Progress in treating brain disorders has been frustratingly slow, in large part due to the extraordinary complexity of the human brain and its inaccessibility to study. Remarkable advances in technologies for studying individual cells, most notably single cell genomics, have revolutionized the study of complex nervous tissues and have been used to map cellular diversity across the entire mouse brain with cell types defined by their specific patterns of gene usage and gene regulatory mechanisms. These highly scalable methods have been successfully applied to brain tissue from human and other species and are ready to be applied to whole brains from humans and non-human primates. A major challenge with studying the human brain is bridging fields and scales from functional MRI and macroscale connectomics to histological, cellular and molecular analyses. Bridging these domains is essential to creating a transformative new cell atlas that will describe the cellular and molecular underpinnings of the functional organization of the human brain. An important recent development from single cell genomic analysis is that cell types can be aligned across species and are highly conserved across mammals from mice to humans, although more similar in evolutionarily closer primates than in rodents. This finding amplifies the value of primate species in helping to understand human brains and infer cellular properties that cannot be measured in humans. The current proposal brings together a unique team of world leaders to tackle the challenge of creating a new human and non-human primate cell atlas linked to functional brain architecture. Single cell transcriptomic, epigenomic and spatial transcriptomics will be used to classify and spatially map cell types across the entire human, macaque and marmoset brain, sampling based on brain maps derived from structural and functional imaging. Function-localizing fMRI in macaques will allow the direct analysis of cellular correlates of functional topography. Advances in spatial transcriptomics will allow an unprecedented whole primate brain map of cell types. Unique access to macaque tissues for analysis of cellular anatomy and physiology allows the characterization of molecularly-defined cell types in many brain regions. Similar techniques will be applied to living neurosurgically-derived human brain tissues, coupled with enhancer-AAV based tools to allow selective genetic labeling of cell types. Finally, profiling regions central to perception, behavior and mood across many individuals and diverse mammals will link genetic, environmental and evolutionary factors to cellular variation. The outcome of these efforts will produce a new reference classification for cell types across the whole human and NHP brain, spatial maps of molecularly defined cell types, and phenotypic characterization of fundamental brain cell types. The classification will align homologous cell types from mice, marmosets, macaques and humans, allowing inference and comparison of cellular properties across species. Furthermore, data will be aligned in common coordinate frameworks, allowing creation of new atlases spanning structural, functional, cellular and molecular information. All data and analyses will be distributed to the research community, including a formal cell ontology of cell types across species and visualization tools for broad community access.

NARRATIVE A major obstacle in basic and clinical neuroscience is a fundamental lack of knowledge of the cellular components of the human brain, the genes that contribute to their properties, how they form the functional circuitry of the brain, how they are differentially vulnerable in disease, and how similar they are in organisms used in biomedical research as experimentally tractable models of human disease. The goal of the proposed research is to create a comprehensive cell atlas of the human and closely related non-human primate brain, using high-throughput single cell molecular, spatial and cell phenotyping assays to map the structural and functional organization of the primate brain. The result will be a transformative catalytic resource for the basic science and biomedical community linking brain structure, function, cellular makeup and genomic characteristics that provide a powerful new foundation to accelerate understanding of human brain function and disease.