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

描述（由申请人提供）：暴露于创伤性压力后，个体通常会发展为创伤后应激障碍（PTSD），其特征是对创伤提醒的焦虑增强，噩梦，重温创伤经历以及获得新恐惧的倾向。创伤后应激障碍的特点是过度饮酒，焦虑和抑郁，在最初的创伤后持续很长一段时间。结果是，PTSD对个人和整个社会的生活都产生了重大影响。一个挑战是找到压力引起的焦虑、酒精摄入和抑郁之间的共同联系。大量数据表明，神经免疫因素可能是其中的联系。神经胶质细胞曾经被认为只是大脑的包装花生，但实际上，大脑和脊髓中的神经胶质细胞对于大脑的正常功能、信号传导和神经元修复是不可或缺的。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。微凝胶的激活产生促炎细胞因子。在创伤后应激障碍和重度抑郁症（MDD）中观察到促炎细胞因子水平的增加。小胶质细胞和促炎细胞因子在酗酒者的大脑中增加。因此，神经免疫因素与创伤后应激障碍、抑郁症和酗酒有关。目前尚不清楚是什么介导了这些长期压力引起的变化，但压力可以产生神经免疫反应，显著改变行为。为了应对这一挑战，我们组建了一个在情绪相关行为（Fanselow）、压力诱导的神经免疫功能（Bradesi & Mayer）和酒精神经生物学（Spigelman）方面具有专业知识的团队。使用创伤后应激障碍的行为模型，我们的目的是确定压力是否与杏仁核内的神经免疫反应有关，并确定这种反应是否预测行为的变化，以及确定阻断胶质细胞激活/神经免疫反应是否会逆转压力的行为后遗症。这种压力模型的初步数据表明，对新奇刺激的反应会夸大，焦虑会增加，对新恐惧的学习能力会增强，这些在压力后至少持续3个月而不会减少。与没有压力的对照组相比，同样的压力增加了自愿饮酒量。该模型还产生了杏仁核基因表达模式的长期改变，上调了几个与细胞因子相关的基因。虽然已经报道了应激诱导中枢神经系统促炎症反应的激活，但关于它们如何导致长期情绪障碍和影响杏仁核的知识存在重大空白。

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.