2023-11-10 01:02:22
November 10, 2023, reading time: 4 minutes.
New findings from the brain: Researchers have discovered in which area of the brain discomfort and aversion arise. They discovered that activation of the subthalamic nucleus in mice causes severe discomfort. Since this brain region is stimulated therapeutically in Parkinson’s patients, the study might explain why depressive side effects sometimes occur when treating Parkinson’s. This area of the brain might therefore also play a role in the development of depression. The results might therefore lead to better treatments for Parkinson’s and other diseases.
In Parkinson’s disease, the brain region of the subthalamus (subthalamic nucleus), which controls voluntary movements and behavior, is overly active. Stimulation of this brain region with implanted electrodes “corrects” this and often eliminates the typical tremors and other motor complaints of this neurodegenerative disease in Parkinson’s patients. However, some patients experience side effects such as severe depression. A research group has now discovered why this is so.
Researchers led by Gian Pietro Serra from Uppsala University have long been using mice to investigate what happens when the subthalamus is activated by deep brain stimulation. In a previous study, they found that mice whose subthalamus was activated in this way tried to escape the stimulation.
Targeted activation of the subthalamic nucleus
Serra and his team have now examined in more detail why their test mice apparently found the brain stimulation unpleasant. To do this, they used an optogenetic method to specifically stimulate the subthalamic nucleus of mice and no other brain tissue. They used light to activate or deactivate individual neurons in the brains of genetically modified mice that had light-sensitive proteins on their surface.
Using specific molecular markers, the researchers precisely distinguished the subthalamic nucleus from its surrounding neuronal structures. This allowed them to examine how individual neurons in the mice’s brains were affected by the light and how the mice behaved when the neurons were more or less active.
Mice avoid feeling unwell
The experiments showed that if the subthalamus in the mice was stimulated, this apparently caused the animals a pronounced feeling of discomfort. They react with a feeling of revulsion or fear. The researchers recognized this because the animals repeatedly groomed the fur on their faces – a behavior that is known from previous studies.
Surprisingly, the animals avoided the experimental situation not only during activation of the subthalamic nucleus, but also when this brain region was not activated in a later experiment. The researchers conclude that the mice remembered the discomfort they experienced and avoided the situation as a precaution. The associations between the experienced situation and the negative feeling were therefore strong enough to maintain the behavior.
“Our study shows that this region of the brain is involved in aversion and avoidance behavior when stimulated,” explains senior author Åsa Wallén-Mackenzie from Uppsala University. She and her colleagues have now identified the place in the brain that causes discomfort and aversion: the subthalamic nucleus. They have also identified neural circuits that connect this region with the brain’s emotional system, which becomes active when people are extremely unwell.
Link to depression and Parkinson’s disease
According to the researchers, the feeling of aversion fulfills a biologically important function: it makes animals and us humans avoid things that make us feel guilty. However, it is also known from previous studies that strong activation of the brain’s aversion system can lead to depression in humans.
“The fact that the subthalamus causes aversion and avoidance behavior is therefore an important finding. “It expands our understanding of the brain’s emotional system and how brain activity can lead to psychiatric symptoms such as depression and apathy,” says Wallén-Mackenzie. “It may also explain why such side effects may occur in people with Parkinson’s disease treated with deep brain stimulation.”
Hope for refined therapy for Parkinson’s
These results not only provide new insights into where in the brain discomfort and aversion arise, they might also be of practical medical use. “Now that we can show that the subthalamus has a direct connection to aversion and is connected to the depression center of the brain, we can neurobiologically understand and explain these side effects when treating Parkinson’s patients,” says Serra.
“Our study paves the way for improved clinical precision of these treatments,” explains Mackenzie. The aim is to treat the symptoms of the disease without causing serious side effects. This might also be helpful for other diseases such as tremors, Tourette’s, and obsessive-compulsive and eating disorders, which are also treated by stimulating the subthalamus. However, further studies are needed to uncover which neurons within the subthalamus are involved in the observed avoidance behavior and depression. (Cell Reports, 2023; doi: 10.1016/j.celrep.2023.113328)
Source: Swedish Research Council
10 November 2023 – Claudia Krapp
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