Prefrontal Cortical Deficits are a Putative Susceptibility Factor for PTSD

A subset of people who experience a traumatic event develop Post-Traumatic Stress Disorder (PTSD) suggesting that there are susceptibility factors influencing PTSD pathophysiology. While post trauma sequelae factors are extensively studied, susceptibility factors are difficult to study and therefore poorly understood. To address this gap, we previously developed an animal model - Revealing Individual Susceptibility to PTSD-like phenotype (RISP). RISP allows studying susceptibility factors by identifying, before trauma, rats that are likely to develop a PTSD-like phenotype after trauma. Hypofunctioning prefrontal cortex has been reported in people with PTSD, however, it is unclear if it is a susceptibility factor, sequalae factor, or both. Using RISP, we tested the hypothesis that altered medial prefrontal cortical (mPFC) function is a putative susceptibility factor. Susceptible male rats showed altered expression of plasticity-related immediate early genes (Arc and Homer1a) in the Prelimbic and Infralimbic subregions of the mPFC following spatial learning. Susceptible rats also showed deficits in attentional set shifting task when task demands increased. These findings suggest that Susceptible rats have mPFC deficits both at the cellular and functional level before trauma. Consistent with the findings in rats, military personnel who showed pre-trauma deficits in cognitive tasks involving mPFC developed PTSD post-trauma. Combined, these findings suggest that mPFC deficits are a putative susceptibility factor for PTSD and enhancing mPFC function in susceptible individuals before trauma may confer resilience to developing PTSD. SummaryA subset of people who experience a traumatic event develop Post-Traumatic Stress Disorder (PTSD) suggesting that there are susceptibility factors influencing (PTSD) pathophysiology. While post trauma sequelae factors are extensively studied, susceptibility factors are difficult to study and therefore poorly understood. In the manuscript, we report data from both an animal model of susceptibility to a PTSD-like phenotype, and from military personnel, which is consistent with the hypothesis that deficits in prefrontal cortex function exist in susceptible individuals before PTSD-inducing trauma. The reported experiments include both a cellular molecular technique (Arc/Homer 1a catFISH), based on the expression of effector immediate-early genes necessary for consolidation of learning-induced plasticity, as well as behavioral experiments for assessing cognitive function in rats and humans.