Predicting susceptibility to a PTSD-like phenotype in female rats

Abstract Post-Traumatic Stress Disorder (PTSD) is a complex mental health disorder that impacts women twice as often as men. This sexual dimorphism makes it imperative to understand the underlying causes. We previously developed the RISP (Revealing Individual Susceptibility to a PTSD-like Phenotype) model to evaluate male rats (RISP-M) for susceptibility to a PTSD-like phenotype before trauma. Here, we hypothesized that the pre-established RISP-M model would be able to predict a PTSD-like phenotype in female rats. Female Sprague-Dawley rats (n = 107) were classified twice: once with RISP-M and a second time with the RISP-F model, reported here for the first time. RISP-M assesses susceptibility with startle and anxiety-like behavior after exposure to a mild stressor (cat hair). RISP-F assessed susceptibility with response to cat hair and anxiety-like behavior in the elevated plus maze. PTSD-like phenotype, after contextual-fear conditioning, was assessed in both models with fear extinction, anxiety-like behavior, and startle. RISP-F included evaluation of persistent avoidance. RISP-M had a poor predictive power for fear extinction in female rats- Positive Predictive Value (PPV) = 0.65, while RISP-F had a PPV = 0.85. Most importantly, the RISP-F model had face and predictive validity across multiple PTSD-associated behaviors. The brief exposure to cat hair was indeed a mild stressor that did not induce conditioned fear in female rats. Importantly, anxiety-like behavior used for classification was induced by the mild stressor, lasted for at least 4 days, and was not phenotypic anxiety. The RISP-F model described here can successfully predict susceptibility to a PTSD-like phenotype in female rats.