Microglial Mechanisms in Panic-PTSD

恐慌-PTSD 中的小胶质细胞机制

• 批准号: 9025958
• 负责人: RENU SAH
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9025958
• 关键词: Acidosis; Acids; Animal Model; Anxiety; Attenuated; Behavior; Behavioral; Biological Assay; Blood - brain barrier anatomy; Blood Pressure; Brain; Breathing; Carbon Dioxide; Cardiovascular system; Cell Death; Chemosensitization; Chronic; Comorbidity; Coupled; Data; Diagnosis; Disease model; Exposure to; Flow Cytometry; Fright; Functional disorder; Genes; Goals; Heart Rate; High Prevalence; Immune; Incidence; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Intervention; Knock-out; Lead; Link; Measures; Mental Health; Microglia; Minocycline; Modeling; Mus; Neurobiology; Organ; Outcome; Panic; Panic Attack; Panic Disorder; Patient Care; Physiological; Plethysmography; Population; Post-Traumatic Stress Disorders; Pre-Clinical Model; Prevention; Reporting; Research; Rodent; Rodent Model; Role; Sensory; Sodium Lactate; Stimulus; Stress; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Time; Translations; Trauma; Treatment Cost; Up-Regulation; Veterans; base; brain cell; carbon dioxide receptor; conditioned fear; cytokine; disability; effective intervention; effective therapy; new therapeutic target; novel; novel therapeutics; pre-clinical; public health relevance; receptor; respiratory; response; sensor; synthetic polymer Bioplex; therapeutic target; therapy resistant; traumatic event; treatment group

 DESCRIPTION (provided by applicant): Panic Disorder (PD) is a chronic and disabling condition that afflicts approximately 6 million people annually. Recent studies report that PD incidence is almost double in veterans. PD has high comorbidity with PTSD and afflicted individuals report higher rates of disability, cost of treatment and treatment resistance. Thus, studies on the search for novel, effective interventions and preclinical models relevant to PD-PTSD comorbidity are of high relevance. Neurobiological models of panic propose a central homeostatically-driven alarm system coupled with a supersensitive fear/anxiety system. Consistently, panic attacks can be triggered in individuals with PD and PTSD following challenges such as carbon dioxide (CO2) inhalation and sodium lactate, suggesting homeostatic imbalance in pH, specifically acidosis. Mechanisms for translation of acidosis to fear/panic are critical to the pathophysiology of panic and may lead to specific therapeutic treatment of panic attacks in veterans. Recently, our group has shown a role of microglial acid-sensing receptor T-cell death associated gene-8 (TDAG8), and ensuing microglial inflammation in CO2-evoked fear and panic responses. Microglial acid-sensing and inflammation may provide a core mechanism to explain the basis of panic, especially following trauma associated with PTSD This Merit Review application proposes to investigate microglial mechanisms in a rodent model of PTSD (single prolonged stress, SPS) expressing panic-like behaviors following CO2 inhalation. The rodent model of SPS simulates intense trauma that leads to PTSD-like behaviors. Importantly, our recent data has shown significant potentiation of CO2-evoked responses, microglial activation and TDAG8 up-regulation in mice exposed to SPS. The objective of this proposal is to delineate the mechanistic link between microglial acid sensing and inflammation with panic and PTSD responses following trauma. Relevance of microglial mechanisms in panic-PTSD model will be investigated under three specific aims. Aim 1 will test the hypothesis that SPS exposure will exacerbate behavioral, cardiovascular and respiratory responses to CO2 inhalation, a panic inducer. Aim 2 will test the hypothesis that increased CO2-evoked fear and cardiovascular responses following SPS exposure are dependent on microglial acid sensing TDAG8. Aim 3 will test the hypothesis that microglial activation and pro-inflammatory cytokine IL-1β is necessary for CO2-evoked panic responses following SPS. Collectively, our data will determine the physiologic relevance of microglial acid sensor TDAG8 and inflammation in panic comorbid with PTSD. Relevance: Microglial inflammatory mechanisms may provide important leads on how exposure to traumatic stress can lead to panic pathophysiology. This association is critical to the pathophysiology of panic comorbid with PTSD in veterans and may lead to more specific and effective therapies.

 描述（由申请人提供）： 恐慌症（PD）是一种慢性疾病，每年遭受约600万人的困扰。最近的研究报告说，在退伍军人中，PD发病率几乎是两倍。 PD与PTSD的合并症很高，受苦的个体报告的残疾率更高，治疗成本和耐药性。这是关于寻找与PD-PTSD合并症相关的新型，有效干预措施和临床前模型的研究。恐慌提案的神经生物学模型中心驱动的警报系统，加上超敏感/焦虑系统。一致地，在患有PD和PTSD的个体中，恐慌发作是在诸如二氧化碳（CO2）吸入和乳酸钠之类的挑战之后触发的，这表明pH值特别是酸中毒的稳态失衡。酸中毒为恐惧/恐慌的机制对于恐慌的病理生理至关重要，可能导致对退伍军人的恐慌发作的特定治疗。最近，我们的小组显示了小胶质细胞酸受体T细胞死亡相关基因-8（TDAG8）的作用，并确保了CO2诱发的恐惧和恐慌反应中的小胶质细胞感染。小胶质细胞酸的感应和感染可能提供了一种核心机制来解释恐慌的基础，尤其是在与PTSD相关的创伤之后，该优点审查的应用建议提案，以调查PTSD的啮齿动物模型（单个延长应力，SP，SPS）表达CO2 Inhaleation后表达恐慌的行为的小胶质细胞机制。 SP的啮齿动物模型模拟了导致PTSD样行为的强烈创伤。重要的是，我们最近的数据显示了暴露于SPS的小鼠中CO2诱发的反应，小胶质细胞激活和TDAG8上调的显着潜力。该提案的目的是描绘出创伤后的小胶质细胞酸敏感性与恐慌和PTSD反应之间的机理联系。小胶质机制在Panic-PTSD模型中的相关性将在三个特定目的下进行研究。 AIM 1将检验以下假设：SPS暴露会加剧对CO2吸入的行为，心血管和呼吸反应，这是一种恐慌。 AIM 2将检验以下假设，即SPS暴露后增加了CO2引起的恐惧和心血管反应取决于小胶质细胞酸传感器TDAG8。 AIM 3将检验以下假设：对于SPS后，小胶质细胞激活和促炎性细胞因子IL-1β对于二氧化碳引起的恐慌反应是必需的。总的来说，我们的数据将确定与PTSD合并症中小胶质细胞酸传感器TDAG8和炎症的生理相关性。相关性：小胶质细胞炎症机制可能会为暴露于创伤应激如何导致恐慌病理生理学提供重要的领先地位。这种关联对退伍军人的恐慌合并症与PTSD的病理生理至关重要，并且可能导致更具体和有效的疗法。