PROJECT SUMMARY Post-traumatic stress disorder (PTSD) is a devastating psychiatric disorder that afflicts more than 7% of all Americans across their lifespan. PTSD increases the risk for inflammatory cardiovascular diseases, such as hypertension, but the etiology of this increased predilection for hypertension after trauma is unknown. Both PTSD and hypertension characteristically display increases in circulating levels of catecholamines, as well as alterations in T-lymphocyte-driven inflammation. T-lymphocytes are highly reactive to catecholamines, and we have previously reported that splenic T-lymphocytes exposed to these neurotransmitters in vitro secrete increased levels of interleukin 6 (IL-6) and interleukin 17A (IL-17A); pro-inflammatory cytokines which have been mechanistically linked to the pathogenesis of hypertension. Furthermore, using an accepted preclinical mouse model of PTSD known as repeated social defeat, we have also recently described increased splenic catecholamine levels, elevated circulating IL-6 and IL-17A levels, as well as a potentiated hypertensive response to angiotensin II (AngII) in animals undergoing this psychological trauma. These observations were abrogated in socially-defeated mice lacking T-lymphocytes, demonstrating these adaptive immune cells are mechanistic in the sensitization to hypertension after trauma. To this end, I hypothesize that psychological trauma increases the splenic catecholamine milieu that drives T-lymphocyte inflammation causing hypertension sensitization. In Specific Aim 1, I will determine the contribution of neuronally-derived catecholamines in the sensitization of hypertension by selectively ablating the splenic nerve. In Specific Aim 2, I will utilize a novel genetic knockout mouse model that lacks tyrosine hydroxylase—the rate-limiting enzyme in catecholamine synthesis—exclusively in T- lymphocytes. I will investigate the contribution of these sources of catecholamines to the A) behavioral phenotype, B) T-lymphocyte autonomic and inflammatory profiles, and C) development of hypertension. Completion of these aims will further our ability to design and implement novel therapies that will ultimately reduce the morbidity and mortality of cardiovascular disease in PTSD patients.

PROJECT NARRATIVE Post-traumatic Stress Disorder (PTSD) is a devastating psychiatric disorder that significantly increases the risk for inflammatory cardiovascular diseases, such as hypertension, yet the etiology of this increased predilection for hypertension remains unknown. This project utilizes a preclinical model of PTSD to investigate the contribution and origin of catecholamines in the T-lymphocyte-driven inflammation seen in PTSD. Further elucidation of this neuroimmune interaction will provide novel insights and potential therapeutic strategies to reduce the cardiovascular morbidity and mortality of PTSD patients.