Pretrauma cognitive traits predict trauma-induced fear generalization and associated prefrontal functioning in a longitudinal model of posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a chronic psychiatric condition that develops in susceptible individuals exposed to traumatic stress, challenging clinicians to identify risk factors and mechanisms for mitigating vulnerability. Here we investigated behavioral predictors of high fear generalization, a core PTSD symptom, and its neural correlates longitudinally in rats. In a comprehensive behavioral test battery of emotional and cognitive function, pretrauma lower operant learning performance emerged as high predictor of fear generalization following trauma. Posttrauma operant training facilitated fear extinction, suggesting an overlap in neural circuits governing operant learning and fear expression. Neuronal activity mapping revealed significant changes in the medial prefrontal cortex (mPFC) in high fear generalizers, with alterations in CRH/VIP+ interneuron functioning. Silencing prefrontal Crh expression after fear memory consolidation enhanced mPFC activation and reduced fear expression, favoring resilience. These findings highlight operant learning and mPFC alterations as vulnerability markers and mediators of excessive fear generalization, with implications for prevention and targeted therapy in PTSD.