FROM RESILIENCE TO ALLOSTATIC OVERLOAD: MALE VIOLENCE INTENSITY REPROGRAMS THE FEMALE PREFRONTAL CORTEX

Intimate partner violence (IPV) is a major public health concern with long-lasting neurobiological consequences in women. Key unresolved questions concern the vulnerability of specific brain regions, including the prefrontal cortex (PFC), and the boundary between adaptive molecular responses and maladaptive allostatic overload driven by increasing violence intensity. Using a preclinical model of reiterated male-to-female violent interaction (RMFVI), previously shown to induce hippocampal dysfunction through a sex-specific estrogen receptor β-dependent mechanism, we investigated how violence intensity shapes molecular profiles in the female PFC. Adult C57BL/6J female mice were exposed to RMFVI with male aggressors displaying distinct aggressiveness, generating low- and high-violence exposure groups. Non-exposed females served as controls. Transcriptomic profiling of the PFC was performed, followed by Ingenuity Pathway Analysis (IPA). Relative to controls, 1,147 genes were differentially expressed in low-violence–exposed females and 1,455 in high-violence–exposed females. Gene expression changes showed opposite directionality between groups, indicating a shift from compensatory to maladaptive molecular programs with increasing violence intensity. IPA revealed opposing functional profiles: low violence was associated with pathways supporting synaptic function and cell survival, whereas high violence engaged pathways related to apoptosis and cell death. Although estrogen receptor transcripts were undetectable, protein analysis demonstrated increased ERα levels and a significant shift in the ERα/ERβ ratio (+1.5-fold) in high-violence mice. Notably, SIRT3 was strongly downregulated, suggesting involvement of epigenetic regulatory mechanisms. These findings support an allostatic load model in which escalating violence intensity drives maladaptive transcriptomic, mitochondrial, and neuroendocrine dysregulation in the PFC.