MIT researchers created a detailed cellular atlas of the brain's striatum, identifying 31 distinct subpopulations of neurons that could guide drug development for neurological and psychiatric conditions, MIT reported on Tuesday.
The study, published in Cell, was led by MIT postdoc Raleigh Linville and graduate student Benjamin James. Senior authors include Picower Institute director Myriam Heiman, MIT computer science professor Manolis Kellis, and Harvard Medical School neurology professor Dana Gabuzda.
Scientists analyzed postmortem human tissue collected from brain banks across the United States and Canada. The team combined single-cell RNA sequencing with multiplexed fluorescent in situ hybridization and spatial transcriptomics to examine medium spiny neurons, an inhibitory cell type that responds to dopamine.
The analysis classified nine types of medium spiny neurons, including two outlier groups linked to psychiatric disorders. One group, designated D1 outliers, showed high expression of genes related to substance use disorder and opioid response. A second group, D2 outliers, expressed genes linked to antidepressant response. Both outlier populations responded strongly to clozapine, an antipsychotic drug used for schizophrenia.
Huntington's vulnerability
The researchers determined why the upper dorsal region of the striatum shows heightened vulnerability to Huntington’s disease. Dorsal medium spiny neurons expressed elevated levels of the genes MSH2 and MSH3, which drive the expansion of CAG repeat sequences in the huntingtin gene. A rare population of medium spiny neurons arranged in island-like clusters within the ventral striatum resisted CAG repeat accumulation.
Cross-species differences
Comparing human tissue with mouse striatum revealed notable genetic discrepancies between the species. Human D1 outlier neurons expressed high levels of the OPRM1 gene, which encodes the mu opioid receptor, whereas the corresponding mouse neurons did not.
Funding for the research came from the National Institutes of Health, the G. Harold and Leila Y. Mathers Charitable Foundation, the Freedom Together Foundation, the Natalia Mental Health Foundation, the Biswas Family Foundation, and the Milken Institute.
