A novel composite model of PTSD induced by social bullying: validation via multidimensional behavioral and molecular biomarkers.

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition characterized by persistent fear memory, hyperarousal, and social impairment. Mounting evidence highlights the critical role of social stress, such as bullying, in triggering PTSD. However, progress in elucidating the underlying mechanisms and developing effective treatments has been hindered by the lack of animal models that accurately recapitulate the multidimensional etiology of social trauma-related PTSD. To address this gap, we developed a novel triple-composite social bullying (SB) model in mice, which integrates social aggression, physiological pain, and psychological isolation to mimic the pathogenesis of PTSD induced by social bullying. Mice subjected to social bullying paradigm exhibited robust PTSD-like phenotypes, including anxiety- and depression-like behaviors, enhanced cue-induced fear responses, along with a prominent social avoidance phenotype that was not observed in the conventional foot shock (FS) model. Systemic administration of fluoxetine (10 mg/kg, intraperitoneal injection) significantly alleviated these behavioral deficits. Paralleled with these behavioral changes, neural hyperactivation in brain regions associated with fear and stress (anterior cingulate cortex [ACC], basolateral amygdala [BLA]), suppressed activity in the dorsal hippocampus (dHIP), reduced dendritic complexity in limbic areas, elevated expression of the FKBP51-glucocorticoid receptor (GR) complex, and increased cortisol levels. Collectively, this study demonstrates that the SB model faithfully recapitulates the core clinical manifestations of social trauma-induced PTSD across behavioral, neural, cellular, and molecular dimensions. The model thus provides a rigorously validated preclinical tool for investigating mechanisms of social trauma-related PTSD and screening potential therapeutic interventions.