In patients with Huntington’s disease, neurons in a part of the brain called the striatum are among the most affected. The degeneration of these neurons contributes to the loss of motor control in patients, which is one of the main characteristics of the disease.
MIT neuroscientists have now shown that two distinct cell populations in the striatum are affected differently by Huntington’s disease. They believe that neurodegeneration of one of these populations leads to motor impairments, while damage to the other population, located in structures called striosomes, may explain the mood disorders often seen in the early stages of the disease.
“Up to 10 years before motor diagnosis, Huntington’s patients can experience mood disorders, and one possibility is that striosomes may be involved in these,” says Ann Graybiel, MIT Institute Professor, McGovern Institute Fellow for the MIT Brain. Research, and one of the lead authors of the study.
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 the cells’ striosomes and other structure, the womb, they 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 disease could help develop 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 say.
Myriam Heiman, Associate Professor in MIT’s Department of Brain and Cognitive Sciences and Fellow of the Picower Institute for Learning and Memory, and Manolis Kellis, Professor of Computer Science in MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and a member of the Broad Institute of MIT and Harvard, are also lead authors of the study. Ayano Matsushima, a research scientist at the McGovern Institute, and Sergio Sebastian Pineda, an MIT graduate student, are the lead authors of the paper, which appears in nature communications.
Huntington’s disease leads to the degeneration of brain structures called the basal ganglia, which are responsible for movement control and also play a role in other behaviors as well as emotions. For many years, Graybiel has been studying the striatum, a part of the basal ganglia that is involved in decision-making that requires evaluating the results of a particular action.
Many years ago, Graybiel discovered that the striatum is divided into striosomes, which are groups of neurons, and the matrix, which surrounds the striosomes. He has also shown that striosomes are necessary for making decisions that require anxiety-inducing cost-benefit analysis.
In a 2007 study, Richard Faull of the University of Auckland found that in the postmortem brain tissue of Huntington’s patients, striosomes showed extensive degeneration. Faull also discovered that while these patients were alive, many of them had shown signs of mood disorders, such as depression, before motor symptoms developed.
To further explore the connections between the striatum and the mood and motor effects of Huntington’s disease, Graybiel partnered with Kellis and Heiman to study gene expression patterns in striosome and matrix cells. To do that, 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. D1 and D2 neurons can be found within striosomes and the matrix.
Analysis of RNA expression in each of these cell types revealed that striosome neurons are more affected by Huntington’s disease than matrix neurons. Furthermore, within striosomes, D2 neurons are more vulnerable than D1.
The researchers also found that these four main cell types begin to lose their identifying molecular identities and become more difficult to distinguish from one another in Huntington’s disease. “Overall, the distinction between the striosomes and the matrix gets really blurry,” says Graybiel.
The findings suggest that damage to striosomes, which are known to be involved in mood regulation, may be responsible for the mood disorders that affect Huntington’s patients in the early stages of the disease. Later, degeneration of neurons in the matrix likely contributes to decreased motor function, the researchers say.
In future work, the researchers hope to explore how degenerative or abnormal gene expression in striosomes may contribute to other brain disorders.
Previous research has shown that hyperactive striosomes can lead to the development of repetitive behaviors such as those seen in autism, obsessive-compulsive disorder, and Tourette syndrome. In this study, at least one of the genes that the researchers found to be overexpressed in striosomes from Huntington’s brain is also linked to autism.
In addition, many neurons from the striosome 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 likely to involve the striatum, and now, partly through transcriptomics, we’re working to understand how all of this might fit together,” says Graybiel.
The research was funded by the Saks Kavanaugh Foundation, the CHDI Foundation, the National Institutes of Health, the Nancy Lurie Marks Family Foundation, the Simons Foundation, the JPB Foundation, the Kristin R. Pressman and Jessica J. Pourian ’13 Fund. , and Robert Buxton.