 mutant develops a dorsal ventricular ridge-like[32] subdivide the reptilian ADVR into dorsolateral and structure in the lateral pallium [18], which according to theventromedial moieties (Fig. 2). These components would authors may consist of cells that failed to migrate to thecorrespond to the hyperstriatum (which isEmx1 positive) lateral isocortex and other regions. However, this DVR-and the neostriatum (Emx1 negative) of birds, respectively. like structure may derive of subpallial components and ofThese authors further argue that the hyperstriatum/dorsola- components originating in the dorsal, lateral and ventralteral component of the avian/ reptilian ADVR (Emx1 pallium (all positive toPax6 and dependent on this genepositive) might correspond to the mammalian dorsolateral for migration). If this is the case, it may not be strictlyclaustrum, the dorsal endopiriform nucleus and the ba- comparable to the sauropsidian DVR, which originatessomedial amygdala (and perhaps some elements of the mostly from the ventral pallium.lateral isocortex). On the other hand, the neostriatum/ The above evidence may suggest that in the evolution ofventromedial component of the ADVR (Emx1 negative) the vertebrate pallium, expansion of the domains ofcorresponds to the ventromedial claustrum, ventral endo- expression of regulatory genes, produced by overall dor-piriform nucleus and laterobasal amygdala of mammals. salizing or ventralizing factors, may have had a key

One additional issue concerns the homologies between influence in the origin of new brain architectures such asparts of the mammalian amygdalar complex and the that of mammals. For example, it is possible that in thereptilian PDVR/avian archistriatum. Some authors [54,95] origin of the isocortex, the IT/VP was dwarfed as adivide the amygdala into pallial (cortical and basolateral consequence of some dorsalizing influence that enhancedamygdala) and subpallial (central and medial amygdala) Emx1 expression and was concomitant with the emergence

´moieties. According to Smith Fernandez et al. [87], the and expansion of the isocortex. Nevertheless, only areptilian PDVR and the avian archistriatum express pallial change in boundaries may not be sufficient for the expan-markers and are comparable to the corticomedial and sion of the mammalian isocortex. Substantial increases incentral amygdala of mammals, while Puelles et al. [66] cell proliferation within the territory destined to the dorsalargue that only the posterior archistriatum is pallial. An pallium were probably required to produce the enormousadditional interpretation, based on hodological studies, is growth of this structure in early and late mammalianthat the reptilian PDVR is homologue to the mammalian evolution.laterobasal amygdala [46]. Dubbeldam [23] claims that the In an argumentation in favor of homology between theavian archistriatum consists of a sensorimotor moiety that mammalian isocortex and the reptilian ADVR, Reiner [76]receives projections from the ADVR, and an ‘amygdalar’ has proposed that the structure ancestral to both ADVRmoiety. Perhaps further embryological studies will help and ventrolateral isocortex was eitherEmx1 negative andclarify the compartmentalization and homologies of the acquiredEmx1 expression in the origin of mammals, or itmammalian amygdala and the reptilian PDVR/avian ar- wasEmx1 positive and lostEmx1 expression in thechistriatum. evolution of reptiles and birds. In our view, shifts in the

