Szente, L.; Balla, G. Y.; Varga, Z. K.; Toth, B.; Biro, L.; Balogh, Z.; Hill, M. N.; Toth, M.; Mikics, E.; Aliczki, M.

Traumatic experiences result in the development of posttraumatic stress disorder (PTSD) in 10-25% of exposed individuals. While human clinical studies suggest that vulnerability is potentially linked to endocannabinoid (eCB) signaling, neurobiological PTSD vulnerability factors are poorly understood. Employing a rat model of PTSD, we characterized distinct resilient and vulnerable subpopulations based on generalized fear, a core symptom of PTSD. Vulnerable subjects showed lower prelimbic and higher ventral hippocampal levels of eCB 2-arachidonoyl-glycerol (2-AG). Ventral hippocampal 2-AG content positively correlated with the strength of fear generalization. Furthermore, vulnerability was associated with downregulation of neuronal activity and neuroplasticity markers, and altered expression of eCB-related genes. Unsupervised and semi-supervised statistical approaches highlighted that hippocampal gene expression patterns possess strong predictive power regarding vulnerability. Taken together, the marked eCB and neuroplasticity changes in vulnerable individuals associated with abnormal activity patterns in the fear circuitry possibly contribute to context coding deficits, resulting in generalized fear.