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。它们的共同点是 在恶劣的环境中，暴露在创伤应激中会导致创伤后应激障碍(PTSD)。作为一名 结果，多达31%的士兵在生活中的某个时候患有创伤后应激障碍。除了让人虚弱的 除了创伤后应激障碍对精神健康的影响外，创伤后应激障碍还会增加患心血管疾病的风险。红衣主教 创伤后应激障碍的特征是交感神经系统活动增加(即去甲肾上腺素增加)，即 被认为会导致创伤后应激障碍的精神症状和心血管疾病风险的增加。在……里面 大脑蓝斑(LC)是去甲肾上腺素(NE)的主要来源，NE是大脑中一个能够促进行为的区域 以及定义创伤后应激障碍的心血管异常。因此，降低LC活性的疗法，因此 抑制NE释放是治疗PTSD合并心血管疾病的有吸引力的靶点。IL-1b 在应激敏感个体的特定脑区积聚，并促进LC-NE 多动症。我们已经发现，当老鼠被限制在攻击性居民的保护区内时 笼子，被迫见证了两个男性之间以社会失败的形式出现的社会创伤，它产生了持久的 行为和自主神经高度警戒指数。通过在男性和女性中进行这项研究，这使得 以平行理解LC如何监管两性的高度警惕，并填补 了解创伤后应激障碍的病理学知识。提出的研究项目的首要目标是使用这种动物模型 以确定可抑制过度觉醒的神经调节的可用药靶点。我们 认为应激诱导LC内IL-1b的适应启动了促进LC-NE过度活动的级联反应 并以两种方式易受影响。1)IL-1b在见证者应激暴露的LC中慢性上调 其直接作用是刺激LC-NE神经元。2)IL-1b促进ROS的积累(即， 超氧化物)，在LC中，它通过下调µ-阿片受体(MOR)来解除主要的抑制输入。 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、翻译和尖端技术 为了验证IL-1b和ROS联合作用调节中枢的LC-NE过度活动的假设 促进男性和女性创伤后行为和自主神经功能障碍的实现 在这些目标下，大鼠将接受LC载体、IL-1受体拮抗剂(IL-1ra)、N-乙酰半胱氨酸(NAC)、 抗氧化剂)或两者的组合。这些治疗方法的具体作用是阻断行为和 将确定高度觉醒的自主神经指数(目标1)，并由此修正分子机制 将在非应激对照组和应激雄性和雌性大鼠中确定治疗方法，此外，在死后 来自退伍军人事务部脑库的LC组织也将被评估(目标2)。此外，Aim 3还测试了治疗方法 侧脑室注射IL-1ra和NAC逆转大鼠高警戒表型的能力 以达到两大目标：1)确认疗效部位为抗心绞痛的治疗效果 炎症和抗氧化治疗是LC和2)测量心血管遥测与同步 清醒行为动物的LC电生理学，首次证明了LC与Lc之间的协变性 高度警觉表型的男性和女性的神经元放电和交感迷走神经平衡。建议数 研究意义重大，因为了解过度警觉易感性的神经机制将导致 预防性和治疗性治疗能够直接改善我们退伍军人的生活。此外，这一点 这项工作具有巨大的潜力，可以帮助识别FDA批准的干预措施的临床前筛查 被重新用于治疗人类的创伤后应激障碍过度觉醒，并迅速转化为我们的老兵群体。

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.