A Novel Mouse Model of Depression: Advantages in Immune Research and Clinical Translation

The role of neuroimmune mechanisms in major depressive disorder (MDD) has been gradually highlighted, but existing classical animal models of MDD have limitations in immune inflammation research due to physical injury, high mortality rates, and immune tolerance. This study developed a novel mouse model of depression called the post-witness social defeat stress (PWSDS) model, which combines witness stress with the social defeat paradigm. The model was evaluated based on behavior, central and peripheral immune responses, and predictive validity. The findings revealed that PWSDS-exposed mice exhibited significant anxiety-like behavior, depressive-like behavior, cognitive deficits, and enhanced peripheral and central neuroimmune responses. Additionally, the antidepressant fluoxetine effectively ameliorated the depressive-like phenotypes and immune response in stressed mice. The model captured certain aspects of the behavioral and peripheral immune features of MDD patients. The levels of cortisol and proinflammatory cytokines such as TNFα in the serum of MDD patients with adult stressors increased compared with healthy controls, and were alleviated by SSRIs treatment, accompanied by improvement in depressive symptoms, anxiety symptoms and cognitive impairments. This study establishes an improved mouse model of MDD, which has specific advantages in immune research and offers a novel approach to further study the pathogenesis and new treatment of MDD.