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boundaries of distinct telencephalic territories could cer- sory information: one receiving mainly olfactory andtainly happen, with the result that cell groups that were lemnothalamic information, which is connected with theinitially destined to one compartment become incorporated hippocampus, and the other, receiving mainly col-into another, without need of tangential migration of its lothalamic information (and some lemnothalamic infor-cellular constituents. However, in most reptiles the topog- mation), which is more related to the amygdalar systemraphic relation between the IT/VP and the isocortex is (see Fig. 2).such that the lateral cortex is interposed between them In many mammals, the primary visual cortex (with[1,2,66,67], so that a mere shift in gene expression lemnothalamic input) projects heavily into extrastriateboundaries may perhaps not be sufficient to transform the areas (especially V2), and these to higher-order visualIT/VP into an isocortical area. The only exception to this cortices. Since extrastriate and higher-order visual areassituation may be the turtle dorsal cortex, which develops a also receive collicular input (via the pulvinar nucleus),structure called pallial thickening (Fig. 1), located deep to there is an important degree of convergence betweenthe olfactory cortex, and topographically between the lemniscal and collicular pathways (Fig. 2). Both pathwaysdorsal cortex and the ADVR. Although definitely not an eventually route their information to the hippocampus andIT/VP derivative [87], the pallial thickening deserves amygdala. Although there are some species differences infurther embryological studies. It is possible that the pallial hippocampal connectivity, most species show similarthickening is a derived character of turtles, which may be overall patterns of connections [99]. In the rat and in thesupported by recent phylogenetic analyses indicating that monkey, nearly all areas in the neocortical mantle (visual,turtles are a rather modified group of diapsid reptiles, and auditory and somatosensory) are bidirectionally connectedunrelated to ancestral reptiles [52,77,106]. 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

6 . Different patterns of brain organization in reptiles somatosensory information is transmitted to the mam-and mammals malian amygdala by a series of modality-specific cortico-

cortical pathways [55]. These two structures, the hip-As opposed to sauropsids, in which lemniscal and pocampus and the amygdala, process different types of

collicular sensory pathways are largely (but not totally) mnemonic information (spatial and emotional, respective-separated in the dorsal cortex and the ADVR, in the ly) [50,53]. Thus, the mammalian hippocampus maymammalian isocortex there is a strong confluence of the receive a much heavier sensory projection than is the caselemniscal and collicular pathways, especially in the case of in reptiles and birds, who may rely more on amygdalarthe visual pathways. This suggests different patterns of components (PDVR/archistriatum) than on the former tobrain organization in mammals and in reptiles /birds (Fig. process certain types of mnemonic information. For exam-2). ple, although the hippocampus of sauropsids is known to

In reptiles and birds, the collicular pathways are appar- be involved in spatial memory as it is in mammals [78], inently more important to perception and anatomically more birds not all forms of spatial memory depend on therobust than the lemniscal projections [97,98]. In reptiles, hippocampus. In homing pigeons, hippocampal lesionsthe dorsal cortex (receiving lemnothalamic projections) is disrupt certain types of spatial learning such as using thestrongly connected with the medial /dorsomedial (hip- sun compass directional information, while the capacity topocampal) and the lateral (olfactory) cortices. The ADVR, learn on the basis of landmark beacons remains sparedwhich receives most collothalamic projections, is con- [29].nected primarily to the PDVR (comparable to parts of themammalian amygdalar complex). In turtles and lizards,projections from the dorsal cortex and medial cortex into 7 . A scenario for isocortical origins: olfaction, thethe ventromedial (Emx1 negative) ADVR are sparse, but hippocampus and the thalamofugal visual systemthe pallial thickening (related to the dorsal cortex) and therostrolateral (somatosensory) dorsal cortex are reciprocally The reviewed evidence provides important insights intoconnected to the dorsolateral ADVR (Emx1 positive) [32]. the developmental mechanisms leading to the evolutionaryTherefore, some integration or convergence of lem- emergence of the isocortex. However, an equally importantnothalamic and collothalamic pathways may occur in the question (but more difficult to address) concerns thedorsolateral ADVR (Fig. 2). Both the ventromedial ADVR functional context in which these transformations tookand the dorsolateral ADVR project to the PDVR, in which place. In other words, we might ask what are the be-convergence of different sensory modalities may occur, as havioral correlates of the expansion of the dorsal palliumit also happens in the mammalian amygdala. The PDVR and the lemnothalamic visual pathway in early mammals,projects to hypothalamic nuclei, perhaps modulating social and of the IT/VP and the collothalamic visual pathway inand aggressive behavior and visceral responses [46]. sauropsids. We postulate that the divergent evolution of theSummarizing, in the telencephalon of reptiles and birds brains of reptiles and mammals was related to emphasis ontwo relatively separate systems exist for processing sen- different strategies for processing sensory information.

