Developing rodent models of PTSD/AUD: leveraging clinic-based strategies

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RFA-AA-17-016 states that “Studies examining alcohol related behaviors in current models of PTSD and potentially in novel animal models of PTSD are sought”. Animal models of PTSD are on the cutting edge of exploiting individual differences to understand mechanisms underlying resilience and susceptibility to psychopathology. Validated models of PTSD recapitulate the prevalence of PTSD in trauma-exposed individuals (~15-30% depending on trauma). We will use 2 well-validated animal models of PTSD, social defeat stress and predator stress, to understand in what biological contexts trauma and subsequent enduring stress response provokes drinking behavior. Predator stress models the enduring effects of a severe single traumatic event while social defeat stress models effects of chronic physical and emotional stress. Both models produce variance in enduring response rates to trauma exposure, (30-50% of animals exhibit prolonged behavioral and neurobiological change), providing etiological validity for PTSD. We propose to examine if two highly translatable markers of trauma-symptom development, sleep disturbance and increased peripheral immune signaling, predict development and/or maintenance of drinking after stress in rodents. This approach addresses the RFA mandate to “identify biomarkers that will predict transition of PTSD to comorbid PTSD-alcohol misuse.” The goal is to (1) develop robust cross-species biomarkers of long term-trauma effects associated with increased alcohol consumption and (2) identify biomarkers that are predictive for treatment response. We will test the hypothesis that sleep and inflammation abnormalities after trauma predict increased drinking and treatment response. To test this hypothesis we will use a large (N=200/model) prospective, longitudinal design based on clinical research approaches. This strategy enables use of sophisticated statistical models to identify biological predictors of drinking behavior. We will assess clinical relevance by comparing these findings to humans by leveraging our clinical database of a prospective, longitudinal study of trauma in active duty service members (N=2600). This database includes data on trauma, PTSD symptoms, alcohol dependence, sleep and peripheral inflammation both before and after a combat deployment. Once validated, sleep and immune biomarkers identified in our animal models and validated in humans can be used to screen for prophylactic and therapeutic treatment effects of novel pharmacotherapies.