MIT Creates a Striatal Atlas to Seek Treatments for Huntington's and Addiction
**An atlas created by researchers at MIT identifies 31 neuronal subgroups in the striatum and shows why some cells are particularly vulnerable to Huntington's disease, while others are involved in addiction, depression, and schizophrenia.
- The team analyzed post-mortem human tissue and distinguished 31 neuronal subpopulations using various molecular and spatial techniques.
- Atypical D1 and D2 neurons showed links to substance use disorders, antidepressants, and response to clozapine.
- Differences between humans and mice, especially in the opioid receptor OPRM1, could necessitate refining research models.
Researchers from the Massachusetts Institute of Technology have developed a cellular atlas of the striatum, a deep brain region linked to movement, decision-making, habits, and reward processing. The map identifies 31 subgroups of neurons based on the genes they express and provides a guide for studying diseases such as Huntington's, schizophrenia, depression, and substance use disorders.
The work, published in Cell, combines single-cell RNA sequencing with techniques capable of locating these populations within brain tissue. According to MIT News, the results could help design drugs that act on specific cells, rather than relying on more general treatments that can produce severe side effects.
A Map to Organize the Complexity of the Striatum
The striatum receives signals from the cerebral cortex, midbrain, hippocampus, and other areas, functioning as an integration point to coordinate planning, movement, decisions, and reward. This position also makes it a relevant structure for addiction and one of the territories most affected by Huntington's disease, schizophrenia, and other neurological disorders.
The study focused on medium spiny neurons, the most abundant cell type in the striatum and a population that responds to dopamine. Most belong to the direct pathway, which favors movement, or the indirect pathway, which helps suppress unwanted actions; both are largely distinguished by their dopamine receptors D1 and D2.
However, this basic division does not explain all the functional diversity of the region, especially in its ventral areas. Previous research had examined specific subregions and used different criteria to classify cells, a fragmentation that made it difficult to establish general principles about the organization of the human striatum.
To address this issue, scientists worked with brain banks from the United States and Canada and gathered post-mortem samples from different anatomical areas. They then applied single-cell RNA sequencing, multiplexed in situ fluorescent hybridization, and spatial transcriptomics, tools that allowed them to identify both the active genes and the location of each population in the tissue.
Neurons Related to Addiction and Psychosis
The analysis distinguished nine types of medium spiny neurons within the 31 identified subpopulations. Among them were two atypical groups that, according to the observed genetic patterns, could be particularly important for understanding schizophrenia, depression, and substance use disorders.
The population termed atypical D1 showed high expression of genes related to addiction and substance response, including genes associated with opioids. In particular, researchers observed a strong presence of the gene OPRM1, which encodes the mu opioid receptor and plays a central role in how certain cells respond to these compounds.
The atypical D2 population, for its part, showed a high expression of genes that respond to antidepressant medications. Both populations appeared to respond intensely to clozapine, an antipsychotic used against schizophrenia and considered one of the most effective treatments available for certain patients.
Clozapine can cause serious adverse effects, including a potentially fatal blood disorder in a small percentage of patients. Myriam Heiman, Picower Professor of Neuroscience and director of the Picower Institute for Learning and Memory at MIT, stated that understanding the cells on which the drug acts could allow for the development of more specific therapies against psychosis, with fewer harmful effects.
Vulnerability to Huntington's Disease
The atlas also provides a molecular explanation for the greater vulnerability of the dorsal striatum to Huntington's disease. This hereditary condition arises from a version of the huntingtin gene that contains too many CAG repeats, repetitive DNA segments that can increase over time and make the mutated protein more harmful.
Researchers found that the dorsal populations of medium spiny neurons express higher levels of the genes MSH2 and MSH3. Both are involved in mechanisms that promote the increase of CAG repeats in the huntingtin gene, an accumulation that can intensify the cellular damage associated with the disease.
The team also identified an unusual population of medium spiny neurons that form island-like structures in the ventral striatum. These cells appeared to be more resistant to the accumulation of CAG repeats, making them a potential natural model to study how other neurons might acquire similar protection.
Heiman noted that comparing the genes expressed by these cells, and those they keep inactive, could provide clues to enhance the resistance of other medium spiny neurons. The finding does not yet constitute a treatment but delineates biological targets that could guide new research on the progression of Huntington's disease and the protection of the most vulnerable cells.
A Warning for Mouse Models
Scientists compared human tissue with mouse samples and found significant differences in the expression of genes related to drug response and substance use disorders. The most notable contrast was related to OPRM1, which is highly expressed in human atypical D1 neurons but not in the corresponding population of rodents.
The difference suggests that standard mouse models may not fully replicate human biology regarding opioid response. To make them more accurate, researchers propose that it may be necessary to develop animals that express that receptor in a way more similar to what is observed in humans.
The divergence between species does not automatically invalidate research with rodents, but it does require using it with greater precision. Heiman explained that animal models can still be useful for studying genes conserved across species, while other questions may require partially humanized models.
The atlas was constructed with tissue donated by families and with the collaboration of various disciplines and institutions, an aspect that the authors consider essential to represent the anatomical diversity of the human striatum. Myriam Heiman described the map as a foundation for future projects on Huntington's disease and opioid use disorder, because before testing new strategies, it was necessary to know more accurately which cells form the region.
The study had among its main authors Raleigh Linville, a postdoctoral researcher at MIT, and Benjamin James, a graduate student at the institution. Myriam Heiman, Manolis Kellis, a professor of Computer Science at the Computer Science and Artificial Intelligence Laboratory at MIT and a member of the Broad Institute of MIT and Harvard, and Dana Gabuzda, a principal investigator at the Dana-Farber Cancer Institute and a professor of neurology at Brigham and Women's Hospital and Harvard Medical School, are listed as principal authors.
The research received partial funding 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. Its subsequent impact will depend on whether other teams can convert cell populations and their genetic signatures into safe pharmacological targets, a task that still requires experimental and clinical validation.
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