The human basal ganglia (BG) are a collection of subcortical regions whose diverse, specialized cell types influence motor control, emotional regulation, habit formation, and higher cognition. Recent advances in single-cell transcriptome and epigenome sequencing have revolutionized our ability to systematically define cell types and states across complex tissues, reaching sufficient levels of throughput and robustness to be deployable to large brain tissue regions like the primate BG. However, to date, despite the central role of BG cell types in many neurodegenerative and neuropsychiatric diseases, their molecular definitions in the human and primate are distinctly lacking. Here, we propose to use a combination of high-throughput single-nucleus RNAseq, a novel high-resolution spatial technology, Slide-seq, and a new approach to jointly profile transcription and ATAC signatures called SHARE-seq, to systematically identify and anatomically map cell types across the macaque BG. We will use these same methods to characterize cell type diversity across a set of 200 postmortem human brains, an unprecedentedly large sample size that will enrich our understanding of inter-individual variation in this clinically relevant set of brain regions. We will then use these data to build new viral tools for the functional interrogation of four principal BG cell types in the primate. Together, this work will provide a comprehensive and high-resolution molecular characterization of BG cell types, provide tools for linking these molecular definitions to functional ones, and establish a framework for such cell type characterization across the entire human brain.
The human basal ganglia are a collection of brain regions that mediate motor activities, emotional regulation, habit formation, and higher thinking. Specific neuronal types in these structures are selectively and preferentially affected by neurodegenerative diseases like Parkinson?s disease and Huntington?s disease. The proposed work will leverage cutting-edge technologies to provide the first comprehensive genomic characterization of the cell types in these structures, enabling us to more deeply understand their normal function, as well as dysfunction in neurodegenerative diseases.