MIT News breed · Wetenschap

Brain’s Striatum Atlas Could Aid Drug Treatment Development

MIT researchers have created a detailed atlas of the striatum, a brain region crucial for motor control, decision-making, and reward processing, which is implicated in disorders like addiction, Huntington's disease, and schizophrenia. This new map identifies 31 distinct neuron subgroups, offering potential pathways for developing novel drug treatments.

The striatum plays a vital role in cognitive and motor functions, including decision-making, movement control, habit formation, and reward processing. It is also significantly affected in conditions such as addiction, Huntington's disease, schizophrenia, and other disorders.

By employing single-cell RNA sequencing and other advanced techniques on postmortem brain samples from diverse anatomical regions, the researchers identified 31 neuron subgroups based on gene expression. These subgroups include neurons linked to addiction, depression, and schizophrenia.

The study also revealed why certain striatal neurons are more susceptible to Huntington's disease. The findings are expected to facilitate the development of new therapeutic drugs for these conditions.

Myriam Heiman, a senior author and professor at MIT, stated that the atlas serves as a foundational roadmap for ongoing research into Huntington's disease and opioid use disorder.

The research focused on medium spiny neurons, the most abundant cell type in the striatum, which are responsive to dopamine and are divided into direct and indirect pathways. While previous studies hinted at subpopulations, a comprehensive classification was lacking.

The researchers identified two "outlier" populations of medium spiny neurons. One, "D1 outliers," showed high expression of genes related to addiction and opioid response. The other, "D2 outliers," expressed genes responsive to antidepressants. Both populations reacted strongly to clozapine, an antipsychotic for schizophrenia.

Understanding which cells clozapine targets could lead to the design of more specific therapeutics for psychosis with fewer harmful side effects, according to Heiman.

Regarding Huntington's disease, the study found that dorsal striatal neurons express higher levels of MSH2 and MSH3 genes, which contribute to the accumulation of harmful CAG repeats in the huntingtin gene. This explains the dorsal striatum's vulnerability.

Conversely, a rare population of medium spiny neurons in the ventral striatum showed resistance to CAG repeat accumulation, suggesting potential avenues for making other neurons more resilient to the disease.

Comparisons between human and mouse striatal samples revealed species-specific differences in gene expression related to drug response, particularly for the mu opioid receptor (OPRM1). This highlights limitations in current mouse models for studying opioid responses and suggests the need for 'humanized' models.

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