Neuroimmune Factors and Co-Morbid Fear, Depression and Alcohol Consumption

神经免疫因素和共病恐惧、抑郁和饮酒

• 批准号: 7938672
• 负责人: Michael S Fanselow
• 金额: $ 47.27万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938672
• 关键词: Address; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Animal Model; Animals; Anxiety; Astrocytes; Attenuated; Behavior; Behavioral; Behavioral Model; Brain; Cells; Chronic; Comorbidity; Control Groups; Data; Depressed mood; Disease model; Emotional Disturbance; Emotions; Exposure to; Fright; Gap Junctions; Gene Expression; Genes; Heavy Drinking; Immune; Individual; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Knowledge; Lead; Learning; Life; Link; Major Depressive Disorder; Mediating; Mental Depression; Microglia; Modeling; Neuraxis; Neurobiology; Neuroglia; Neurohormones; Neuromodulator; Neurons; Neurotransmitters; Nightmare; Pathogenesis; Pathway interactions; Patients; Pattern; Peanuts - dietary; Post-Traumatic Stress Disorders; Rattus; Reaction; Regimen; Relative (related person); Reporting; Role; Serum; Shock; Signal Transduction; Signaling Molecule; Societies; Spinal Cord; Stimulus; Stress; Structure; Swimming; Symptoms; Testing; Trauma; Up-Regulation; anakinra; chemokine; conditioned fear; cytokine; experience; foot; neuroinflammation; novel; problem drinker; programs; public health relevance; response

DESCRIPTION (provided by applicant): Following exposure to traumatic stress individuals often go on to develop Post-Traumatic Stress Disorder (PTSD), which is characterized by enhanced anxiety to reminders of the trauma, nightmares, reliving the traumatic experience and a propensity to acquire new fears. PTSD is characterized by excessive drinking, anxiety, and depression that lasts for a prolonged period after the initial trauma. The result is that PTSD has a significant impact on the lives of individuals as well as on society as a whole. One challenge is to find the common link between stress-induced changes in anxiety, alcohol intake and depression. Considerable data suggest that neuroimmune factors may be that link. Once thought to be merely the packing peanuts of the brain, glial cells in the brain and spinal cord are integral to the proper functioning, signaling, and neuronal reparation in the brain. Microglia specifically are involved in neuroinflammation, which is associated with destructive chronic neuroimmune response. Activation of microgila produces pro-inflammatory cytokines. Increases in levels of pro-inflammatory cytokines are observed in PTSD, and major depressive disorder (MDD). Microglia as well as pro-inflammatory cytokines are increased in the brains of alcoholics. Thus, neuroimmune factors lay at a nexus of PTSD, depression and alcoholism. It is not known what mediates these long-term stress-induced changes, but stress can produce a neuroimmune response that significantly alters behavior. To address this challenge, we have assembled a team with demonstrated expertise in emotion related behavior (Fanselow), stress-induced neuroimmune function (Bradesi & Mayer), and the neurobiology of alcohol (Spigelman). Using a behavioral model of PTSD, our aims are to determine if stress is associated with a neuroimmune response within the amygdala and to determine if this response predicts changes in behavior, as well as determine if blockade of glia activation/neuroimmune response will reverse the behavioral sequelae of stress. Preliminary data with this stress model indicates exaggerated reactions to novel startling stimuli, increased anxiety and enhanced learning of new fears, which persist at least 3 months after stress without diminution. The same stress increased voluntary alcohol consumption relative to an unstressed control group. The model also produces prolonged alterations in gene expression patterns in the amygdala with up-regulation of several genes related to cytokines. Although stress-induced activation of central nervous system pro- inflammatory responses have been reported, there are significant gaps in knowledge about how they contribute to long term emotional disturbances and influence the amygdala. PUBLIC HEALTH RELEVANCE: Post-Traumatic Stress Disorder is characterized by excessive drinking, anxiety, and depression that develop and last for a prolonged period after the initial trauma. We will test the hypothesis that neuroimmune factors, such as cytokines and chemokines released in the CNS that are activated by stress mediate these long-lasting changes in behavior by acting like neurotransmitters, neuromodulators, or neurohormones in the brain. We will also determine if pharmacologically interfering with these neuroimmune pathways mitigate the symptoms of PTSD.

描述（由申请人提供）：暴露于创伤压力后，通常会继续发展创伤后应激障碍（PTSD），其特征是增强了焦虑，以提醒创伤，噩梦，重新获得创伤经历和获得新恐惧的倾向。 PTSD的特征是过度饮酒，焦虑和抑郁症，在初次创伤后持续了长时间。结果是PTSD对个人和整个社会的生活都有重大影响。一个挑战是找到压力引起的焦虑，酒精摄入和抑郁症的变化之间的共同联系。大量数据表明，神经免疫因子可能是该链接。一旦被认为仅仅是大脑的填料花生，大脑和脊髓中的神经胶质细胞是大脑中适当的功能，信号传导和神经元赔偿不可或缺的一部分。小胶质细胞特别参与神经炎症，这与破坏性的慢性神经免疫反应有关。小胶质菌的激活产生促炎性细胞因子。 PTSD和主要抑郁症（MDD）观察到促炎细胞因子的水平升高。酗酒者的大脑中，小胶质细胞和促炎性细胞因子增加。因此，神经免疫因子在PTSD，抑郁和酒精中毒的Nexus上。尚不知道是什么介导了这些长期应力引起的变化，但是压力会产生明显改变行为的神经免疫反应。为了应对这一挑战，我们组建了一个在情感相关行为方面具有专业知识的团队（Fanselow），压力引起的神经免疫功能（Bradesi＆Mayer）以及酒精的神经生物学（Spigelman）。使用PTSD的行为模型，我们的目的是确定应力是否与杏仁核内的神经免疫反应有关，并确定此响应是否预测行为的变化，并确定胶质激活/神经免疫反应的阻断是否会逆转应力的行为序列。使用这种压力模型的初步数据表明，对新型惊人刺激，增加焦虑和增强新恐惧的学习的反应夸大了，这些反应至少在压力后至少3个月持续存在而不会减少。相同的压力增加了相对于无压力对照组的自愿性饮酒。该模型还产生了杏仁核中基因表达模式的长时间改变，并在与细胞因子有关的几种基因上进行了调节。尽管已经报道了压力引起的中枢神经系统促炎性反应的激活，但知识的知识差距很大，它们如何促进长期情绪障碍并影响杏仁核。 公共卫生相关性：创伤后应激障碍的特征是过度饮酒，焦虑和抑郁症，最初创伤后长时间持续了持续时间。我们将检验以下假设：神经免疫性因子，例如中枢神经系统中释放的细胞因子和趋化因子，这些因子通过压力激活，通过像神经递质，神经调节剂，神经调节剂或脑中神经激素的作用，介导了这些长期行为的变化。我们还将确定药理学是否会干扰这些神经免疫性途径减轻PTSD的症状。