VTA-projecting cerebellar neurons mediate stress-dependent depression-like behavior

Abstract

Although cerebellar alterations have been implicated in mental depression, the exact contribution of the cerebellum to depressive symptoms remains to be elucidated. Here, we demonstrated the crucial role of cerebellar neurons projecting to the ventral tegmental area (VTA) in the chronic stress-induced development of depression-like behavior. The combination of adeno-associated virus-based circuit mapping and electrophysiological recording identified network connections from crus I to the VTA via the dentate nucleus (DN) of the deep cerebellar nuclei. Chronic chemogenetic activation of inhibitory Purkinje cells in crus I suppressed c-Fos expression in the DN and depression-like behavior, which were triggered by chronic stress application. Furthermore, specific inhibition of neurons in the DN that project to the VTA prevented stressed mice from showing depression-like behavior, whereas specific activation of these neurons alone triggered depression-like behavior that was comparable with the one triggered by chronic stress application. Our results indicate that the VTA-projecting cerebellar neurons proactively regulate depression-like behavior, raising the possibility that cerebellum may be an effective target for the prevention of depressive disorders.