Neuroimmune mechanisms in stress and alcohol comorbidity

压力是酒精使用障碍（AUD）的危险因素。一般来说，患有焦虑症的人 由于创伤后应激障碍（PTSD）也有较高的比率，AUD，更严重的酒精戒断 症状和更大的复发风险。越来越多的证据表明，免疫相关的途径是 中枢神经系统功能和功能障碍的关键生物成分。我们公布的初步结果显示， 典型的细胞因子，如白细胞介素（IL）-18，具有影响神经元功能的深刻能力， 并调节杏仁核内GABA和谷氨酸的传递。值得注意的是，IL-18及其受体是 在杏仁核中高度表达，杏仁核是一个与焦虑和成瘾相关的大脑区域。 行为、应激史和酒精暴露增加IL-18表达。最近的人类研究 发现IL-18受体基因表达与不同的PTSD亚型有关， IL-18基因（rs 1946518）的核苷酸多态性（SNP）与AUD高度相关， 受过创伤的平民大多患有创伤后应激障碍值得注意的是，IL-18基因中的相同SNP也是 与焦虑时杏仁核的反应有关该提案的目标是1）识别细胞 IL-18在正常神经元活动的稳态调节中的基本作用机制 和杏仁核回路，以及2）测试IL-18信号转导有助于发展的假设， 适应不良压力引起的焦虑和AUDs。为了实现我们的目标，我们将采用创新和 互补技术：行为，电生理学，核糖体分析与下一代相结合 测序、原位杂交/RNA显微镜和免疫组织化学，以及药理学和 病毒载体介导的杏仁核中IL-18系统的敲低。我们将确定 外周和中枢免疫元素的健康和病理功能，比较脆弱与。 在分子、细胞、电路和行为水平上的弹性主体。我们将确定IL-18的作用 用改进的“2-hit”方法研究雄性和雌性大鼠杏仁核回路中突触功能的信号传导 应激大鼠模型，以产生行为和行为的逐步增加的饮酒和高度焦虑样表型， 生理学研究总的来说，这些研究将阐明驱动IL-18的机制， 调节障碍有助于压力诱导的焦虑和AUDs，并可能确定有希望的目标， 焦虑症和酗酒的治疗策略。

Stress is a risk factor for alcohol use disorders (AUDs). Generally, individuals with anxiety disorders such as posttraumatic stress disorder (PTSD) also have elevated rates of AUD, more severe alcohol withdrawal symptoms, and greater relapse risk. Accumulating evidence indicates that immune-related pathways are critical biological components of CNS function and dysfunction. Our published and preliminary results show that canonical cytokines, such as Interleukin (IL)-18, have a profound capacity to affect neuronal function and regulate GABA and glutamate transmission within the amygdala. Notably, IL-18 and its receptors are highly expressed in the amygdala, a brain region that strongly contributes to anxiety- and addictive-related behaviors, and stress history and alcohol exposure increase IL-18 expression. Recent studies in humans found that IL-18 receptor gene expression is associated with distinct PTSD subtypes and that a single nucleotide polymorphism (SNP) in the IL-18 gene (rs1946518) is associated with AUD in a highly traumatized civilian cohort largely comorbid for PTSD. Notably, the same SNP in the IL-18 gene is also associated with amygdala reactivity in anxiety. The goal of this proposal is to 1) identify the cellular mechanisms underlying the essential role of IL-18 in homeostatic regulation of normal neuronal activities and amygdala circuits, and 2) test the hypothesis that IL-18 signaling contributes to the development of maladaptive stress-induced anxiety and AUDs. To accomplish our goal, we will employ innovative and complementary techniques: behavior, electrophysiology, ribosome profiling combined with next generation sequencing, in situ hybridization/RNAScope and immunohistochemistry, as well as pharmacological and viral vector-mediated knock down of the IL-18 system in amygdala. We will determine the interactions of peripheral and central immune elements in healthy and pathological function, comparing Vulnerable vs. Resilient subjects, at the molecular, cellular, circuit and behavioral levels. We will identify the role of IL-18 signaling on synaptic functions in amygdala circuits in both male and female rats using an adapted “2-hit” rat model of stress to generate escalated drinking and high anxiety-like phenotypes for behavioral and physiological studies. Collectively, these studies will elucidate the mechanisms that drive IL-18 dysregulation to contribute to stress-induced anxiety and AUDs, and may identify promising targets for treatment strategies for anxiety disorders and alcoholism.