Characterization of a novel female chronic social defeat stress (femCSDS) model utilizing persistently aggressive CD1 parous females.

Depression shows significant sex differences in prevalence and neurobiological underpinnings, yet preclinical research investigating the pathophysiology of depression and the efficacy of antidepressants has predominantly relied on male models. Here, we establish a novel female chronic social defeat stress paradigm by leveraging the natural aggression of parous CD1 females, co-housed with castrated males to induce aggression while eliminating confounding sexual behaviors and without hormonal or surgical manipulations. Selected aggressive females reliably displayed offensive behaviors toward C57BL/6NCrl intruders across repeated encounters. Defeated female mice exhibited pronounced depression-like behaviors, including social withdrawal, anhedonia, behavioral despair, and elevated anxiety-like responses. Biochemical analysis revealed elevated glutamate levels in Nucleus Accumbens (NAc) and caudate putamen (CPu). Alterations in EAAT1, GRIN2B, and Neurabin expression were observed in CPu, indicating excitotoxic stress and compromised synaptic integrity. Given the extensive literature on male CSDS and its established pathophysiology, we aimed and successfully developed female-specific replica model of traditional male CSDS, enabling direct comparison and elucidation of sex differences in depression pathophysiology.