Sex differences in susceptibility to a PTSD-like phenotype

Experiencing an emotionally traumatic event, even without physical injury, results in developing a debilitating condition, termed Post-Traumatic Stress Disorder (PTSD) in an estimated 20-30% of people. Women are affected at twice the rate of men, present with different symptoms and respond differently to the same therapies that are effective for men. This suggests that PTSD has individual susceptibility and is sexual dimorphic. Prevalence of PTSD is higher in military personnel leading to rising costs to the Veteran's Administration and society, in general, due to loss of productivity and quality of life. Since most cases of PTSD are treatment resistant coupled with a high incidence of people with PTSD who do not seek treatment, understanding susceptibility is critical to building resilience and helping reduce the incidence of PTSD. We define susceptibility factors as those that can be identified and manipulated before trauma such that their manipulation alters the acquisition and/or maintenance of PTSD. With the increase in female soldiers and Veterans, it is important to investigate if there are sex differences in susceptibility factors to inform if the same resilience building task will work for both men and women. We previously developed an animal model for revealing individual susceptibility to a PTSD-like phenotype before trauma (RISP model). However, we discovered that different parameters are needed to reveal susceptibility for male and female rats. Exposure to a mild stressor is necessary but not sufficient to reveal susceptibility in males while in females, the mild stressor is sufficient to reveal susceptibility to developing a PTSD-like phenotype. Thus, we propose two models: RISP-M for male rats and RISP-F for female rats and propose to complete the characterization of RISP-F by investigating whether a mild stressor is not only sufficient but also necessary for revealing susceptibility. Using RISP-M, we have identified putative susceptibility factors: impaired hippocampal and medial prefrontal cortex function, and elevated pro-inflammatory cytokines in the medial prefrontal cortex. We also have evidence that pre trauma interventions that engage the hippocampus and medial prefrontal cortex improved post trauma outcomes in susceptible male rats. Whether these apply to female rats is currently unknown. The current proposal builds on our expertise and previous work, supported by the VA. It will test the overarching hypothesis that susceptibility to a PTSD-like phenotype is sexually dimorphic: it requires different behavioral determinants, has different susceptibility factors, and can inform sex-dependent resilience- building interventions with three specific aims: Aim 1: Test the hypothesis that a brief exposure to a mild stressor (cat hair) is necessary and sufficient to reveal susceptibility to a PTSD-like phenotype in female rats; Aim 2: Test the hypothesis that putative susceptibility factors for a PTSD-like phenotype are sexually dimorphic; Aim 3: Test the hypothesis that resilience-building interventions are not sexually dimorphic. The findings will provide the field with a new model for identifying susceptibility to a PTSD-like phenotype in female rats, begin to address whether male and female rats have similar susceptibility factors and inform the development of resilience-building interventions that may need to be different in males and females.