MIT scientists manipulate brain circuits, reverse Parkinson’s symptoms in mice

A groundbreaking new study on Parkinson’s disease could help combat patients’ symptoms. Massachusetts Institute of Technology neuroscientists were able to identify three distinct circuits in the small region of the thalamus in the brain that influences the development of both motor and nonmotor Parkinson’s symptoms.

When scientists manipulated these circuits in mice with Parkinson’s disease, they were able to reverse symptoms. Scientists believe new drugs could target these circuits and bring relief to sufferers.

“We know that the thalamus is important in Parkinson’s disease, but a key question is how can you put together a circuit that can explain many different things happening in Parkinson’s disease. Understanding different symptoms at a circuit level can help guide us in the development of better therapeutics,” says study senior author Guoping Feng, a professor in Brain and Cognitive Sciences at MIT, and the associate director of the school’s Institute for Brain Research, in a statement.

In the study, scientists found that neurons of the parafascicular (PF) thalamus “project to three different parts of the basal ganglia, a cluster of structure involved in motor control and other functions: the caudate putamen (CPu), the sub thalamic nucleus (STN), and the nucleus accumbens (NAc).” Patients with Parkinson’s usually have degeneration of these structures.

“We started with showing these different circuits, and we demonstrated that they’re mostly non overlapping, which strongly suggests that they have distinct functions,” explains study lead author Dheeraj Roy.

According to scientists, the CPu circuit is involved in general locomotion; the STN circuit is important for motor learning; and the NAc is linked to motivation and not involved in motor activity. Scientists then used a mouse model to explore how these circuits might be affected by Parkinson’s.

They found a decrease in overall movement in mice after the connection between the PF thalamus and the CPu was enhanced. Also, the connections from the PF thalamus to the STN were weakened, making it more difficult for mice to learn a task.

In this image of the parafascicular (PF) thalamus, the blue cells participate in reward processing/depression, the red cells are critical for motor learning, and the green cells are important for general locomotion. The ‘fr’ stands for a fiber bundle. (Credit: Ying Zhang and Dheeraj Roy)

Mice even exhibited depression-like symptoms when the PF thalamus connections to the NAc were disrupted.

Scientists were able to manipulate these three circuits and reverse each set of Parkinson’s symptoms by using chemogenetics and optogenetics. They then looked for molecular targets that might be “druggable,” “and found that each of the three PF thalamus regions have cells that express different types of cholinergic receptors.” Researchers were able to block or activate those receptors and were also able to reverse Parkinson’s symptoms.

“We found three distinct cholinergic receptors that can be expressed in these three different PF circuits, and if we use antagonists or agonists to modulate these three different PF populations, we can rescue movement, motor learning, and also depression-like behavior in PD mice,” says study lead author Ying Zhang, a J. Douglas Tan Postdoctoral Fellow at the McGovern Institute.

Scientists hope these circuits could be targets for new Parkinson’s therapies.

The study is published in the journal Nature.

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