A Role for IL-1Beta in Ethanol Withdrawal-Induced Increase of PTSD-Like Phenotype

项目总结/摘要 暴露于创伤事件的个体有可能出现一系列症状， 创伤后应激障碍（PTSD）。有证据表明，PTSD和 酒精使用障碍（AUD），PTSD患者发生AUD的风险增加三倍。 虽然人们普遍认为PTSD的进展，是一个危险因素，AUDs，也有证据表明，先前的 AUD的历史可能使个体在生物学上更容易受到严重压力的影响， 很可能会患上创伤后应激障碍尽管PTSD和AUDs之间的共病证据越来越多，我们的研究表明， 了解潜在的神经基质介导这些共病疾病，以及现有的 药物治疗有限。这个应用程序汇集了一个调查小组来解决这个问题 科学问题以收敛的方式与神经免疫机制的专业知识， PTSD样行为（Lysle），过量酒精（乙醇）摄入的神经生物学（Thiele）， 了解星形胶质细胞生理学（Reissner）。有趣的是，与目前团队的研究相比， 表明共同的重叠神经免疫机制可能是每种病理学发展的基础。 博士Lysle发现，严重的应激诱导背海马（DH） 白细胞介素-1 β（IL-1β），以及严重应激后直接阻断DH中IL-1信号传导（重复 不可预测的足部电击）防止压力增强恐惧学习（SEFL），这是一种PTSD的动物模型。 因此，目前的研究小组发现，慢性乙醇暴露后的戒断症状增加， 海马IL-1β mRNA，以及研究小组之间最近的一个合作试点项目显示， 乙醇提取增强了SEFL的大小。这些观察结果支持了我们的总体假设， 海马IL-1β代表了酒精中应激反应加剧的细胞机制， 独立/依赖的人。具体目标1将检验以下假设：戒断诱导的 SEFL与（A）星形胶质细胞中特异性IL-1β信号传导的增强相关， SEFL的大小，（B）在戒断期间DH IL-1 R的药理学阻断将防止戒断- 诱导PTSD样表型的增强，以及（C）外源性IL-1β的DH输注将取代 酒精戒断的影响具体目标2将检验形态测量变化的假设， 星形胶质细胞的性质和/或星形胶质细胞/神经元相互作用的改变与星形胶质细胞的增加相关。 IL-1β水平源于乙醇戒断和SEFL中使用的严重应激。这里提出的研究 适用于R21补助金机制，因为它们具有高回报，可能填补我们 了解星形胶质细胞衍生的细胞因子在共病PTSD和AUD疾病中的作用。他们是 也是高风险的，因为我们目前没有直接证据表明DH中的IL-1β信号传导是一种机制， 用于PTSD样表型的戒断诱导增强。

Project Summary/Abstract Individuals that have been exposed to a traumatic event are at risk for developing a set of symptoms known as post-traumatic stress disorder (PTSD). Evidence suggests that there is a high comorbidity between PTSD and alcohol use disorders (AUDs), with a three-fold increased risk for experiencing an AUD in sufferers of PTSD. While it is generally thought PTSD proceeds, and is a risk factor for, AUDs, there is also evidence that a prior history of AUDs may leave individuals biologically more vulnerable to the impact of severe stress and thus more likely to develop PTSD. Despite converging evidence of co-morbidity between PTSD and AUDs, our understanding of the underlying neuronal substrates mediating these comorbid disorders, as well as available pharmaceutical treatments, are limited. This application brings together a team of investigators to address this scientific question in a convergent manner with the expertise of the neural immune mechanisms that underlie PTSD-like behavior (Lysle), the neurobiology of excessive alcohol (ethanol) intake (Thiele), and the understanding of astrocyte physiology (Reissner). Interestingly, a comparison of the present team’s research suggests that common overlapping neuroimmune mechanisms may underlie the development of each pathology. Dr. Lysle has discovered that severe stress induces a time-dependent increase in dorsal hippocampal (DH) interleukin-1β (IL-1β), and that directly blocking IL-1 signaling in the DH after severe stress (repeated unpredictable foot shock) prevents stress-enhanced fear learning (SEFL), an animal model of PTSD. Consistently, the present research team has found that withdrawal following chronic ethanol exposure increases hippocampal IL-1β mRNA, and a recent collaborative pilot project between the research team revealed that ethanol withdrawal potentiates the magnitude of SEFL. These observations support our overarching hypothesis, that hippocampal IL-1β represents a cellular mechanism for exacerbated stress response in alcohol- withdrawn/dependent individuals. Specific Aim 1 will test the hypothesis that withdrawal-induced potentiation of SEFL is associated with (A) a potentiation of IL-1β signaling specifically in astrocytes that correlates with the magnitude of SEFL, (B) pharmacological blockade of DH IL-1R during withdrawal will protect against withdrawal- induced potentiation of PTSD-like phenotypes, and (C) that DH-infusion of exogenous IL-1β will substitute for the effects of ethanol withdrawal. Specific Aim 2 will test the hypothesis that changes in the morphometric properties of astrocytes, and/or alterations of astrocyte/neuron interactions, correlate with increased astrocyte IL-1β levels stemming from ethanol withdrawal and the severe stress used in SEFL. The studies proposed here are appropriate for the R21 grant mechanism because they are high-reward, potentially filling a gap in our understanding of the role that astrocyte-derived cytokines play in co-morbid PTSD and AUD disorders. They are also high-risk because we currently do not have direct evidence that IL-1β signaling in the DH is a mechanism for withdrawal-induced potentiation of PTSD-like phenotypes.