Stress-induced depression is common worldwide. Nucleus accumbens (NAc), a “reward” center, is recently reported to be critical to confer the susceptibility to chronic social defeat stress (CSDS) and the depression-related outcome. However, the underlying molecular mechanisms have not been well characterized. In this study, we induced depression-like behaviors with CSDS and chronic mild stress (CMS) in male mice to mimic social and environmental factors, respectively, and observed animal behaviors with social interaction test, tail suspension test and sucrose preference test. To determine the role of neuronal nitric oxide synthase (nNOS) and its product nitric oxide (NO), we employed brain region-specifically nNOS overexpression and stereotaxic injection of NO inhibitor or donor. Moreover, the downstream molecular cyclin-dependent kinase 5 (CDK5) was explored by conditional knockout and gene mutation. We demonstrate that nNOS-implicated mechanisms in NAc shell (NAcSh), including increased cell number, incre...