Neural regulation of susceptibility to hyperarousal

自2001年以来，已有近200万美军在阿富汗或伊拉克战争中服役。常见于这些 在恶劣的环境中，暴露于创伤性应激可能导致创伤后应激障碍（PTSD）。作为 结果，高达31%的士兵在他们生命中的某个时候患有PTSD。除了使人衰弱的 创伤后应激障碍对心理健康的影响，也增加了患心血管疾病的风险。把握的根本 PTSD的特征是交感神经系统活动升高（即，去甲肾上腺素（NE）增加， 被认为是导致创伤后应激障碍的精神症状和心血管疾病风险增加的原因。在 在大脑中，蓝斑（LC）是NE的主要来源，NE是能够促进行为的脑区域。 和心血管异常导致创伤后应激障碍因此，降低LC活性的疗法， 抑制NE释放是治疗伴有心血管疾病PTSD的有吸引力的靶点。IL-1b 在应激敏感个体的特定脑区中积累，并用于促进LC-NE 多动症。我们已经确定，当老鼠被限制在一个有攻击性的居民的保护区时， 笼子里，被迫目睹了社会创伤的形式，两个男性之间的社会失败，它产生了长期持久的 行为和自主神经过度警觉指数。通过在男性和女性中进行这项研究， 对于LC如何调节两性的过度警惕以及如何填补两性之间的关键差距的平行理解， 创伤后应激障碍病理学知识该研究项目的首要目标是使用这种动物模型 以确定可以抑制过度觉醒的神经调节的药物靶点。我们 我提出，LC中IL-1b的应激诱导适应启动了促进LC-NE过度活跃的级联反应 并以两种方式得出结论。1)IL-1b在见证应激暴露的LC中慢性上调 大鼠，其直接起刺激LC-NE神经元的作用。2)IL-1b促进ROS的积累（即， 超氧化物），其在LC中通过下调μ-阿片受体（莫尔）释放主要的抑制性输入。 因此，这种应激敏感的LC-NE反应有望促进潜在的病理生理机制， LC-NE过度觉醒。以下具体目标将利用综合、转化和尖端技术 为了检验IL-1b和ROS的联合作用调节LC-NE过度活跃的假设， 促进男性和女性创伤引起的行为和自主神经功能障碍 为了达到这些目的，将用LC内载体、IL-1受体拮抗剂（IL-1 ra）、N-乙酰半胱氨酸（NAC， 抗氧化剂）或两者的组合。这些治疗的具体作用，以阻止行为和 将确定过度觉醒的自主神经指数（目标1），并通过这些指数修改分子机制。 此外，还将在非应激对照组和应激雄性和雌性大鼠中确定处理， 还将评价VA Brain Bank的LC组织（目标2）。此外，目标3测试治疗 侧脑室注射IL-1 ra和NAC逆转高警觉表型的能力 为了达到两个主要目标：1）确认抗- 炎症和抗氧化剂治疗是LC和2）测量心血管遥测，同时 清醒行为动物的LC电生理学，首次证明LC之间的协方差 神经元放电和交感迷走神经平衡的男性和女性的高度警惕表型。拟议 研究是重要的，因为了解神经机制的敏感性，以高度警觉将导致 能够直接改善我们退伍军人生活的预防性和治疗性治疗。而且这 这项工作具有巨大的潜力，可以帮助确定FDA批准的干预措施的临床前筛选， 被重新用于治疗人类的创伤后应激障碍，并迅速转化为我们的退伍军人群体。

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.