Transcriptional profiles of supragranular-enriched genes associate with corticocortical network architecture in the human brain
Proceedings of the National Academy of Sciences of the United States of America
The human brain is patterned with disproportionately large, distributed cerebral networks that connect multiple association zones in the frontal, temporal, and parietal lobes. The expansion of the cortical surface, along with the emergence of long-range connectivity networks, may be reflected in changes to the underlying molecular architecture. Using the Allen Institute's human brain transcriptional atlas, we demonstrate that genes particularly enriched in supragranular layers of the human
... ral cortex relative to mouse distinguish major cortical classes. The topography of transcriptional expression reflects large-scale brain network organization consistent with estimates from functional connectivity MRI and anatomical tracing in nonhuman primates. Microarray expression data for genes preferentially expressed in human upper layers (II/III), but enriched only in lower layers (V/VI) of mouse, were cross-correlated to identify molecular profiles across the cerebral cortex of postmortem human brains (n = 6). Unimodal sensory and motor zones have similar molecular profiles, despite being distributed across the cortical mantle. Sensory/motor profiles were anticorrelated with paralimbic and certain distributed association network profiles. Tests of alternative gene sets did not consistently distinguish sensory and motor regions from paralimbic and association regions: (i) genes enriched in supragranular layers in both humans and mice, (ii) genes cortically enriched in humans relative to nonhuman primates, (iii) genes related to connectivity in rodents, (iv) genes associated with human and mouse connectivity, and (v) 1,454 gene sets curated from known gene ontologies. Molecular innovations of upper cortical layers may be an important component in the evolution of long-range corticocortical projections. corticocortical connectivity | human transcriptome | association cortex | supragranular | brain evolution P atterns of gene expression in the cerebral cortex are generally conserved across species, reflecting strong constraints in the development and evolution of cortical architecture (1-6). Previous work examining transcriptional variation in nonhuman primates and rodents indicate that molecular similarities between cortical regions in the adult brain are best explained by spatial proximity (7, 8). Molecular variation often takes the form of graded expression along a principal axis, in many cases appearing as rostrocaudal gradients across the cortex (8). The strong tendency for transcriptional variation to follow spatial proximity in the adult cortex likely reflects both functional gradients, as well as their developmental origins in terms of physical and temporal adjacency during neurogenesis of cells destined for neighboring locations in the cortex (at least for cells derived from the ventricular proliferative pool) (7). Spatial proximity likely captures the major features governing how molecular profiles vary across the cortex in all species, including humans. However, the expansion of the cerebral cortex in primates generally, and humans specifically, was accompanied by changes to both microstructural and connectional organization (9-11). In particular, connectivity patterns in humans, mapped by noninvasive imaging techniques, reveal a set of distributed, interdigitated networks that tile the expanded portions of the association cortex. These distributed networks have certain organizational properties that depart from evolutionarily conserved unimodal sensory and motor zones, where connectional topography between areas or fields is often densest between neighboring locations (12). Higher-order cortical regions also possess local connections, but are distinguished by the relative prevalence of long-range connections (13-15 ). An open question is how the molecular architecture underlying these different cortical classes supports their distinct connectivity patterns. In particular, the distributed nature of networks that interconnect the prefrontal, parietal, temporal, and cingulate association cortex together raises the possibility that innovations in molecular profiles will be associated with the emergence of extended forms of long-range connectivity in those regions (16, 17) . A recent study of expression profiles of 1,000 genes in the mammalian cerebral cortex found that 79% have conserved laminar expression patterns between mice and humans (18). Several of the remaining 21% exhibited species-or region-specific distributions. Some had different laminar expression patterns in Significance The human cerebral cortex is patterned with distributed networks that connect disproportionately enlarged association zones across the frontal, temporal, and parietal lobes. We asked herein whether the expansion of the cortical surface, with the concomitant emergence of long-range connectivity networks, might be accompanied by changes to the underlying molecular architecture. We focused on the supragranular layers of the cortex, where most corticocortical connections originate. Genes that are enriched in supragranular layers in the human cerebral cortex relative to mouse are expressed in a topography that reflects broad cortical classes (sensory/motor, paralimbic, associational) and their associated network properties. Molecular innovations of upper cortical layers may be an important component in the evolution of increased long-range corticocortical projections.