The architecture of mammalian cortical connectomes in light of the theory of the dual origin of the cerebral cortex

Abstract

Uncovering organizational principles of the cerebral cortex is essential for proper understanding of this prominent structure of the mammalian brain. The theory of the dual origin of the cerebral cortex offers such organizational principle. Here, we demonstrate that a duality pertains to the connectional architecture of the cerebral cortex of different mammals. This dual structure also constitutes a major axis of organization of the transcriptional architecture of the cortex and reflects the expression of different morphogens stemming from distinct patterning centers in the developing pallium. The duality of the cortex is also reflected in its spatial dimension, highlighting cortical areas as spatially ordered constellations that are centered around the paleocortex and archicortex, with the later primordial moieties reminiscent of antipodal points in the cortical sheet. The ontogeny of the uncovered dual connectional structure might be rooted in heterochronous neurodevelopmental gradients in the developing pallium, a suggestion corroborated by computational modeling. In all, the current results exemplify the duality of the cerebral cortex as an overarching organizational principle, reflected across the different levels of cortical architecture of different mammalian species, defining a natural axis of mammalian cortical organization.

Introduction

Understanding the organization of the cerebral cortex requires uncovering the fundamental principles pertaining to its architecture. Like the rings of a tree, the cerebral cortex consists of rings of progressive laminar differentiation emanating from two sources, that is, the piriform cortex (paleocortex) and the hippocampus (archicortex). These dual sources of differentiation of the cortex constitute the basic premise of the dual origin theory of the cerebral cortex (Fig. 1). The concept of the dual nature of the cerebral cortex can be traced back at least to the first decades of the last century and has been observed in reptiles, marsupials, monotremes, human and non-human primates (Shellshear, 1929, Dart, 1934, Abbie, 1940, Abbie, 1942, Sanides, 1962, Sanides, 1970, Sanides and Hoffmann, 1969) (Fig. 1). The dual origin of the cerebral cortex has been primarily inferred from cytoarchitectonic and myeloarchitectonic analysis. Cortical areas are parts of two gradients (or trends) of progressive laminar differentiation. Criteria for defining such gradients can include the progressive appearance and successive thickness and neuronal density of layer IV and the overall more pronounced laminar differentiation, that is, distinguishability of cortical layers, as well as increased overall myelination. In sum, in the dual origin framework, cortical areas can be conceptualized as waves of laminar differentiation emanating from two origins, that is, the piriform cortex (paleocortex) and the hippocampus (archicortex) (Fig. 1).

The concept of the dual origin of the cerebral cortex was adopted and further expanded through a series of cytoarchitectonic and tract-tracing studies in the macaque monkey cortex by Pandya and co-workers (e.g., Pandya et al., 1988, Barbas and Pandya, 1989; Cipolloni and Pandya, 1999, Morecraft et al., 2004; for a review see Pandya and Yeterian, 1985, Pandya et al., 2015). These foundational studies offer two fundamental insights concerning the macaque monkey cortex. First, the widely used dorsal/ventral dichotomy of sensory systems and lobes in the macaque monkey, e.g., in the visual (Ungerleider & Mishkin, 1982) and sensorimotor systems (Pandya et al., 1988) or the prefrontal cortex (Barbas & Pandya, 1989), is actually a snapshot of the global dual origin architecture of the macaque monkey cortex. Second, the duality of the cortex is also mirrored in the organization of cortico-cortical connections, that is, cortical areas that are affiliated with one of the two trends are primarily connected with cortical areas of the same trend (Pandya & Yeterian, 1985; for a thorough review, see Pandya et al., 2015).

More recently, the dual connectional architecture of the cortex was conceptualized as a topologically symmetric constellation of areas (Bezgin et al., 2014). This definition allows the explicit, quantitative, connectivity-based analysis of cortical areas within the dual origin framework and results from such approach align very well with cytoarchitectonic analysis demonstrating the duality of the cortex (Bezgin et al., 2014) (Fig. 2A,B). Specifically, this computational connectivity-based approach has uncovered a dual connectional organization for the auditory/prefrontal and visual systems of the macaque monkey, that is, the dorsal and ventral streams of these systems, a division that aligns well with prior cytoarchitectonic, connectional and functional observations (Romanski et al., 1999, Mishkin and Ungerleider, 1982). Hence, the conceptualization and quantification of the dual architecture of the cortex as two topologically symmetric structures (or dual connectional trends) is offering a tool for examining the presence of such structure in other mammalian species.

The aforementioned studies revealed a duality of the cerebral cortex primarily on a cytoarchitectonic and connectional basis. Does the duality of the cerebral cortex constitute an organization axis of the transcriptional architecture of the cerebral cortex? Is this duality reflected in the physical layout of the cortical sheet? What are the plausible developmental mechanisms that result in such dual architecture? Such questions remain unanswered and are necessary to be addressed in order to understand the dual origin of the cerebral cortex at a more substantial level, elevate it to a key organizational principle of the mammalian cerebral cortex, and thus provide a framework that recapitulates the different levels of architecture of the mammalian cortex.

In the current study, we undertake this task. Specifically, we demonstrate, on a connectional basis and at a whole-cortex level, the existence of a dual architecture in the mouse, rat, cat, and macaque monkey cortex. We show that this dual architecture is reflected in the geometry of the cortical sheet, with the primordial areas of the dual trends reminiscent of antipodal points of the cortical sheet. We exploit recent detailed transcriptional data on the mouse cortex and show that the dual architecture is related to the transcriptional dimension of cortical organization. Lastly, we demonstrate, with the aid of computational modeling, that heterochronous development and connectivity formation in the cortex can give rise to the dual connectional architecture observed in the adult cerebral cortex.

We conclude that the duality of the adult cerebral cortex constitutes an organizational axis that epitomizes different levels of cortical organization. This duality is rooted in heterochronous neurodevelopmental events and encompasses multiple species across the mammalian spectrum, thus constituting a principle with a potentially universal scope.