Social preferences: Reducing the activity of dopamine receptors in two regions of the mouse cerebellum, Crus I and Crus II, makes the mice more sociable; increasing receptor activity does the opposite.
Courtesy of Emmanuel Valgent
Activity of the signaling molecule dopamine in the cerebellum plays a key role in regulating social behavior, a new study in mice reveals.
The cerebellum, a brain structure located at the base of the skull, is traditionally thought to control movement. But growing evidence suggests that it also plays a role in social behavior and other complex cognitive functions, a link that has sparked growing interest in the structure among autism researchers.
Dopamine signaling in other brain regions is also known to be involved in social behavior, but few studies have looked at dopamine in the cerebellum. The new study links the social role of dopamine in the cerebellum to a specific type of cell in a specific region, similar to how functions such as language and visual processing are located in specific parts of the cerebral cortex.
The task of correlating location and function in the cerebellum is particularly difficult, making the work “groundbreaking,” said Sam Wang, a professor of neurology at Princeton University who was not involved in the study. “This provides some resolution to the question of how it is possible for the cerebellum to be involved in the regulation of higher functions.”
In the past, scientists have had trouble mapping the location of dopamine receptors — proteins that are found on the cell surface and bind to the molecule — in the cerebellum. Not only are there relatively few of them, but experimental techniques are not sensitive enough to pinpoint their location, says study leader Emmanuel Valgent, research director at the National Institute of Health and Medical Research (INSERM) and the Institute of Functional Genomics in the University of Montpellier in France.
Valgent and his collaborators used two genetically modified lines of mice to show that a particular class of dopamine receptors, known as D2 receptors, are located in the outer layer of the cerebellum. Specifically, D2 receptors are found primarily in Purkinje cells, which integrate and filter information and then transmit signals from the cerebellum to other parts of the brain. Postmortem brains of people with autism show loss of Purkinje cells.
“Dopamine is there, and the function is perhaps more important than we expect,” Valgent says.
Chemically stimulating the D2 receptor in mouse cerebellar slices suppresses excitatory signaling, indicating one way Purkinje cells do their job of modulating and integrating neural signaling, Valgent says. The work appeared on June 16 in Nature Neurology.
To gain better insight into the function of dopamine signaling in the cerebellum, the researchers then used a genetically engineered virus to turn off D2 receptor activity in Purkinje cells in adult male mice.
Because of the cerebellum’s well-known role in movement coordination, “we expected to find motor impairment by manipulating the level of the D2 receptor,” Valgent says. “But there was nothing there.” Mice lacking D2 receptor activity in the Purkinje cells loiter, balance on a beam, and move on a treadmill just as well as control mice.
Researchers were at an impasse when one of the first papers on dopamine in the cerebellum appeared in 2019, implicating dopamine in the deep cerebellar nuclei in social behavior. Inspired by these results, Valgent and his colleagues decided to test the animals’ social behavior. Mice lacking D2 receptor activity in Purkinje cells spent more time sniffing another mouse placed in their cage than control mice, and also showed a stronger preference for a newly introduced mouse over a familiar one.
A second genetically engineered virus designed to enhance D2 receptor expression in Purkinje cells produced mice with the opposite characteristics: they were less interested in interacting with other mice and less interested in mice they had not met before, in compared to controls.
D2 receptors are most abundant in Purkinje cells in Crus I and Crus II, regions of the cerebellum previously implicated in social behavior. When the researchers manipulated D2 receptor levels in Purkinje cells in Crus I and Crus II alone, it produced the same effects on social behavior as altering D2 levels in the cerebellum as a whole.
“They were able to demonstrate that Purkinje cell expression of the D2 dopamine receptor is not necessary and sufficient throughout the cerebellum to change these behaviors, but really in this focused area,” says Eric Carlson, assistant professor of psychiatry and Behavioral Sciences at the University of Washington in Seattle. “It’s really surprising; it’s really deep and really strong.
Because D2 receptors are also found elsewhere in the cerebellum and in cell types other than Purkinje cells, “they haven’t ruled out the possibility that there are other cells that are involved in this dopamine function,” Wang says.
Valjent and his team are now examining cerebellar D2 receptors in the brains of several mouse models of autism, including mice lacking the FMR1, MECP2 and SHANK3 genes.
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