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One of the most well-known symptoms of Parkinson’s disease is its movement disorders. Patients often experience tremors, loss of balance, and difficulty initiating movement.
Now, the study of a small region of the thalamus has allowed a team of neuroscientists from the Massachusetts Institute of Technology-MIT (USA) to identify three different circuits that influence the development of these motor symptoms, but also of those that are not related to movement, such as depression.
But, the most important thing is that they have seen that by manipulating these circuits, they could reverse the symptoms of Parkinson’s in mice.
The findings suggest that these circuits could be a target for the design of new drugs that could help combat many of the symptoms of Parkinson’s disease.
“We know that the thalamus is important in Parkinson’s disease, but a key question is how you can put together a circuit that can explain many different things that happen in Parkinson’s disease. Understanding different symptoms at the circuit level can help guide us in developing better therapies.” Guoping Fenglead author of the study published in “Nature”.
The thalamus consists of several different regions that perform a variety of functions. Many of these, including the parafascicular (PF) thalamus, help control movement. Degeneration of these structures is seen in many patients with Parkinson’s disease, which is thought to contribute to their motor symptoms.
This study has investigated how the PF thalamus is connected to other brain regions, hoping to learn more about its functions. They thus discovered that PF thalamic neurons project to three different parts of the basal ganglia, a group of structures involved in motor control and other functions: the caudate putamen (CPu), the subthalamic nucleus (STN) and the nucleus accumbens (NAc). ).
Later studies revealed those functions. The circuit that projects to the CPu appears to be involved in general locomotion and functions to dampen movement. When the researchers inhibited this circuitry, the mice spent more time moving around the cage.
The circuitry that extends into 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 bar that rotates with increasing speed.
Finally, they found that, unlike the others, the circuit connecting the PF thalamus with the NAc is not involved in motor activity. Instead, it appears to be linked to motivation. Inhibiting this circuit generates depression-like behaviors in healthy mice, and they will no longer seek a reward like sugar water.
Once the researchers established the functions of these three circuits, they set out to explore how they might be affected in Parkinson’s disease. To do this, they used a mouse model of Parkinson’s, in which dopamine-producing neurons in the midbrain are lost.
They found that in this model of Parkinson’s, the connection between the PF thalamus and the CPu was enhanced, and that this led to a decrease in overall movement. In addition, connections from the PF thalamus to the STN were weakened, making it difficult for the mice to learn the speed bar task.
Finally, the researchers showed that in the Parkinson’s model, connections from the PF thalamus to the NAc were also disrupted, and that this led to depression-like symptoms in the mice, including loss of motivation.
Using chemogenetics or optogenetics, which allows them to control neural activity with a drug or light, they found they could manipulate each of these three circuits and, in doing so, reverse each set of Parkinson’s symptoms.
In addition, they searched for molecular targets that could be ‘medicable’ and found that each of the three regions of the PF thalamus has cells that express different types of cholinergic receptors, which are activated by the neurotransmitter acetylcholine. By blocking or activating those receptors, depending on the circuitry, they 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 mice with Parkinson’s,” explains Zhang.
Parkinson’s patients are usually treated with L-dopa, 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.
The researchers hope that the circuits they characterized in this study could be targets for new Parkinson’s therapies. The types of neurons they identified in mouse brain circuits are also found in the brains of nonhuman primates, and the researchers are now using RNA sequencing to find genes that are specifically expressed in those cells.
“RNA sequencing technology will allow us to do much more detailed molecular analysis in a cell-type-specific way,” Feng says. There may be better drug targets on these cells, and once you know the specific cell types you want to modulate, you can identify all sorts of potential targets on them.”
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