Data-Driven Analysis Identifies Novel Modulation of Social Behavior in Female Mice Witnessing Chronic Social Defeat Stress

Background: Chronic social defeat stress is a widely used depression model in male mice. Several proposed adaptations extend this model to females with variable, often marginal effects. We examined if the widely used male-defined metrics of stress are suboptimal in females witnessing defeat. Methods: Using a data-driven method, we comprehensively classified social interaction behavior in 761 male and female mice after chronic social witness/defeat stress, examining social modulation of behavior and associations with conventional metrics (i.e., social interaction ratio). Results: Social stress induced distinct behavioral adaptation patterns in defeated males and witness females. Social interaction ratio led to underpowered analyses in witness females with limited utility to differentiate susceptibility/resilience. Data-driven analyses revealed changes in social adaptation in witness females that were captured in attenuated velocity change from no target to target trials. We explored the utility of this metric in 4 female social stress models and in male witnesses. Combining social interaction ratio and velocity change optimally differentiated susceptibility/resilience in witness females and revealed resilient-specific adaptation in a resilience-associated neural circuit in female mice. Conclusions: Chronic witness stress induced behavioral changes in females that were qualitatively distinct from those observed in defeated males and not adequately sampled by standard male-defined metrics. Modulation of locomotion is a robust and easily implementable metric for rigorous research in witness female mice. Overall, our findings highlight the need to critically evaluate sex differences in behavior and implement sex-based considerations in preclinical model design.