Targeting the thalamic circuits may reverse Parkinson’s disease symptoms in mice

Parkinson’s disease is known as a movement disorder. Patients often experience tremors, loss of balance, and difficulty initiating movement. The disease also has less well-known non-motor symptoms, including depression.

In a study of a small area of ​​the thalamus, neuroscientists at the Massachusetts Institute of Technology have now identified three distinct circuits that influence the development of motor and non-motor symptoms of Parkinson’s disease. Moreover, they found that by manipulating these circuits, they could reverse the symptoms of Parkinson’s disease in mice.

The researchers say the findings suggest that these circuits could be good targets for new drugs that can help combat many of the symptoms of Parkinson’s disease.

We know that the hypothalamus is important in Parkinson’s disease, but the key question is how do you put together a circuit that can explain the many different things that happen in Parkinson’s disease. Understanding the different symptoms at the circuit level can help guide us in developing better treatments. “


Guoping Feng is the James W. and Patricia T. Poitras Professor of Brain and Cognitive Science at MIT, a member of the Broad Institute at Harvard and MIT, and associate director of the McGovern Institute for Brain Research at MIT.

Feng is the lead author of the study, which appears today in temper nature. Ying Zhang, J. Douglas Tan Postdoctoral Fellow at the McGovern Institute, and Dheeraj Roy, NIH K99 Laureate and McGovern Fellow at the Broad Institute, are the paper’s lead authors.

tracking circles

The thalamus consists of several different areas that perform a variety of functions. Several of these, including the paraventricular thalamus (PF), help control movement. Degeneration of these structures is often seen in patients with Parkinson’s disease, which is thought to contribute to their motor symptoms.

In this study, the MIT team set out to try to trace how the PF thalamus relates to other brain regions, in hopes of learning more about its functions. They found that neurons in the PF thalamus divide into three different parts of the basal ganglia, a group of structures involved in motor control and other functions: the putamen caudate (CPu), the hypothalamic nucleus (STN), and the nucleus accumbens (NAc). ).

“We started by showing these different circuits, and we demonstrated that they are mostly non-overlapping, strongly suggesting that they have distinct functions,” Roy says.

Other studies have revealed these functions. The circuit firing into the CPU appears to be involved in the general movement, damping the movement. When the researchers blocked this circuit, the mice spent more time moving around the cage they were in.

The circuit extending to the STN, on the other hand, is important for motor learning -; The ability to learn a new motor skill through practice. The researchers found that this circuit is necessary for a task in which mice learn to balance on a rod rotating at an increased speed.

Finally, the researchers found that, unlike others, the circuit connecting the hypothalamic PF to the NAc is not involved in motor activity. Instead, it appears to be related to motivation. Blocking this circuit generates depression-like behaviors in healthy mice, and they will no longer seek a reward like sugar-sweetened water.

smuggable targets

Once the researchers had identified the functions of these three circuits, they decided to explore how they might be affected by Parkinson’s disease. To do this, they used a mouse model of Parkinson’s disease, in which dopamine-producing neurons are lost in the midbrain.

They found that in this Parkinson’s disease model, connectivity between the PF’s thalamus and the CPu was enhanced, resulting in a decrease in overall motility. In addition, the connections from the PF thalamus to the STN were impaired, making it difficult for rats to learn the penis acceleration task.

Finally, the researchers showed that in the Parkinson’s disease model, connections from the PF thalamus to the NAc were also severed, and this led to depression-like symptoms in mice, including a loss of motivation.

Using chemical genetics or optogenetics, which allow them to control neuronal activity with a drug or light, the researchers found that they could manipulate each of these three circuits and, in so doing, reverse each set of Parkinson’s symptoms. Next, they decided to search for molecular targets that might be ‘treatable’, and found that each of the three PF hypothalamic regions had cells expressing different types of cholinergic receptors, which are activated by the neurotransmitter acetylcholine. By blocking or activating those receptors, depending on the circuit, they were also able to reverse the symptoms of Parkinson’s disease.

“We found three distinct cholinergic receptors that can be expressed in the three different PF circuits, and if we use antagonists or agonists to modulate the three different PF combinations, we can rescue movement, locomotor learning, and also depression-like behavior in PD mice,” Zhang says.

Parkinson’s patients are usually treated with L-dopa, which is a precursor to dopamine. While this drug helps patients regain motor control, it does not help with motor learning or any non-motor symptoms, and over time, patients become resistant to it.

The researchers hope that the circuits they describe in this study may be targets for new Parkinson’s treatments. The types of neurons identified in mouse brain circuits have also been found in the brain of non-human primates, and researchers are now using RNA sequencing to find genes that are specifically expressed in those cells.

“The RNA sequencing technology will allow us to perform a more detailed molecular analysis in a cell-type-specific manner,” says Feng. “There may be better psychedelic targets in these cells, and once you know the specific types of cells you want to modify, you can identify all kinds of potential targets in them.”

The research was funded in part by the K. Lisa Yang and Hock E. MIT Center, the National Institutes of Health BRAIN Initiative, and the National Institute of Mental Health.

source:

Massachusetts Institute of Technology

Journal reference:

Chang, Wai. et al. (2022) Targeting of the thalamic circuits rescues motor and mood deficits in PD rats. temper nature. doi.org/10.1038/s41586-022-04806-x.

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