Social Preference: Decreasing dopamine receptor activity in two regions of the mouse cerebellum, Crus I and Crus II, makes mice more sociable; Improving receptor activity does the opposite.
Courtesy of Emmanuel Valjent
The activity of the dopamine signaling molecule 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 believed to control movement. But growing evidence suggests that it also plays a role in social behavior and other complex cognitive functions, a connection that has aroused growing interest in structure among autism researchers.
It is also known that dopamine signaling in other regions of the brain is involved in social behavior, but few studies have analyzed dopamine in the cerebellum. The new study links the social role of dopamine in the cerebellum with a specific cell type in a specific region, similar to how functions such as language and visual processing are located in particular parts of the cortex. cerebral.
The task of matching location and function in the cerebellum has been especially difficult, making the work “pioneering,” says Sam Wang, a professor of neuroscience at Princeton University who did not participate in the study. “It offers a solution to the question of how the cerebellum might be involved in the regulation of higher functions.”
In the past, scientists had trouble mapping the location of dopamine receptors (proteins that sit on the cell surface and bind to the molecule) in the cerebellum. Not only are there relatively few, but experimental techniques were not sensitive enough to accurately identify them, says study leader Emmanuel Valjent, research director at the National Institute of Health and Medical Research ( INSERM) and the Institute of Functional Genomics at the University of Montpellier in France.
Valjent and his collaborators used two lines of genetically designed mice to show that a particular class of dopamine receptors, known as D2 receptors, are found throughout the outer layer of the cerebellum. Specifically, D2 receptors are found primarily in Purkinje cells, which integrate and filter information and then pass signals from the cerebellum to other parts of the brain. The postmortem brains of people with autism show a loss of Purkinje cells.
“Dopamine is there and function is perhaps more important than we expect,” Valjent says.
Valjent says chemical stimulation of the D2 receptor in the slices of the mouse cerebellum reduced excitatory signaling, indicating a way in which Purkinje cells do their job of modulating and integrating neuronal signaling. The play appeared on June 16 Neuroscience of nature.
To learn more about the function of dopamine signaling in the cerebellum, the researchers used a genetically modified virus to inactivate D2 receptor activity in Purkinje cells in adult male mice.
Because of the known role of the cerebellum in coordinating movement, “we expected to find motor impairment by manipulating the D2 receptor level,” Valjent says. “But there was nothing.” Mice lacking D2 receptor activity in Purkinje cells were run, balanced on a beam, and mounted on a rotating bar just like control mice.
Researchers were in a dead end when, in 2019, one of the first articles on dopamine in the cerebellum emerged, involving dopamine in the deep cerebellar nuclei in social behavior. Inspired by these results, Valjent and his colleagues decided to test the social behavior of animals. Mice lacking D2 receptor activity in Purkinje cells spent more time smelling another mouse placed in their cage than control mice, and also showed a stronger preference for a newly introduced mouse. than a familiar one.
A second genetically engineered virus designed to enhance D2 receptor expression in Purkinje cells resulted in mice with opposite characteristics: they were less interested in interacting with other mice and less interested in mice they had not known before in comparison with controls.
D2 receptors are more abundant in Purkinje cells in Crus I and Crus II, regions of the cerebellum that have previously been implicated in social behavior. When the researchers manipulated D2 receptor levels in Purkinje cells only in Crus I and Crus II, it produced the same effects on social behavior as altering D2 levels in the cerebellum as a whole.
“They were able to show that Purkinje cell expression of the dopamine D2 receptor was not only necessary and sufficient throughout the cerebellum to alter these behaviors, but really in this focused area,” says Erik Carlson, adjunct professor. of psychiatry and behavioral sciences. at the University of Washington in Seattle. “This is really amazing; this is really deep and very powerful. “
Because D2 receptors are also found elsewhere in the cerebellum and in cell types other than Purkinje cells, however, “they have not ruled out the possibility that there are other cells involved in this function of the brain. dopamine, ”says Wang.
Valjent and his team are investigating the cerebellar D2 receptors in the brain of several autism mouse models, including mice that do not have the FMR1, MECP2, and SHANK3 genes.
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