The cerebellum interacts with many brain areas through both direct and indirect synaptic connections, and one of the brain areas receiving direct inputs from the deep cerebellar nuclei (DCN), which is the major cerebellar output, is the ventral tegmental area (VTA) ( Snider et al., 1976 Parker et al., 2014 Beier et al., 2015 Carta et al., 2019). Although the accumulating lines of evidence indicate the involvement of the cerebellum in stress responses and stress-associated disorders, the exact role played by the cerebellum remains unclear. Alterations of the cerebellum, such as decreased volume, abnormal neuronal activity, and disrupted cortical connectivity, have also been observed in patients with major depressive disorder and post-traumatic stress disorder, and such alterations are often correlated with symptoms of these disorders ( De Bellis and Kuchibhatla, 2006 Alalade et al., 2011 Baldaçara et al., 2011 Liu et al., 2012 Guo et al., 2012 Guo et al., 2013 Phillips et al., 2015 Córdova-palomera, 2016 Xu et al., 2017 Depping et al., 2018 Moreno-Rius, 2019). The cerebellum is affected by stress, as is evident from the alterations in function, structure, and molecular expression that occur in the cerebellum after the exposure of animals or humans to stressful events ( Gounko et al., 2013 Huguet et al., 2017 Bambico et al., 2018 Moreno-Rius, 2019). Consistent with the common notion that reward circuitry regulates stress-driven behavioral changes or depressive symptoms ( Nestler and Carlezon, 2006 Russo and Nestler, 2013 Pignatelli and Bonci, 2015 Fox and Lobo, 2019), many studies have demonstrated that abnormalities of the cerebellum are associated with stress responses or mental disorders, latter of which include major depressive disorder and post-traumatic stress disorder that can be triggered or worsened by stress. One such non-motor cognitive function is reward-related processing ( Carta et al., 2019 Medina, 2019 Hull, 2020 Sendhilnathan et al., 2020). Whereas the cerebellum has traditionally been considered to be important solely for motor coordination and learning, it became apparent that the cerebellum is also involved in higher cognitive functions ( Rochefort et al., 2013 Hull, 2020 Wagner and Luo, 2020). Our results indicate that the VTA-projecting cerebellar neurons proactively regulate the development of depression-like behavior, raising the possibility that cerebellum may be an effective target for the prevention of depressive disorders in human. Furthermore, chronic inhibition of specific neurons in the DN that project to the VTA prevented stressed mice from showing such depression-like behavior, whereas chronic activation of these neurons alone triggered behavioral changes that were comparable with the depression-like behaviors triggered by chronic stress application. 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 an increase in immobility in the tail suspension test or forced swimming test, which were triggered by chronic stress application. Here, we demonstrated the crucial role of cerebellar neurons projecting to the ventral tegmental area (VTA) in the development of chronic stress-induced behavioral alterations in mice. Although cerebellar alterations have been implicated in stress symptoms, the exact contribution of the cerebellum to stress symptoms remains to be elucidated.
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