The isocortex is a distinctive feature of mammalian brains, which has no clear counterpart in the cerebral hemispheres of other amniotes. This paper speculates on the evolutionary processes giving rise to the isocortex. As a first step, we intend to identify what structure may be ancestral to the isocortex in the reptilian brain. Then, it is necessary to account for the transformations (developmental, connectional, and functional) of this ancestral structure, which resulted in the origin of the isocortex. One long-held perspective argues that part of the isocortex derives from the ventral pallium of reptiles, whereas another view proposes that the isocortex originated mostly from the dorsal pallium. We consider that, at this point, evidence tends to favor correspondence of the isocortex with the dorsal cortex of reptiles. In any case, the isocortex may have originated partly as a consequence of an overall “dorsalizing” effect (that is, an expansion of the territories expressing dorsal-specific genes) during pallial development. Furthermore, expansion of the dorsal pallium may have been driven by selective pressures favoring the development of associative networks between the dorsal cortex, the olfactory cortex, and the hippocampus, which participated in spatial or episodic memory in the early mammals. In this context, sensory projections that in reptiles end in the ventral pallium, are observed to terminate in the isocortex (dorsal pallium) of mammals, perhaps owing to their participation in these associative networks.

This commentary focuses on the “olfactory cortices–hippocampal formation” axis, proposed by Aboitiz et al. to be that network which allowed the first mammals to create elaborate representations of space. I argue here that this neural axis can be extended to a triangle of structures which also includes the orbital cortex.

One hypothesis of isocortical evolution requires tangential migration of glutaminergic neurons. A second requires invasion of collothalamic afferents into the dorsal pallium, a territory that in sauropsids is solely lemnopallial. A third alternative is noted here – duplication of the original collopallial territory. The duplicated region would be formed by radial migration of excitatory neurons and would maintain its collothalamic innervation.

Aboitiz et al. suggest that the mammalian isocortex is derived from the dorsal cortex of reptiles and birds, and that there has been a major divergence in the connectivity patterns (and hence function) of the mammalian and reptilian/avian hippocampus. There is considerable evidence to suggest, however, that the avian hippocampus serves the exact same function as the mammalian hippocampus.

Two issues in synapsid brain evolution are discussed: the presumed structure and function of the brain of the Synapsida/Diapsida common ancestral, and the enlargement of dorsal telencephalon. Ecological niches possibly occupied by some Carboniferous tetrapods are considered in order to speculate about evolution of major telencephalic sectors. An alternative interpretation of isocortical origins, based on differences in Pax-6 expression, is suggested for discussion.

Fossil remains witness the relationship between the appearance of the middle ear and the expansion of the brain in early mammals. Nevertheless, the lack of detachment of ear ossicles in the mammaliaform Morganucodon, despite brain enlargement, points to other factors that triggered brain expansion in early mammals. Moreover, brain expansion in some early mammalian groups seems to have favored brain regions other than the cortex.

The origin of the isocortex may be seen as a series of gradual changes (each one with an adaptive value) from a reptilian-like cerebral cortex, as proposed by Aboitiz et al., or as a new dorsal pallium derivative in mammals which undergoes a surface expansion concomitant with the expansion of the dorsal tier of the dorsal thalamus.

Aboitiz and colleagues propose that the tectorotundal pathway of birds and reptiles is homologous not to the mammalian colliculopulvinar system but to the posterior complex/intralaminar nuclei. However, as outlined below, a large amount of strong evidence points to a homology of the tectorotundal and the colliculopulvinar system. This makes it likely that DVR and isocortex might be in part homologous.

The first cortically based associative circuits integrated olfactory, motivational, and motor information. Many of the neural dynamics present in these evolutionarily ancient, olfactory-motor circuits, such as the broadband frequency, phase, and amplitude modulations seen during recognition of a rewarded olfactory stimulus, are also found in isocortical circuits. These results suggest that mechanisms permitting olfactory associative processing formed the basis for evolutionarily more recent large-scale couplings involving isocortical areas.

