Network adaptability governs resilience and susceptibility to social defeat

Abstract Stress resilience—the ability to maintain mental health after adversity—manifests in humans and rodents as efficient threat–safety discrimination and fear extinction. Although behavioral differences between resilient and susceptible individuals are well documented, the brain-wide structural signatures that distinguish resilience, susceptibility, and impaired threat learning remain poorly defined. Using a translational mouse model of chronic social defeat stress in male C57BL/6 J mice (n = 55), combined with preregistered multimodal magnetic resonance imaging with graph-theoretical analyses, we identify structural and network-level correlates of three behavioral phenotypes. Resilient animals exhibited greater microstructural complexity in prefrontal regions, and showed signatures consistent with enhanced inhibitory gating within amygdalar circuits. In contrast, susceptible animals—defined behaviorally by fear generalization and resistance to extinction—exhibited dentate gyrus alterations across all measures, suggesting diminished microstructural adaptability. A third phenotype, impaired threat learning—mice that failed to avoid individuals from a threatening strain—was associated with altered CA1/CA2 microstructure and reduced structural connectivity in pons, pointing to disrupted hippocampal–brainstem interactions during memory consolidation. These findings demonstrate that resilience, susceptibility, and impaired threat learning arise from dissociable patterns of brain organization, with resilience reflecting adaptive circuit-level organization and susceptibility and impaired threat learning exhibiting distinct forms of microstructural and network reorganization.