Chronic Stress Disrupts Immune and Endocrine Axis, Inducing Persistent Behavioral Impairments in Male Rats: In Silico and In Vivo Insights.

Chronic stress disrupts immune-endocrine balance and contributes to major depressive disorder (MDD) through dysregulated autophagy and neuroinflammation pathways, yet their interactions and persistence remain unclear. This study investigated these mechanisms using chronic restraint stress (CRS) in male Wistar rats and in silico MDD gene analysis. Rats were exposed to CRS for 15 days (Res15) or 30 days (Res30), followed by a 30-day stress-free recovery period without intervention (Res30/Rec30). Behavioral assessments (anxiety, depression-like behaviors, and cognition) were conducted via standard tests. Blood samples were analyzed for neutrophil-to-lymphocyte ratio (NLR) and corticosterone levels. Hippocampal cytokine expression (TNF-α, IL-1β, IL-16), Beclin1 levels, and neuronal damage were evaluated via molecular and histopathological methods. In silico analysis linked these pathways to human MDD by identifying upregulated autophagy- and inflammation-related genes (including IL1B, PTGS2, GNAI3, RAB1A, MAP1LC3B, SQSTM1, and KIF5B), bridging rodent stress models to clinical depression. CRS induced anxiety- and depression-like behaviors, cognitive impairment, hippocampal neurodegeneration, elevated corticosterone and NLR, and upregulation of pro-inflammatory and autophagy markers. Although partial recovery in depression-like behaviors and cytokine levels was observed after 30 days, anxiety-like behaviors, cognitive impairment, elevated NLR, and hippocampal neurodegeneration persisted. These findings reveal persistent neurobiological consequences of chronic stress, advancing understanding of MDD pathophysiology and suggesting that targeting autophagy and neuroinflammation could offer novel treatments for depression, particularly for symptoms that endure post-stress.