Abstract Background Comprehending sex differences in stress vulnerability and the associated neurocircuitry has been elusive until the development of a method for investigating social defeat in female mice. Methods The Stress Alternatives Model (SAM) uses conditioning-induced agonistic behavior from novel male aggressors to separate distinct phenotypes characterized by stress-resilient active avoidance (Escape) or vulnerability (no Escape = Stay). Results Unlike males, females predominantly display Escape behavior, which is reversible (to Stay) by adding more social stress to behavioral environments. Despite this, females exhibit both stress-resilient and vulnerable phenotypic segregation. Stress-vulnerable females exhibit double conditioning-induced corticosterone secretion, more contextual fear conditioning, and reduced social preference. Systemic and intra-BLA injections of Orx 2 R or α 2 antagonists resulted in slower escape (Escape S ), increased social avoidance, as well as increased cued and contextual freezing in stress-vulnerable females. Neurons in BLA express Orx 2 R mRNA ( Hcrtr2) predominantly in cholecystokinin-positive GABA neurons. In slower escape (Escape S ) females expression of Hcrtr2 and Adra2a in BLA is elevated. Conclusions Female and male mice exposed to social stress exhibit distinct behavioral adaptations, but similarly, separate into resilient and susceptible subpopulations. Inhibiting Orx 2 R promotes stress-vulnerable behavior in females, and modifies transcription in BLA microcircuits, suggesting a role for Orx 2 R defining stress behavior.
Yaeger et al. (Sun,) studied this question.