Neural regulation of susceptibility to hyperarousal

过度觉醒易感性的神经调节

• 批准号: 10485538
• 负责人: Susan Kathleen Wood
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10485538
• 关键词: Acetylcysteine; Address; Afghanistan; Animal Model; Animals; Antiinflammatory Effect; Antioxidants; Autonomic Dysfunction; Autopsy; Behavioral; Brain; Brain Diseases; Brain region; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular system; Cerebrospinal Fluid; Chronic; Development; Disinhibition; Down-Regulation; Electrophysiology (science); Environment; Equilibrium; Exhibits; Exposure to; FDA approved; Female; Functional disorder; Goals; Heart Rate; Human; Hyperactivity; Individual; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 Receptors; Interleukins; Intervention; Iraq; Knowledge; Link; Measures; Mediating; Mental Health; Microglia; Modeling; Molecular; Negative Valence; Neurons; Neurotransmitters; Norepinephrine; Opioid Receptor; Pathology; Patients; Phenotype; Phosphorylation; Post-Traumatic Stress Disorders; Predisposition; Prevalence; Rattus; Reactive Oxygen Species; Receptor Activation; Regulation; Research; Research Project Grants; Risk; Rodent; Role; Signaling Molecule; Soldier; Source; Stress; Superoxides; Sympathetic Nervous System; Techniques; Telemetry; Testing; Therapeutic; Time; Tissues; Translating; Trauma; Treatment Efficacy; Veterans; War; Withdrawal; Woman; Work; antagonist; antioxidant therapy; awake; blood pressure elevation; cardiovascular disorder risk; cardiovascular risk factor; combat; combat trauma; comorbidity; desensitization; druggable target; fighting; glial activation; heart rate variability; human tissue; immune activation; improved; indexing; locus ceruleus structure; male; men; military veteran; neuromechanism; neuroregulation; norepinephrine system; post-traumatic symptoms; pre-clinical; psychiatric symptom; resilience; response; screening; sex; social; social defeat; stressor; therapeutic evaluation; therapeutic target; traumatic stress

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.

自2001年以来，已有近200万美军参加了阿富汗或伊拉克战争。 恶劣的环境，暴露于创伤性应激可能导致创伤后应激障碍（PTSD）。 结果，高达 31% 的士兵在一生中的某个阶段患有创伤后应激障碍 (PTSD)。 除了对心理健康的影响外，创伤后应激障碍还会增加患心血管疾病的风险。 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），即 人们认为它会导致创伤后应激障碍（PTSD）的精神症状，并增加心血管疾病的风险。 在大脑中，蓝斑（LC）是NE的主要来源，NE是一个能够促进行为的大脑区域 以及定义 PTSD 的心血管异常，因此需要降低 LC 活性的疗法，从而降低 LC 活性。 抑制 NE 释放是治疗伴有心血管疾病的 PTSD 的有吸引力的靶标。 在压力敏感个体的特定大脑区域积聚并促进 LC-NE 我们发现，当老鼠被限制在攻击性居民的保护区内时，就会出现过度活跃的情况。 笼子里，被迫目睹两个男性之间以社会失败形式出现的社会创伤，它产生了持久的影响 通过在男性和女性中进行这项研究，这使得行为和自主神经过度警觉指数。 平行理解 LC 如何调节两性的过度警觉并填补 拟议研究项目的总体目标是使用这种动物模型。 与战斗相关的创伤，以确定可以抑制过度兴奋的神经调节的可药物靶点。 提出应激诱导的 LC 中 IL-1b 的适应启动了促进 LC-NE 过度活跃的级联反应 并可能以两种方式产生：1) IL-1b 在见证人压力暴露的 LC 中长期上调。 2）IL-1b促进ROS的积累（即， 超氧化物），在 LC 中通过下调 µ-阿片受体 (MOR) 释放主要的抑制输入。 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 过度唤醒的具体目标将利用综合、转化和尖端技术。 检验 IL-1b 和 ROS 的联合作用调节 LC-NE 过度活跃这一假设 促进男性和女性创伤引起的行为和自主神经功能障碍 为了实现这些目标，大鼠将接受LC内载体、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在阻止行为和行为方面的具体作用。 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，将在无应激对照和应激雄性和雌性大鼠中确定治疗方法，并进行尸检 来自 VA 脑库的 LC 组织也将接受评估（目标 2）此外，目标 3 测试治疗效果。 脑室内注射 IL-1ra 和 NAC 能够逆转患者的过度警觉表型 为了实现两个主要目标：1）确认抗-治疗效果的功效轨迹 炎症和抗氧化治疗是 LC 和 2) 同步测量心血管遥测 清醒行为动物的 LC 电生理学，首次证明 LC 之间的协方差 具有高度警惕表型的男性和女性的神经放电和交感迷走神经平衡。 研究意义重大，因为了解过度警惕的神经机制将导致 此外，预防和治疗能够直接改善我们退伍军人的生活。 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查，这些干预措施可以 被重新用于治疗人类的创伤后应激障碍（PTSD）过度觉醒，并迅速转化为我们的退伍军人群体。