Neural regulation of susceptibility to hyperarousal

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Since 2001 nearly 2 million US troops have served in the wars in Afghanistan or Iraq. Common to these hostile environments, exposure to a traumatic stress can lead to post traumatic stress disorder (PTSD). As a result, up to 31% of soldiers suffer from PTSD at some point in their lives. In addition to the debilitating consequences on mental health, PTSD also increases the risk of developing cardiovascular disease. A cardinal feature of PTSD is elevated sympathetic nervous system activity (ie., increased norepinephrine, NE) that is thought to contribute to both the psychiatric symptoms of PTSD and increased risk of cardiovascular disease. In the brain, the locus coeruleus (LC) is the major source of NE, a brain region capable of promoting the behavioral and cardiovascular abnormalities that define PTSD. Therefore, therapies that reduce LC activity, and thus suppress NE release are attractive targets to treat PTSD with comorbid cardiovascular disease. IL-1b accumulates in specific brain regions in stress susceptible individuals and serves to promote LC-NE hyperactivity. We have identified that when rats are confined in a protected region of an aggressive resident’s cage, forced to witness a social trauma in the form of social defeat between two males, it generates long lasting indices of behavioral and autonomic hypervigilance. By conducting this study in males and females, this allows for a parallel understanding of how the LC regulates hypervigilance in both sexes and fulfills a critical gap in knowledge in PTSD pathology. The overarching goal of the proposed research project is to use this animal model of combat-related trauma to identify druggable targets that can suppress neural regulation of hyperarousal. We propose that stress-induced adaptations of IL-1b in the LC initiate the cascade that promotes LC-NE hyperactivity and resulting susceptibly in two ways. 1) IL-1b is chronically upregulated in the LC of witness stress-exposed rats, which directly functions to stimulate LC-NE neurons. 2) IL-1b promotes accumulation of ROS (i.e., superoxide) which, in the LC disengages a major inhibitory input via downregulation of µ-opioid receptors (MOR). Thus, this stress-sensitive LC-NE response is poised to promote the pathophysiological mechanisms underlying LC-NE hyperarousal. The following specific aims will utilize integrative, translational and cutting-edge techniques to test the hypothesis that a combined effect of IL-1b and ROS regulate LC-NE hyperactivity that is central to promoting trauma-induced behavioral and autonomic dysfunction in males and females To achieve these goals, rats will be treated with intra-LC vehicle, IL-1 receptor antagonist (IL-1ra), n-acetylcysteine (NAC, an antioxidant) or a combination of the two. The specific role of these treatments to block behavioral and autonomic indices of hyperarousal will be determined (Aim 1) and the molecular mechanisms modified by these treatments will be identified in unstressed controls and stressed male and female rats in addition, postmortem LC tissue from the VA Brain Bank will also be evaluated (Aim 2). Furthermore, Aim 3 tests the therapeutic capability of intracerebroventricular IL-1ra and NAC administration to reverse the hypervigilant phenotype in order to achieve two major goals: 1) To confirm that the locus of efficacy for the therapeutic effects of anti- inflammatory and anti-oxidant therapy is the LC and 2) to measure cardiovascular telemetry with simultaneous LC electrophysiology in awake behaving animals, demonstrating for the first time the covariance between LC neuronal firing and sympathovagal balance in males and females with a hypervigilant phenotype. The proposed studies are significant because understanding neural mechanisms of susceptibility to hypervigilance will lead to preventative and therapeutic treatments capable of directly enhancing the lives of our veterans. Moreover, this work has the immense potential to help identify preclinical screening of FDA-approved interventions that could be repurposed to treat PTSD hyperarousal in humans and rapidly translated into our veteran population.