Neuroimmune mechanisms in stress and alcohol comorbidity

压力和酒精合并症的神经免疫机制

基本信息

批准号：
10190745
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
项目类别：
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/10190745
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 systemic inflammatory response theories transcriptome transcriptome sequencing transmission process treatment strategy

项目摘要

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) 的 AUD 发生率也升高，酒精戒断情况更严重症状和更大的复发风险表明免疫相关途径。我们发表的初步结果表明，中枢神经系统功能和功能障碍的关键生物成分。经典细胞因子，例如白细胞介素 (IL)-18，具有影响神经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、压力、酒精史和接触会增加人类中 IL-18 的表达。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 高度相关值得注意的是，IL-18 基因中也存在相同的 SNP。与焦虑中的杏仁核反应相关。该提案的目标是 1) 识别细胞。 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为了实现我们的目标，我们将采用创新和方法。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中 IL-18 系统的敲低我们将确定相互作用。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具有弹性的受试者，在分子、细胞、回路和行为水平上我们将确定 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。