A Multimodal Atlas Reveals the Anatomical Distribution of Medium Spiny Neuron Subtypes and a Novel RGS6+ Population in the Primate Striatum.
A Multimodal Atlas Reveals the Anatomical Distribution of Medium Spiny Neuron Subtypes and a Novel RGS6+ Population in the Primate Striatum.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Pittsburgh, US · Author affiliation
Neuroscience Institute, Carnegie Mellon University, Pittsburgh PA 15213, USA.Location evidence
US · Author affiliation · country only
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase MD 20815, USA.Location evidence
Atlanta, US · Author affiliation
Department of Neurology, Emory National Primate Research Center, Emory University, Atlanta GA 39329, USA.Location evidence
Publication status: preprint
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Original abstract
The primate striatum and its principal neuron type, the medium spiny neuron (MSN), integrate cortical and subcortical signals related to movement, cognition, and emotion. These signals are processed through cell type specific circuits traditionally defined by MSN dopamine receptor expression. However, classification by dopamine receptor type alone fails to fully specify MSN diversity and falls short of capturing the functional complexity of the striatum. Here, we combined single-nucleus multi-omic sequencing and high-plex spatial transcriptomics to build a comprehensive atlas of MSNs in the macaque striatum. Using multi-omic sequencing, we profiled MSNs across four anatomically and functionally defined territories, and we mapped these subtypes back into their anatomical context by integrating the multi-omic data with ~5.4 million spatially resolved cells sampled across the full rostral-caudal and dorsal-ventral extent of the striatum. This approach revealed two previously undocumented ventral striatum (VS) subtypes, D1-VS-RGS6 and D2-VS-RGS6, which are molecularly distinct from known ventral striatal MSNs yet share core limbic features. We also uncovered gradients in matrix-compartment cell types along the rostral-caudal axis. Finally, by integrating MSN subtype-specific transcriptomes and ATAC-seq-derived regulatory annotations with human GWAS data, we demonstrate strong, cell-type-specific enrichment of polygenic risk for Parkinson's disease, substance use disorders, and psychiatric and cognitive traits, including a striking association of D2-VS-RGS6 with schizophrenia and bipolar disorder. Together, this multimodal atlas provides a foundation for linking primate striatal cell types to circuit function and disease mechanisms.