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，例如 由于创伤后应激障碍 (PTSD) 的 AUD 发生率也升高，酒精戒断情况更严重 症状，以及更大的复发风险。越来越多的证据表明，免疫相关途径 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 经典细胞因子，例如白细胞介素 (IL)-18，具有影响神经元功能的深远能力 并调节杏仁核内的 GABA 和谷氨酸传输。值得注意的是，IL-18 及其受体 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、压力史和酒精暴露会增加 IL-18 的表达。最近对人类的研究 发现 IL-18 受体基因表达与不同的 PTSD 亚型相关，并且单个 IL-18 基因 (rs1946518) 中的核苷酸多态性 (SNP) 与 AUD 高度相关 受创伤的平民群体大多患有创伤后应激障碍 (PTSD)。值得注意的是，IL-18 基因中的相同 SNP 也 与焦虑时杏仁核的反应有关。该提案的目标是 1) 识别蜂窝 IL-18 在正常神经元活动稳态调节中重要作用的机制 和杏仁核回路，2) 检验 IL-18 信号传导有助于发展的假设 适应不良的压力引起的焦虑和 AUD。为了实现我们的目标，我们将采用创新和 补充技术：行为、电生理学、核糖体分析与下一代相结合 测序、原位杂交/RNAScope 和免疫组织化学，以及药理学和 病毒载体介导的杏仁核 IL-18 系统敲低。我们将确定以下相互作用 外周和中枢免疫元件在健康和病理功能中的作用，比较易感者与非易感者 在分子、细胞、回路和行为层面上具有弹性的受试者。我们将确定 IL-18 的作用 使用改编的“2-hit”对雄性和雌性大鼠杏仁核回路中的突触功能进行信号传导 大鼠压力模型会产生饮酒量增加和行为和高度焦虑样表型 生理学研究。总的来说，这些研究将阐明驱动 IL-18 的机制 调节失调会导致压力引起的焦虑和 AUD，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.