Establishment of the Mouse Model of Social Avoidance Induced by Female-Directed Female Aggression

Abstract

Background: Most preclinical research on the effects of stress has been done on male subjects, even though women are more prone than men to experience stress-related problems. Chronic social defeat stress (CSDS) is a rodent model of psychosocial stress. However, this model has been challenged in female mouse studies since neither male nor female resident mice attack intruder females. A female-to-female CSDS model is needed to investigate the physiological and behavioral aspects. Methods: The intruders were either male or female C57BL/6J mice, whereas the residents were male or ovariectomized (OVX) female CD-1 mice. The CD-1 aggressor mice had direct physical contact with the C57BL/6J mice for 10 min before initiating sensory contact with them for 24 h. Jump escape and freezing were evaluated during the social defeat of days 1 and 12. Experimental C57BL/6J mice underwent a social interaction test after suffering social defeat for 12 days. Results: We found that the number of attack bites and attack latency had a significant negative correlation during the selection of aggressors. In the single-housed OVX mice, 34% of mice met the criterion of the selection of aggressors. However, single-housed OVX mice did not show sustained aggressive behavior (eg, attack bites) through the 12-day CSDS. As a result, we did not find susceptible mice during the social interaction test. In contrast, during the selection of aggressors, 42% of OVX mice housed with partners satisfied the criterion and displayed consistently aggressive behavior. CSDS produced susceptible (50%) and resilient (50%) phenotypes during the social interaction test. Notably, male and OVX female CD-1 mice housed with partners had similar amounts of attack bites and attack rates over the 12-day CSDS. Finally, we found that chronically socially defeated male and female mice displayed different coping behaviors (eg, active vs passive) with social defeat. Conclusions: Our study demonstrates that OVX CD-1 mice housed with mates exhibited territorial aggression toward female intruders, producing susceptibility and resilience to social avoidance. Additionally, socially defeated male and female mice displayed different behavioral susceptibility to social defeat.