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

项目摘要/摘要 暴露在创伤性事件中的个人有发展一系列症状的风险，称为 创伤后应激障碍(PTSD)。有证据表明，创伤后应激障碍和创伤后应激障碍的发病率很高。 酒精使用障碍(AUDS)，创伤后应激障碍患者经历AUD的风险增加三倍。 虽然人们普遍认为创伤后应激障碍是AUDS的一个危险因素，但也有证据表明， AUDS的病史可能会使个人在生物学上更容易受到严重压力的影响，因此 有可能发展为创伤后应激障碍。尽管有证据表明创伤后应激障碍和AUDS并存，但我们的 对介导这些共病障碍的潜在神经元底物的了解，以及可用的 药物治疗是有限的。这个应用程序汇集了一组调查人员来解决这个问题 以一种收敛的方式提出科学问题，并利用作为基础的神经免疫机制的专业知识 创伤后应激障碍样行为(Lysle)，过量酒精(乙醇)摄入的神经生物学(Thiele)，以及 对星形胶质细胞生理学的理解(赖斯纳)。有趣的是，目前团队的研究比较 提示共同的重叠神经免疫机制可能是每种病理发生的基础。 Lysle博士发现，严重的压力会引起背侧海马区的时间依赖性增加。 白介素1β(IL-1β)，以及在严重应激后直接阻断DH中的IL-1信号(重复 不可预测的脚部电击)可防止压力增强型恐惧学习(SEFL)，这是创伤后应激障碍的动物模型。 目前的研究小组一致地发现，长期接触酒精后戒断会增加 海马区IL-1的β基因，以及最近一个研究小组之间的合作试点项目显示 停用乙醇可增强SEFL的幅度。这些观察结果支持了我们的总体假设， 海马区IL-1β代表了酒精应激反应加剧的细胞机制- 孤僻/受供养的人。特定目标1将测试戒断诱导的增强的假设 SEFL与(A)星形胶质细胞中IL-1β信号的增强有关，这与 (二)戒断期间药物阻断卫生署IL-1R可预防戒断- 创伤后应激障碍样表型的诱导增强，以及(C)外源性IL-1β的DH输注将取代 酒精戒断的影响。特定目标2将检验形态测量中的变化的假设 星形胶质细胞的特性和/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有关 IL-1β水平源于乙醇戒断和SEFL使用的严重应激。在这里提出的研究 适用于R21奖励机制，因为它们是高额奖励，有可能填补我们 了解星形胶质细胞衍生的细胞因子在PTSD和AUD共病中的作用。他们是 风险也很高，因为我们目前没有直接证据表明IL-1β信号在DH中是一种机制 用于戒断后PTSD样表型的增强。

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.