The striatum, a brain region involved in movement, decision-making, habit formation, and reward processing, is also implicated in some of the most difficult-to-treat neurological and psychiatric disorders, including Huntington’s disease, schizophrenia, depression, and substance use disorder. Now, MIT researchers have created a single-cell atlas of the striatum that could help explain why particular neuronal populations are vulnerable in different diseases and potentially point toward more targeted drug strategies.

The study, published in Cell, is titled “Cross-species single-cell atlas of the striatum defines cell type and subregion disease vulnerabilities.” The team used single-nucleus RNA sequencing across 109 human and 22 mouse samples spanning the dorsal and ventral striatum, together with spatial transcriptomics and multiplexed fluorescent in situ hybridization, to map cellular and molecular specialization across the region.

The researchers focused in part on medium spiny neurons, the most abundant neuronal cell type in the striatum. These inhibitory neurons are often divided into two major pathways: a direct pathway that helps promote movement and an indirect pathway that suppresses unwanted movement. But prior studies had suggested that the striatum contained many additional subpopulations, particularly in ventral regions, without a clear consensus on how those cells should be classified.

By profiling postmortem striatal tissue samples from brain banks in the United States and Canada, the MIT-led team identified 31 neuronal subpopulations, including nine types of medium spiny neurons. The atlas revealed two “outlier” populations with potential relevance to neuropsychiatric disease. One, known as D1 outliers, showed high expression of genes involved in substance use disorder, including genes related to opioid response. Another, D2 outliers, showed high expression of genes that respond to antidepressants. Both populations also appeared to respond strongly to the antipsychotic drug clozapine, which is used to treat schizophrenia.

The atlas also helped clarify why the dorsal striatum is especially vulnerable in Huntington’s disease, which is caused by an inherited expansion of CAG repeats in the huntingtin gene. The researchers found that dorsal medium spiny neuron populations expressed higher levels of MSH2 and MSH3, genes involved in increasing CAG repeat length. As those repeats accumulate, the mutant huntingtin protein becomes more toxic to cells.

In contrast, a rare population of medium spiny neurons forming island-like structures in the ventral striatum appeared more resistant to CAG repeat accumulation. “Looking at the genes that these neurons express or don’t express might give us some clues as to how to make other medium spiny neurons resilient like them,” said Myriam Heiman, PhD, the Picower Professor of Neuroscience and director of MIT’s Picower Institute for Learning and Memory.

Comparisons between human and mouse samples further showed that some disease-relevant features of the human ventral striatum may not be fully captured in standard rodent models. For example, OPRM1, which encodes the mu opioid receptor, was highly expressed in the human D1 outlier population but not in corresponding mouse neurons. “Some of the diversity we’re seeing in the human ventral striatum is species-specific and has implications for modeling substance use disorder in rodents,” Heiman said.

Taken together, the findings provide a cellular roadmap of the striatum and its disease-linked vulnerabilities. The authors wrote that the work “lay[s] the foundation for understanding how striatal cell types and subregions contribute to brain function and neurological disorders,” offering a resource for researchers studying Huntington’s disease, substance use disorder, schizophrenia, and related conditions.

“We see this as the foundation that will allow more studies in our Huntington’s disease and opioid use disorder projects. We needed a roadmap of what is there,” added Heiman.

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