F. Aboitiz et al. / Brain Research Reviews 39 (2002) 141–153 149

In an attempt to shed some light on this problem, we cues (like odors) may be used in the elaboration of spatialsuggest below that the mammalian isocortex originated in maps in the mammalian and reptilian hippocampi, andthe dorsal pallium by virtue of the relations of the dorsal possibly in mammalian ancestors. Furthermore, more thancortex with the medial /dorsomedial cortex (hippocampus) being strictly involved in spatial memory, the hippocampusand the olfactory cortex (Fig. 2), and their participation in has been recently considered to be crucial for storinghippocampal episodic and spatial memory [1]. Briefly, in episodic memory, that is, the remembrance of behaviorallyearly mammals spatial memory may have strongly de- relevant events and sequences of events, from whichpended on nonspatial clues like olfaction to develop maps spatial maps and other forms of memory emerge [27].of space. For example, odors may permit to recognize Therefore, these olfactive–hippocampal networks mayspecific places and routes made by the animal in its daily have participated in rather broad aspects of memoryroutine. Thus, the circuit connecting olfactory cortex and formation beside purely spatial memory.hippocampus may have been quite important for the We postulate that the lateral, dorsal, and medial corticesbehavior of early mammals. With the colonization of were put to use by the first mammals to make relativelydiurnal niches after the demise of dinosaurs, the visual elaborate, largely olfactory-based representations of spacesystem perhaps became also important for spatial memory. and other behaviorally relevant items, in which specificIn this condition, the dorsal cortex of early mammals, odors labeled particular objects, places and routes. As-originally receiving visual and somatosensory lem- sociative networks between the dorsal cortex and thenothalamic input, may have become progressively in- olfactory system, via the hippocampus, may have becomevolved in associative networks for hippocampal memory. increasingly important in these animals to develop mul-This may have triggered the expansion of the dorsal cortex tisensorial maps of space. Eventually, the contribution ofinto an isocortex, which also begun to receive collicular the visual system became undoubtedly necessary in thevisual and auditory information to participate in associative elaboration of more precise maps of space. The dorsalnetworks with other sensory modalities. cortex, receiving visual information from the thalamofugal

This proposal is partly based on Lynch’s [50] original visual pathway, may have thus become an importanthypothesis of the origin of the isocortex, and assumes that sensory processing system in the early mammalian brainthe development of olfaction was a key event in early [1]. Other parts of the isocortex (visual extrastriate andmammalian evolution. It has been repeatedly proposed that auditory) may have originated from an expansion of thein ancestral mammals, olfaction was an important sensory dorsal cortex to accommodate the incoming mesencephalicmodality [37,38,44]. Endocasts of mesozoic mammals inputs that became increasingly involved in associativeindicate relatively large olfactory bulbs and perhaps an interactions with the primary visual cortex, and with theelevated rhinal fissure [38], suggesting a large olfactory olfactory system through the hippocampus.cortex in relation to the rest of the pallium. Likewise, in The early involvement of the primary visual cortex insmall-brained insectivores and in some marsupials, olfac- processing spatial information implies that it developed attory-related structures occupy a much larger proportion of least a crude spatial representation of the visual field. Thethe volume of the brain than is the case in larger-brained visual cortex of reptiles has a rather poor visuotopicspecies with a well-developed isocortex [25,26,88,101]. In organization, due to its tangential synaptic organizationthe subsequent evolution of early and late mammals, [1,3,4,96,98]. In these animals, visual topographic infor-olfactory and limbic (including hippocampal) structures mation is mostly processed in the optic tectum. Thescale together but in large part separately of the isocortex development of a columnar organization of the isocortex,[88], perhaps indicating that the latter has become largely associated with the increase in cellular depth and theindependent of limbic components for certain types of acquisition of an inside-out neurogenetic gradient duringsensory and motor processing. development allowed the establishment of more sophisti-

