Male and female mice are similarly susceptible to chronic nondiscriminatory social defeat stress despite differences in attack frequency from aggressor

Abstract

Rationale Chronic stress is a major precipitating factor for mood disorders, which are diagnosed twice as frequently in women as in men. However, most preclinical models of chronic social defeat stress have limited use in females due to reduced aggression toward female intruders. The chronic non-discriminatory social defeat stress (CNSDS) model addresses these limitations by enabling the study of stress susceptibility across sexes in a variety of behavioral tasks including avoidance and simple reward behaviors. However, the effect of CNSDS susceptibility on complex reward behaviors has yet to be studied. Objectives Building on previous work validating CNSDS in both sexes, we aimed to refine the protocol for identifying CD-1 aggressors for CNSDS, optimize criteria for classifying susceptibility and resilience to stress, and assess how stress susceptibility affects complex reward behavior. Methods We evaluated aggression through attack frequency and submissive posture during CD-1 aggressor screening and CNSDS sessions to establish screening parameters. Following CNSDS exposure, male and female intruder mice were tested in an operant satiety-based outcome devaluation task. Results We observed that despite receiving fewer attacks, female mice are equally susceptible to CNSDS as males. CNSDS abolished satiety-based outcome devaluation, regardless of sex, in susceptible mice, but not in resilient mice. Conclusions These data suggest that CNSDS-defined stress phenotypes are behaviorally relevant across sexes and extend to deficits in complex reward behaviors, supporting CNSDS as a valuable model for studying sex-specific stress outcomes in mood disorders.

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