Neuroimmune mechanisms in stress and alcohol comorbidity

压力是酒精使用障碍(AUDS)的风险因素。一般来说，患有焦虑症的人 由于创伤后应激障碍(PTSD)也有更高的AUD发生率，更严重的酒精戒断 症状，以及更大的复发风险。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学成分。我们已发表的和初步的结果表明 经典的细胞因子，如白介素18，具有深刻的影响神经功能的能力 并调节杏仁核内的GABA和谷氨酸的传递。值得注意的是，IL-18及其受体 杏仁核中高度表达，这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创伤后应激障碍亚型相关，并且单个 IL-18基因(Rs1946518)的核苷酸多态(SNP)与AUD密切相关 饱受创伤的平民群体大多与创伤后应激障碍并存。值得注意的是，IL-18基因中相同的SNP也是 与焦虑症中的杏仁核反应有关。这项提议的目标是1)识别蜂窝 IL-18在正常神经元活动的动态平衡调节中的作用机制 和杏仁核回路，以及2)检验IL-18信号有助于糖尿病的发生的假说。 适应不良应激导致的焦虑和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、核糖体图谱与下一代相结合 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系统的敲除。我们将确定以下因素的相互作用 外周和中枢免疫成分在健康和病理功能中的作用，比较易损性和 坚韧的受试者，在分子、细胞、电路和行为水平上。我们将确定IL-18的作用 大鼠杏仁核内突触功能的信号转导 应激大鼠模型，产生不断升级的饮酒和高焦虑样表型的行为和 生理学研究。总的来说，这些研究将阐明推动IL-18的机制 调节失调导致应激诱导的焦虑和AUDS，并可能确定有希望的靶点 焦虑症和酒精中毒的治疗策略。

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.