Sex-Dependent Neurobiological and Behavioral Signatures of Environmental Enrichment and Stress Re-exposure in Mice Following Social Defeat Stress

Abstract

Treating post-traumatic stress disorder (PTSD) effectively remains a significant challenge, as the efficacy of standard approaches like exposure therapy varies among patients. Exposure therapy aims to mitigate trauma’s impact through gradual re-exposure to the stressor within a safe setting. Despite its use, exposure therapy’s neurobiological foundations behind its beneficial impact on stress recovery are not well understood, primarily because suitable preclinical models that utilize translationally relevant, escalating stress paradigms to inoculate rodents are currently lacking. Furthermore, understanding sex-specific variations in trauma responses is crucial for developing more personalized interventions, yet preclinical work has predominantly focused on male rodents. To address these gaps, we implemented four stress paradigms: no stress (Ctrl), 10 days of social defeat (Reg), 10-day defeat followed by 20-day gradual re-exposure (Reg+Esc; modeling exposure therapy) and 20-day gradual exposure followed by 10-day defeat (Esc+Reg; modeling stress inoculation). Based on pilot data indicating that escalating stress requires environmental enrichment (EE) housing to effectively improve behavior, our Reg+Esc and Esc+Reg cohorts were housed in enriched cages. Our main goal was to clarify how EE and escalating stress (before or after 10-day defeat) impacts behavior and region-specific mRNA expression in male and female C57BL/6 mice. Our findings revealed several sex-, region-, and paradigm-specific results. Notably, EE conferred greater behavioral resilience against chronic stress in females compared to males. While the modeled ‘exposure therapy’ paradigm (Reg+Esc) induced distinct molecular changes in the female nucleus accumbens (elevated Bdnf and Crh mRNA), these changes did not translate into superior outcomes in generalized anxiety or sociability compared to the ‘stress inoculation’ approach (Esc+Reg). We also uncovered complex sex- and region- dependent correlations between specific molecular markers and behavioral phenotypes, highlighting an intricate interplay between environment, stress re-exposure, and neurobiology. This thesis is novel in showing that EE works in combination with gradual re-exposure to shape mRNA expression and associations between various markers and behavior in a sex- and region-dependent manner. Our findings underscore the critical need to incorporate sex- and region-specificity into holistic PTSD-related preclinical research and treatment.