Social defeat stress responses in the stress alternative model are dependent on sex and anterior basolateral amygdala orexin 2 receptors.

Biology of sex differences 2026

["Yaeger J", "John M", "Ledesma L", "Greschke T", "Gale J", "Meyer L", "Brummels R", "Korzan W", "Waters R", "Summers C"]

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 Orx2R or α2 antagonists resulted in slower escape (EscapeS), increased social avoidance, as well as increased cued and contextual freezing in stress-vulnerable females. Neurons in BLA express Orx2R mRNA (Hcrtr2) predominantly in cholecystokinin-positive GABA neurons. In slower escape (EscapeS) 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 Orx2R promotes stress-vulnerable behavior in females, and modifies transcription in BLA microcircuits, suggesting a role for Orx2R defining stress behavior.

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