Inter-individual variation of the adult human striatum

Understanding how cells and genes shape human behavior and vulnerabilities faces a key challenge: no two individuals think or behave in the same way. A critical start is to identify systematically the ways in which key behavior-shaping brain structures such as the striatum vary from person to person, and to begin to recognize underlying influences that generate and sculpt this variation. Here we describe an atlas of cellular, cytoarchitectural and gene-expression variation across four key striatal structures -- the caudate, putamen, nucleus accumbens, and internal capsule -- which we constructed from 3.2 million nuclei sampled from >150 brain donors and analyzed by high-volume single-nucleus RNA-seq and/or spatial transcriptomics (Slide-tags). The resulting data and analyses establish surprisingly broad ranges for normal variation in striatal cell-type composition and gene expression, with age (across 26-90+ years old) and common genetic variants associating strongly with many aspects of this variation, but with modest-to-no association to other aspects. Analyses uncovered more than 10,000 effects of common genetic variants on cell-type-specific gene expression levels, many of which corresponded to genetic influences on neurological and neuropsychiatric disorders. This atlas of human striatal variation will serve as a resource for efforts to understand how the abundant genetic and environmental variation in humans shapes striatal biology and its vulnerabilities to neurodegenerative and neuropsychiatric disorders.

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Funding agency

NIMH

Grant numbers

UM1MH130966

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open

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