I agree with the view expressed in the target article that the early structural organization of the mammalian neocortex (the primordial neocortical organization) is different from its final one and resembles the more primitive organization of reptilian cortex. During the early development of the neocortex, a distinctly mammalian multilayered pyramidal-cell plate is introduced within a more primitive reptilian-like cortex, establishing simultaneously layer I (marginal zone) above it and layer VII (subplate zone) below it. This multilayered pyramidal-cell plate represents a recent mammalian innovation in the evolution of the cerebral cortex of vertebrates. Hence, the term neocortex is preferable to isocortex.

A rigorous cladistic analysis of the dorsal pallium of amniotes indicates that the stem amniote lacked sensorimotor areas. Reptiles apparently acquired a visual cortex by parcellation from the multimodal, hippocampal-like mediodorsal pallium of stem amniotes. The high number of sensory areas of the mammalian isocortex might derive from the specific properties it shows, such as growth-promoting influence on thalamic axons.

An alteration in the developmental mechanisms that regulate telencephalic patterning or pallial growth may have led to an enlargement of the dorsal pallium during evolution, and to the origin of isocortex. Developmental mechanisms that may have produced a pallial enlargement, and the parallelism of this event with the enlargement of the dorsal thalamus during evolution are discussed.

The target article is an elegant synthesis of the developmental and functional data and views on the evolutionary origin of the mammalian isocortex, integrating results from cell and molecular biology, experimental neuroanatomy, and chemoarchitectonic studies. Complementarily, we give here an account of two modes of isocortical evolution (prosomere reshuffling and invention) in terms of costs of radiation and neural tissue.

Structural similarity is helpful in recognizing homologous structures, but it does not define them. Such structures must also have phylogenetic continuity, a criterion that is ignored by Aboitiz et al. and by proponents of “field homology.” “Similar” structures, as well as “field homologues” from “the same” embryonic field, are not necessarily homologous, and an outgroup analysis of developmental stages should be performed to establish homologies.

Our understanding of paleoneurology can benefit through considerations of how ontogenetic patterns of skull suture ossification can limit the phylogenetic expansion of underlying brain tissue to specific regions. Additionally, the influence of biochemical, rather than biomechanical, mechanisms on skull suture morphogenesis enable a reconceptualization of the skull as an independent evolutionary system from the brain.

The overall dorsalizing effect proposed by the authors may be consistent with behavioral evidence showing that the dorsal cortex of reptiles functions like the hippocampal formation of mammals. It is suggested that the dorsal cortex of reptiles expanded in this dorsalizing process to become both entorhinal/subicular cortex and sensory neocortex.

The position that Aboitiz et al. have taken on the regions of the stem amniote brain from which neocortex arose, and on homologies among telencephalic pallial regions in mammals and sauropsids, is premature. Nonetheless, if their intent is to promote thought, discussion, and experimentation on this important topic, then their paper is valuable.

The dorsal and medial pallial formations of mammals, birds, and reptiles show overall functional striking similarities. Most of these similarities have been frequently considered examples of convergent evolution. However, a considerable amount of neurobiological comparative evidence suggests the presence of a common basic pattern of vertebrate forebrain organization. This common pattern can support functional conservation.

The target article about the origin and evolution of the isocortex triggers questions about unresolved issues that still need to be dealt with, including: (1) the evolutionary scenario of the origin of the lateral isocortex, (2) the expansion of the dorsal pallium in nonmammals, and (3) the heterogeneity of the anterior dorsal ventricular ridge.

Aboitiz et al. describe a hypothesis on the origin of the isocortex. They propose the reptilian dorsal cortex to be the ancestral brain structure to the mammalian isocortex. But why did the dorsal cortex expand in mammals and not in reptiles? A change in development may have provided the mammalian cortex with the ability to organize and therefore the potential to expand.