Overexpression of FoxO3a in the dentate gyrus alleviates CUS-induced anxiety- and depression-like behaviors and cognitive impairment.

BACKGROUND: Excessive stress leads to injury and dysfunction, but the underlying mechanism remains unclear. As a human longevity gene, forkhead box O3a (FoxO3a) is a transcription factor that regulates various cellular processes, including the response to oxidative stress, apoptosis, and autophagy. This study aims to explore whether FoxO3a in the dentate gyrus (DG) of the hippocampus is involved in the formation of anxiety- and depressive-like behavior and cognitive impairment in stressed rats and to investigate the detailed mechanism. METHODS: This study was conducted using the 6-week chronic unpredictable stress (CUS) model. Before the stress treatment, we injected an adeno-associated virus (AAV) vector to overexpress FoxO3a specifically in the DG. Following the 6-week CUS treatment, a series of behavioral tests was conducted. Depression-like behavior was assessed using the sucrose preference test (SPT) and the open field test (OFT). The state of desperation was assessed with the forced swim test (FST) and tail suspension test (TST). Anxiety-like behavior was measured in the elevated plus maze (EPM) and OFT. Cognitive function was examined using the Y-maze test (Y-maze), novel object recognition test (NORT), and Morris water maze test (MWM). The level of reactive oxygen species (ROS) and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were measured. The levels of inflammatory factors were detected by ELISA. Pathological injury in DG was observed using thionine staining. The expression levels of FoxO3a, brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD95), synaptophysin (SYN), and proliferation marker Ki67 (Ki67) were determined using western blot. RESULTS: CUS leads to various abnormal changes, including anxiety- and depressive-like behavior, cognitive impairment, oxidative stress, neuroinflammation, neuropathological alterations in the DG, and decreased expression of FoxO3a, BDNF, PSD95, SYN, and Ki67. All these abnormal changes were significantly alleviated by targeted AAV-FoxO3a injection in the DG. CONCLUSIONS: In conclusion, our study demonstrates that the downregulation of FoxO3a induced by CUS in the DG triggers oxidative stress and inflammatory response, inhibits cell proliferation, and induces abnormal synaptic plasticity, ultimately leading to anxiety- and depressive-like behaviors and cognitive impairment.