Evaluation of the role of CRFergic neurotransmission in anxiety and BNST neuronal activity in male and female mice exposed to psychosocial stress

Abstract

Anxiety disorders are increasingly prevalent, and the exposure to psychosocial stress is an important influencing factor; however, the underlying neurobiological mechanisms in female populations remain largely unexplored in animal models. This study investigated the role of the corticotropin-releasing factor type 1 receptor (CRF1R) in the bed nucleus of the stria terminalis (BNST) in anxiety-like behaviors induced by vicarious social defeat stress in female and male mice. Swiss-Webster mice underwent 10 sessions of witnessing social defeat stress (WSDS) or witnessing non-aggressive interactions (WNAI). Subsequently, their behaviors were evaluated in the social interaction test (SIT). Twenty-four hours later, each mouse received treatment with the CRF1R antagonist, CP376395, and after 1 h, was exposed to the elevated plus maze (EPM). Immunofluorescence for c-Fos was employed to assess BNST activation. WSDS female mice exhibited anxiety-like behavior, which was effectively reversed by CP3763995. Additionally, these stressed females exhibited greater c-Fos expression in the ventral BNST, a response attenuated by CRF1 receptor blockade. Notably, no significant behavioral or neural activation changes were observed in males under identical conditions. These findings underscore a sex-specific role for CRF1R signaling in the BNST in mediating anxiety-like responses to vicarious stress, highlighting the relevance of this neurobiological mechanism as a potential target for female-focused therapeutic strategies.