PROJECT SUMMARY Post-traumatic stress disorder (PTSD) is a debilitating psychological condition that increases the risk of life-threatening comorbid inflammatory diseases such as hypertension by over 50%. The goal of this project is to focus specifically on the neurological-T-lymphocyte mechanisms that regulate psychological trauma-induced inflammation and the predisposition to hypertension. Previous results from our laboratory using a preclinical model of PTSD known as repeated social defeat stress (RSDS) have demonstrated splenic T-lymphocytes as a primary source of inflammation after psychological trauma. Furthermore, we identified that RSDS-mice display a heightened blood pressure response to angiotensin II (AngII), which mimics the cardiovascular disease sensitization observed in PTSD patients. Importantly, mice lacking T-lymphocytes were not sensitized to AngII, which implies T-lymphocyte-driven inflammation as a mechanistic regulator of blood pressure after RSDS. We have additionally elucidated tight links between pro-inflammatory cytokine production from T- lymphocytes, sympathetic nervous system activation, the mitochondrial redox environment (primarily superoxide) in T-lymphocytes, anxiety-like behavior, and the development of a blood pressure sensitization to AngII, which suggests these physiological elements are mechanistically-intertwined. Given this information, we will test the central hypothesis that increased sympathoexcitation after RSDS drives splenic T- lymphocyte inflammation through increased mitochondrial superoxide to enhance sensitivity to hypertension. Our Specific Aims will determine neuroimmune pathways and intracellular mechanisms that control T-lymphocyte inflammation in the RSDS model of PTSD. The innovation in this proposal lies in the concept of central and local autonomic control of T-lymphocytes regulating blood pressure sensitization, the biological identification of mitochondrial superoxide regulating T-lymphocyte inflammation after psychological trauma, and the technological advances of our new genetically-engineered animal models and neuromodulation techniques. Overall, this project will reveal the impact of T-lymphocyte inflammation after psychological trauma, and aims to utilize this evidence to inform clinical management of PTSD via earlier cardiovascular screening or targeted therapeutic intervention.

PROJECT NARRATIVE Psychological trauma, and its pathological sequelae known as post-traumatic stress disorder (PTSD), increases the risk of developing cardiovascular diseases including hypertension by over 50%. Understanding that inflammation is a major regulator of hypertension, the main objective of this grant is to identify how psychological trauma initiates inflammation to lead to hypertension. Interventions that attenuate inflammation after psychological trauma may prevent life-threatening cardiovascular events in patients with PTSD.