<p>Chronic stress increases the risk of developing depression. However, the neurological mechanism by which chronic stress elicits depression remains largely unknown. Here, we identify that somatostatin-positive neurons in the zona incerta (ZI^SST neurons) regulate chronic restraint stress response and are involved in regulating depression-like behaviors. Activation of the ZI^SST neurons produces antidepressant-like behaviors, which is triggered by the direct input from the vesicular glutamate transporter 2-positive neurons in the anterior cingulate cortex (ACC). Inactivation of ZI^SST neurons produces depression-like behaviors by activating neurons in the lateral habenula (LHb). Interestingly, (2 R,6 R)-hydroxynorketamine (HNK) alleviates chronic restraint stress-induced depression-like behaviors through the activation of ZI^SST neurons. Collectively, these findings reveal a critical role of ZI^SST neurons in encoding chronic stress-induced depression and suggest that activating ZI^SST neurons may offer a new strategy for treating depression.</p>