The olfactory cortex is heavily connected with the cated retinotopic maps in the primary visual cortex [1,3,5–hippocampal cortex in both reptiles and mammals. In 7]. This permitted the latter to drive the activity of otherreptiles, there is a circuit interconnecting the medial cortical areas that begun to receive visuotopically orga-(hippocampal) cortex, the dorsal cortex (receiving the nized tectofugal projections. In addition, the auditorylemnothalamic pathways) and the olfactory cortex [50,96]. projection to the cerebral cortex may have benefited fromFurthermore, there is evidence that the medial and dorsal the cortical representation of space through the elaborationcortices of reptiles participate in spatial navigation, and of a more sophisticated sound localization system (see Ref.these structures have been recently found to use nonspatial [1], and below).clues in tasks of spatial orientation [22]. Although it haslong been considered that the mammalian hippocampus7 .1. Fossil brainsencodes mainly visual spatial memory [13,72], recentfindings indicate that it also represents olfactory infor- Endocast information indicates that early mammal-likemation [24,59,104], and that there is an interleaved segre- reptiles (therapsids) had narrow, tubular hemispheres withgation of spatial and nonspatial information along the no signs of telencephalic expansion [35,44,69]. Increase inlength of this structure [33]. This suggests that nonspatial 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 inMorganucodon, expansionof the posterior part of the hemisphere can be observed. More advanced mammals likeTriconodon 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 205MYA; Triconodon, about 155 MYA;Didelphys, about 65 MYA to present.

isocortex, occurs in more recent fossil mammals like DVR. The latter appears to be related to ventral pallialHadrocodium andTriconodon [49,81,82] (Fig. 4). The full structures of mammals such as the basolateral amygdalaenlargement of the brain coincides with the detachment of and/or the endopiriform nucleus (ventral claustrum), whilethe auditory bones from the mandible to form the mam- the isocortex originates largely from the dorsal pallium.malian middle ear [49,81,82], and perhaps with the de- Connectional evidence indicating similarity of sensoryvelopment of auditory projections into the isocortex. In input in the reptilian ADVR and the mammalian auditorythis sense, expansion of the brain, which may be attributed and extrastriate isocortex is weakened by other hodologicalto cortical growth and to invasion of the collicular sensory evidence that suggests different interpretations. One im-pathways into the isocortex, was related to the develop- portant assumption held by several workers has been thatment of higher auditory acuity, perhaps in relation to more the modern reptilian brain represents a stage somewhatsophisticated spatial representation of sound sources. Inter- comparable to that of the ancestral mammals. On the otherestingly, Morganucodon, a primitive mammaliaform from hand, the developmental evidence suggests to us that thethe early Jurassic, and taxonomically intermediate between reptilian and mammalian brains may have diverged verythe above forms and smaller-brained, more primitive early in their organization. It is possible that the origin oftherapsids, shows only partial expansion of the brain. In the mammalian isocortex was partly a developmentalthis species, widening of the occipital parts of the hemi- consequence of a generalized dorsalizing tendency whichspheres can be observed [81,82] (Fig. 4), perhaps evidenc- led to the expansion of the dorsal cortex, while theing early expansion of the dorsal cortex. evolution of the sauropsidian pallium may have been

dominated by the action of some ventralizing factor,leading to the expansion of the IT/VP.

8 . Final comment The above proposals have been complemented with ascenario describing the origin of the isocortex from the

We have reviewed developmental evidence for a sepa- dorsal pallium based on the relations of this structure andrate origin of the mammalian isocortex and the reptilian the hippocampus and olfactory cortex. In our view, the

F. Aboitiz et al. / Brain Research Reviews 39 (2002) 141–153 151

Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and dif-main significance of these scenarios is that they provide anferentiation of late born striatal neurons, Neuron 19 (1997) 27–37.evolutionary framework which may guide future studies of

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Supported by FONDECYT Grant 1970294 and by a gift pallium (dorsal ventricular ridge and cortical areas), Dev. Biol. 239from EMEC S.A. and ENAEX S.A. to Francisco Aboitiz. (2001) 30–45.

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