Neuroimmune mechanisms in stress and alcohol comorbidity

压力和酒精合并症的神经免疫机制

• 批准号: 10005104
• 负责人: MARISA ROBERTO
• 金额: $ 47.56万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005104
• 关键词: Address; Adrenal Glands; Affect; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdaloid structure; Anxiety; Anxiety Disorders; Behavior; Behavioral; Binding Proteins; Biochemical; Biological; Biological Markers; Brain; Brain region; Cell Nucleus; Cell physiology; Chronic; Critical Pathways; Development; Disease; Economics; Electrophysiology (science); Elements; Ethanol; Exhibits; Female; Fright; Functional disorder; Gene Expression; Genes; Glucocorticoid Receptor; Glutamates; Goals; Homeostasis; Human; Hypothalamic structure; IL18 gene; Immune; Immune signaling; Immunohistochemistry; In Situ Hybridization; Individual; Inflammation; Inflammatory; Interdisciplinary Study; Interleukin-18; Knowledge; Lead; Link; Measures; Mediating; Memory; Mental disorders; Modeling; Molecular; Nerve Degeneration; Nervous System Physiology; Neuraxis; Neurodegenerative Disorders; Neuroimmune; Neuroimmunomodulation; Neurons; Pathologic; Pathway interactions; Peripheral; Pharmacology; Pharmacology Study; Phenotype; Physiological; Pituitary Gland; Play; Post-Traumatic Stress Disorders; Prevalence; Prevention; Process; Public Health; Publishing; Rattus; Receptor Signaling; Recording of previous events; Regulation; Reporting; Research Project Grants; Ribosomal RNA; Risk Factors; Rodent; Role; Signal Transduction; Single Nucleotide Polymorphism; Site; Slice; Stress; Structure; Surveys; System; Systems Biology; Techniques; Testing; Traumatic Shock; United States; Viral Vector; Withdrawal Symptom; addiction; alcohol comorbidity; alcohol exposure; alcohol use disorder; anxiety-like behavior; behavior change; behavioral outcome; behavioral phenotyping; candidate marker; clinical anxiety; cohort; comorbidity; cytokine; disorder subtype; drinking; gamma-Aminobutyric Acid; hypothalamic-pituitary-adrenal axis; improved; innovation; interleukin-18 receptor; knock-down; male; neuroinflammation; neuropsychiatric disorder; next generation sequencing; novel; receptor; receptor expression; relapse risk; response; ribosome profiling; stress disorder; synaptic function; theories; transcriptome; transcriptome sequencing; transmission process; treatment strategy

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.

压力是饮酒障碍（AUD）的危险因素。通常，患有焦虑症的人这样 由于创伤后应激障碍（PTSD）的aud发生率也升高，因此戒酒更为严重 症状和更大的继电器风险。积累的证据表明与免疫相关的途径是 中枢神经系统功能和功能障碍的关键生物学成分。我们发布的初步结果显示 典型的细胞因子（例如白介素（IL）-18）具有影响神经元功能的深刻能力 并调节杏仁核内的GABA和谷氨酸传播。值得注意的是，IL-18及其受体是 在杏仁核中高度表达，这是一个强烈促进动画和额外相关的大脑区域 行为以及压力病史和酒精暴露会增加IL-18的表达。最近在人类的研究 发现IL-18受体基因表达与不同的PTSD亚型有关，并且 IL-18基因（RS1946518）中的核苷酸多态性（SNP）与高度高度的AUD相关 创伤的平民队列在很大程度上合并为PTSD。值得注意的是，IL-18基因中的同一SNP也是 与动画中的杏仁核反应性有关。该提议的目的是1）确定细胞 IL-18在正常神经元活动的稳态调节中的基本作用的基础机制 和杏仁核电路，以及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动画和音频。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，核糖体谱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物和药物 病毒载体介导的杏仁核中IL-18系统的击倒。我们将确定 在健康和病理功能中的外围和中央免疫元素，比较脆弱的VS。 分子，细胞，电路和行为水平的弹性受试者。我们将确定IL-18的作用 使用改编的“ 2击”的男性和雌性大鼠的杏仁核圆圈中突触功能的信号传导 压力的大鼠模型以产生升级的饮酒和高焦虑样表型，以进行行为和 生理研究。总的来说，这些研究将阐明驱动IL-18的机制 失调会导致压力引起的动画和auds，并可能确定 焦虑症和酒精中毒的治疗策略。