Neurons in the striatum are among the most affected, a part of the brain affected by Huntington’s disease. Degeneration of these neurons causes patients to lose motor control, which is one of the main symptoms of the disease.
MIT neuroscientists have now shown that two distinct cell populations in the striatum are affected in different ways. Huntington’s disease. They believe that neurodegeneration of one of these populations leads to motor impairment, while damage to the other population, located in structures called the striosomes, can cause mood disorders that often accompany the disease. Seen in the early stages.
“At most 10 years ahead Motor assessmentHuntington’s patients can experience mood disorders, and one possibility is that striatal systems may be involved,” said Ann Graybell, M.D., a professor at MIT’s McGovern Institute for the Brain. Research fellow, and one of the study’s senior authors, said.
Using single-cell RNA sequencing to analyze genes expressed in mouse models of Huntington’s disease and postmortem brain samples from Huntington’s patients, the researchers found that cells of striosomes and another structure, the matrix , begin to lose their distinctive features as the disease progresses. . The researchers hope that their mapping of the striatum and how it is affected by Huntington’s may lead to new treatments that target specific cells within the brain.
This type of analysis could also shed light on other brain disorders that affect the striatum, such as Parkinson’s disease and autism spectrum disorder, the researchers said.
Myriam Heiman, an associate professor in MIT’s Department of Brain and Cognitive Sciences and a member of the Picower Institute for Learning and Memory, and Manolis Kellis, a professor of computer science and a member of MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL). The Broad Institute of MIT and Harvard are also senior authors of the study. McGovern Institute research scientist Ayano Matsushima and MIT graduate student Sergio Sebastian Pineda are lead authors of the paper, which appears in Nature Communications.
Huntington’s disease causes degeneration of brain structures called the basal ganglia, which are responsible for controlling movement and play a role in emotions, among other behaviors. For several years, Graybell has been studying the striatum, a part of the basal ganglia involved in making decisions that require evaluating the consequences of a particular action.
Several years ago, Graybell discovered that the striatum is divided into striosomes, which are clusters of neurons, and matrix, which surrounds the striosomes. It has also shown that striosomes are essential for making decisions that require anxiety-inducing cost-benefit analysis.
In a 2007 study, Richard Fall of the University of Auckland discovered that in post-mortem brain tissue from Huntington’s patients, striosomes showed significant degeneration. Fall also found that while those patients were alive, many of them showed symptoms of mood disorders such as depression before they developed motor symptoms.
To further explore the links between the striatum and the mood and motor effects of Huntington’s, Graybell, along with Kells and Hemann, studied the gene expression patterns of striosomal and matrix cells. To do this, the researchers used single-cell RNA sequencing to analyze human brain samples and brain tissue from two mouse models of Huntington’s disease.
Within the striatum, neurons can be classified as either D1 or D2 neurons. D1 neurons are involved in the “go” pathway, which initiates an action, and D2 neurons are part of the “no-go” pathway, which suppresses an action. Both D1 and D2 neurons can be found in the striosomes and matrix.
Analysis of RNA expression in each of these cell types revealed that striosomal neurons are more affected by Huntington than matrix neurons. Furthermore, within the striosomes, D2 neurons are more vulnerable than D1.
The researchers also found that these four major cell types begin to lose their defining molecular identity and become difficult to distinguish from each other in Huntington’s disease. “Overall, the distinction between the striosomes and the matrix gets really blurred,” Graybell said.
The findings suggest that damage to the striosomes, which are involved in regulating mood, may be responsible for the mood disorders that affect Huntington’s patients in the early stages of the disease. Later, the degeneration of matrix neurons likely leads to a decline in motor function, the researchers said.
In future work, the researchers hope to explore how degeneration or abnormal gene expression in the striosomes may contribute to other brain disorders.
Previous research has shown that overactivity of the striatum can lead to the development of repetitive behaviors such as autism, obsessive-compulsive disorder, and Tourette’s syndrome. In this study, at least one gene that the researchers discovered was overexpressed in the striosomes of the Huntington’s brain has also been linked to autism.
Additionally, many striatal neurons project to the part of the brain most affected by Parkinson’s disease (the substantia nigra, which produces most of the brain’s dopamine).
“There are many, many disorders that probably involve the striatum, and now, partly through transcriptomics, we’re working to understand how they might all fit together,” Graybell said.
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