Abstract :Although the cerebellum has traditionally been viewed as responsible primarily for motor coordination and learning, its role in non-motor cognitive functions and mental regulation is increasingly recognized. One non-motor dysfunction with a relatively well-established cerebellar link is autism spectrum disorders (ASD). Our recent findings suggest that multiple epidermal growth factor-like domains protein 11 (MEGF11), previously identified as a risk factor for ASD, may contribute to ASD pathogenesis by regulating proper presynaptic release from developing granule cells. Beyond its link with ASD, we have investigated whether the cerebellum plays a role in chronic stress-mediated depression-like behaviors. We found that chronic stress, which triggers depression-like behaviors, increased c-Fos expression in neurons of the deep cerebellar nucleus (DCN), specifically within the dentate nucleus (DN), indicating heightened neuronal activity in response to stress. Chemogenetic inhibition of DCN neurons projecting to the ventral tegmental area (VTA) during chronic stress exposure prevented the behavioral alterations typically caused by stress. Conversely, chronic excitation of these DCN neurons alone was sufficient to induce behaviors resembling stress-related depression. Further analysis suggests that the stress-induced increase in DCN neuron activity leads to plastic changes in the VTA. Based on these findings, we conclude that the cerebellum directly influences the development of stress-dependent depression-like behaviors via specific DCN neurons modulating VTA functions.