A new study by neuroscientists from the Massachusetts Institute of Technology (MIT) has revealed how two separate populations in the striatum, a neuronal circuit in the brain, are impacted differently by Huntington’s disease.
Patient With Huntington’s Disease. Credit: Frank Gaillard
This discovery could aid in developing treatments that better target cells involved in brain disorders.
Striatal neurons are usually among those that are most affected in Huntington’s. Loss of motor control, a hallmark of this disorder, is linked to the decline or collapse of these neurons.
Read Also: Neuronal Traffic Jams Explained Using Isogeometric Analysis-Based Models
Researchers say the degeneration of one of the striatum’s cell populations brings about motor control issues. The impairment of the second population, which can be found in structures known as striosomes, seems to be culpable for mood disorders commonly seen early in the development of the disorder.
Ann Graybiel, a senior author of this study, noted that this might explain why people with Huntington’s may have mood disorders “as many as 10 years” before a motor diagnosis.
The striosomes and the matrix are chemical compartments in the striatum. The MIT neuroscientists found that, as Huntington’s worsens, cells within these two complementary structures lose their distinctive traits.
Degeneration in the brain
A key phenomenon that is seen in Huntington’s disease is the decline of the basal ganglia. This is a group of nuclei in the subcortical region of the forebrain that helps with motor control. These structures also play a part in other roles, including motor learning, behaviors, emotions, and executive functions.
Read Also: Skin Cells Reprogrammed into Aged Neuron to Aid Research into Age-Related Brain Disorders
Graybiel has been exploring for a long time the striatum, which is an input module for the basal ganglia. This subcortical structure is critical for decision-making that involves evaluating outcomes of actions and voluntary movement control.
Graybiel’s team found out decades ago that the striatum has two compartments: the striosomes and the matrix. Striosomes are clusters of neurons that are surrounded by the matrix.
Striosomes play a key role in decision-making that involves “an anxiety-provoking cost-benefit analysis,” Graybiel found.
Another study by Richard Faull from the University of Auckland revealed significant striosomal degeneration in postmortem brain tissue of people with Huntington’s disease. Many of those patients were found to have displayed signs of depression or other mood disorders before a motor diagnosis.
Probing further
In the current study, researchers wanted to learn more about the links between the striatum and the mood and motor outcomes of Huntington’s. They employed single-cell RNA sequencing to examine gene expressions in mouse models of this disease and postmortem human brain samples.
There are two classes of neurons in the striatum: D1 and D2. Researchers say D1 neurons are relevant to the action-initiating “go” pathway. D2 neurons, on the other hand, are involved in the “no-go” pathway that restrains an action. These two neuron types can be seen together in either the striosomes or the matrix.
Read Also: University of Wisconsin Researchers Use Stem Cells to Treat Parkinson’s
RNA expression analysis of the cell types showed that striosomal neurons are more impacted by Huntington’s disease, compared to matrix neurons. D2 neurons inside the striosomes were also worse affected than their D1 counterparts.
The research team further observed that all major cell types lose their unique features as Huntington’s progresses. Put differently, it became harder to tell between one and the other.
“Overall, the distinction between striosomes and matrix becomes really blurry,” noted Graybiel, who is an MIT Institute Professor and a member of the McGovern Institute for Brain Research.
Striosomal expression and mood disorders
Current study results hint that striosomal damage may be to blame for mood disorders typically seen early in the development of Huntington’s. The researchers stated that matrix neuron degeneration later on in the disorder likely explains the loss of motor control.
Scientists found a link between the overactivity of striosomes and the incidence of repetitive behaviors like those seen in obsessive-compulsive disorder (OCD) and autism in past research. This suggests that the striatum is involved in more than Huntington’s disease.
“There are many, many disorders that probably involve the striatum, and now, partly through transcriptomics, we’re working to understand how all of this could fit together,” said Graybiel.
At least one of those genes that were found to be overexpressed in the striosomes of Huntington’s patients in the study has a link to autism. Numerous neurons of the striosomes also extend to the substantia nigra, a brain region that is worst hit by Parkinson’s disease.
The mapping of the striatum and how Huntington’s disease impacts it could aid the development of treatments that focus on specific brain cells. Graybiel and her colleagues noted that this sort of analysis may help to better understand striatum-linked disorders, including autism.
This study was published in Nature Communications.
The researchers are looking to further probe how irregular striosomal gene expression may play a part in other brain disorders in the future.
References
Matsushima, A., Pineda, S.S., Crittenden, J.R. et al. Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease. Nat Commun 14, 282 (2023). https://doi.org/10.1038/s41467-022-35752-x
