EXPLORING THE EFFICACY OF ENRICHED ENVIRONMENTAL TRAINING IN MITIGATING DEPRESSION SYMPTOMS AND PROTECTING HIPPOCAMPAL NEURONS IN CHRONIC UNPREDICTABLE MILD STRESS MODELS: INTEGRATING PHYSICAL FITNESS AND MENTAL HEALTH STRATEGIES

Abstract

Background: Hippocampal neuron damage and impaired regeneration are critical in depression's pathogenesis. An Enriched Environment (EE) has been shown to ameliorate depressive-like behaviors in animals, suggesting its potential as a daily rehabilitation analog for reducing depression incidence in chronic stress conditions through hippocampal neuron protection. This study aims to investigate the effects and underlying mechanisms of EE training on depression induced by chronic unpredictable mild stress (CUMS) in mice. Method: Forty mice were randomized into four groups: Control, CUMS, Fluoxetine + CUMS, and EE + CUMS. Depression was induced using single-cage isolation and CUMS for 42 days, with intraperitoneal drug administration during this period. EE training commenced on Day 22, continuing through the modeling phase. Depression behavior was assessed using weight monitoring, the Sucrose Preference Test (SPT), Open Field Test (OFT), and Forced Swimming Test (FST). Hematoxylin-Eosin (HE) staining evaluated hippocampal  histopathology. Levels of interleukin 1β (IL-1β), interleukin 6 (IL- 6), phosphorylatedphosphatidylinositol kinase (p-PI3K), phosphorylated protein kinase B (p-Akt), and phosphorylated mammalian target of rapamycin protein (p-mTOR) were analyzed. Results: By Day 21, chronic stress elicited depressive behaviors, with more pronounced effects by Day 42 in the CUMS group, validating the model's stability and success. Interventions post-Day 22, Resembling early clinical depression detection, demonstrated that three weeks of fluoxetine and EE training effectively reduced depressive behaviors. Both interventions notably mitigated hippocampal histopathological damage, decreased inflammatory factors, and significantly increased expression of mTOR pathway-related proteins. Conclusion: EE training effectively mitigates depressive behavior in chronically stressed mice, primarily through anti-inflammatory actions and modulation of the PI3K/Akt/mTOR signaling pathway. These findings underscore the therapeutic potential of integrating physical fitness and mental health strategies into depression management, emphasizing the importance of environmental and lifestyle factors in neuropsychiatric disorder intervention