Serotonergic input into the cerebellar cortex modulates anxiety-like behavior.

Abstract

Because of the important roles of both serotonin (5-HT) and the cerebellum in regulating anxiety, we asked whether 5-HT signaling within the cerebellum is involved in anxiety behavior. Physiological 5-HT levels were measured in vivo by expressing a fluorescent sensor for 5-HT in lobule VII of the cerebellum, while using fiber photometry to measure sensor fluorescence during anxiety behavior on the elevated zero maze. Serotonin increased in lobule VII when male mice were less anxious and decreased when mice were more anxious. To establish a causal role for this serotonergic input in anxiety behavior, we photostimulated or photoinhibited serotonergic terminals in lobule VII while mice were in an elevated zero maze. Photostimulating these terminals reduced anxiety behavior in mice, while photoinhibiting them enhanced anxiety behavior. Our findings add to evidence that cerebellar lobule VII is a topographical locus for anxiety behavior and establish that 5-HT input into this lobule is necessary and sufficient to bidirectionally influence anxiety behavior. These results represent progress toward understanding how the cerebellum regulates anxiety behavior and provide new evidence for a functional connection between the cerebellum and the serotonin system within the anxiety circuit.Significance Statement This is the first analysis of the involvement of the neuromodulator, serotonin, in the cerebellum during anxiety behavior. Our results reveal that serotonin regulates anxiety behavior. This offers new insight into the role of serotonin in the cerebellum, as well as illuminating how the cerebellum interacts with the rest of the brain to produce anxiety. Our results are important for future use of serotonin-related pharmacological therapeutics, such as selective serotonin-reuptake inhibitors, in treating anxiety in humans.