People with Parkinson’s disease experience problems with body movement, motor cognition and mood. Aiming to pinpoint the neuronal elements responsible for these symptoms, a research team led by scientists at the Massachusetts Institute of Technology identified three distinct brain circuits that they say could lead to the development of new therapeutic approaches.
The team made the discovery in parafascicular (PF) thalamus, a region of the brain known to help control movement, and its degeneration is thought to contribute to the symptoms seen in Parkinson’s disease.
In a new study published in Nature, the team showed that distinct subpopulations of PF neurons are connected to three different brain structures involved in the coordination of movement and other functions: the caudate putamen (CPu), the subthalamic nucleus (STN), and the nucleus accumbens (NAc). They also identified specific receptors on the circuits that could be targeted by small-molecule drugs.
“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,” MIT’s Guoping Feng, Ph.D., senior author of the study, explained in a statement.
Heading into the research, the researchers at first thought the three PF subpopulations would all contribute to at least one motor function. But that didn’t seem to be the case.
The scientists blocked the activity of each of the subpopulations in mice and watched the animals perform various tasks. Turns out, the CPu circuit is involved in directional movement. Mice without it spent more time wandering around the cage, the team found.
The STN circuit was found to be important for motor learning—the ability to adopt a new motor skill through practice. Once it was inhibited, mice performed worse on a rotarod training test, which measures how long a rodent could balance itself on a spinning rod.
Unexpectedly, the circuit projecting to NAc didn’t seem to be involved in any motor functions. Instead, blocking the NAc circuit led to a depression-like state in mice as the animals lost interest in rewards such as sugar water.
In a mouse model of Parkinson’s disease, the scientists found those three circuits were indeed altered. The CPu circuit was enhanced, which decreased overall movement. The STN and NAc circuits were weakened.
The scientists then used various light and chemical methods to correct those circuit alternations and showed that by either increasing or decreasing the activity of the implicated neurons they could reverse the circuits’ respective Parkinson’s symptoms.
Next, they went on to identify potential druggable molecular targets that might allow for therapeutic manipulation of the three circuits. The team found that the PF thalamus regions have cells that express different subtypes of nicotinic acetylcholine receptors (nAChRs), which are activated by the neurotransmitter acetylcholine. Compounds that inhibit or activate the receptors—depending on the circuit—could alleviate the Parkinson’s symptoms in mice, the team showed.
Parkinson’s is currently mostly treated by levodopa to control the shaking and stiffness. But the drug doesn’t tackle motor learning or any non-motor complications.
The MIT team hopes the three circuits it identified could help design new therapies for Parkinson’s. Before that, it will be important to test whether the findings also apply to humans, the scientists noted. Taking another step toward that goal, they found that the nAChR receptors are also expressed in the circuits in monkeys’ brains, and they are now using RNA sequencing to profile those cells.
“RNA-sequencing technology will allow us to do a much more detailed molecular analysis in a cell-type-specific way,” Feng said in a statement. “There may be better druggable targets in these cells, and once you know the specific cell types you want to modulate, you can identify all kinds of potential targets in them.”