The striatum, a deep brain region, is essential for decision‑making, motor control, habit formation and reward processing, and it is implicated in addiction, Huntington’s disease, schizophrenia and other disorders. MIT researchers combined single‑cell RNA sequencing, multiplexed fluorescent in situ hybridization and spatial transcriptomics on post‑mortem samples collected from brain banks in the United States and Canada, and produced a comprehensive atlas that resolves 31 neuronal subpopulations, including nine types of medium spiny neurons (MSN). MSNs are inhibitory cells that belong to either the direct pathway (expressing dopamine receptor D1) or the indirect pathway (expressing D2). The study identified two “outlier” MSN groups that show disease‑relevant transcriptional signatures: D1 outliers highly express genes linked to opioid response and substance‑use disorder, while D2 outliers are enriched for genes responsive to antidepressants; both groups are strongly activated by clozapine, an antipsychotic with severe side‑effects. These findings suggest that targeting the specific cell types could yield more precise therapies with fewer adverse effects. The authors also discovered that dorsal MSNs express higher levels of MSH2 and MSH3, genes that promote expansion of CAG repeats in the huntingtin gene, explaining the greater vulnerability of the dorsal striatum to Huntington’s disease. In contrast, a rare ventral MSN population that forms island‑like structures shows resistance to CAG repeat accumulation, offering a potential model for engineering resilience in other neurons. Cross‑species comparison revealed that the mu‑opioid receptor gene OPRM1 is abundant in human D1 outliers but nearly absent in the analogous mouse cells, indicating that standard mouse models may miss key aspects of opioid biology; humanizing this pathway could improve translational studies. The atlas, built from donor tissue and interdisciplinary collaboration, is intended as a roadmap for developing treatments for some of the most challenging brain disorders. Funding came from the NIH, the G. Harold and Leila Y. Mathers Charitable Foundation and other donors.
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