Project Summary/Abstract The human cerebral cortex supports extraordinary cognitive capacities, including unmatched social and technological complexity, elaborate cultural traditions, and language. It also plays a central role in diverse brain disorders that cause profound human suffering, including schizophrenia and Alzheimer's dementia, that may have only limited analogs in non-human species. One key adaptation is the dramatic expansion of the cortical sheet vs other primates, particularly in higher cognitive (association) areas. This expansion is not uniform, but it has proven challenging to accurately map the degree of expansion in different regions and to determine the relative contributions of expansion of evolutionarily conserved areas vs the emergence of new areas. Recent methodological advances make it feasible to generate substantially more accurate cortical expansion maps than heretofore possible. Evolutionary divergence in cortical organization presumably reflects changes in gene expression patterns responsible for the differentiation of cortical areas and the determination of areal size. Recent advances in spatially resolved single-cell transcriptomics have led to the discovery of hundreds of putative cell types whose diversity is a critical substrate of brain evolution. In this proposal both sets of advances will be leveraged to address both evolutionary expansion and transcriptomic cell type divergence in human vs macaque cortex. The proposed analyses will be empowered by active collaboration with multiple consortia, including the Non-human Primate Neuroimaging & Neuroanatomy Project (NHP-NNP), and the Human and Mammalian Brain Atlas (HMBA), a facet of the BRAIN Initiative Cell Atlas Network. State-of-the-art interspecies registration will be performed by integrating putative homologous regions, myelin maps, and resting state networks to derive a substantially more accurate map of the evolutionary expansion of the cortex in macaque vs human than has previously been reported. Comparing this map and other brain maps to patterns of transcription in humans and macaques will allow testing of whether (1) evolutionary expansion has a distinct transcriptional signature from other brain measures, (2) this signature is more evident in cell type distribution than in aggregate gene expression, and (3) human-enriched cell types (e.g., in layer 4) play a prominent role in cortical expansion and diversification. Accurately registered transcription and neuroimaging measures will provide new evidence for distinguishing evolutionally emergent areas from conserved areas that have undergone evolutionary expansion. Taken together, the proposed research will augment the translational potential of studies utilizing non-human primate models, enhance our understanding of the areal and cellular substrates of the complex behaviors, and provide new insights into possible mechanisms of primarily human mental and neurological disorders.