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: 10650796
• 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/10650796
• 关键词: Address; Adrenal Glands; Affect; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdaloid structure; Anxiety; Anxiety Disorders; Association Learning; Behavior; Behavioral; Biochemical; Biological; Biological Markers; Brain; Brain region; Cell Nucleus; Cell physiology; Central Nervous System; Chronic; Critical Pathways; Development; Disease; Economics; Electrophysiology (science); Elements; Ethanol; Exhibits; Female; Fright; Functional disorder; Gene Expression; Glucocorticoid Receptor; Glutamates; Goals; Homeostasis; Human; Hypothalamic structure; IL18 gene; Immune; Immune signaling; Immunohistochemistry; In Situ Hybridization; Individual; Inflammation; Inflammatory; Interdisciplinary Study; Knowledge; Link; Measures; Mediating; Memory; Mental disorders; Modeling; Molecular; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neuroimmune; Neuroimmunomodulation; Neurons; Operant Conditioning; Pathologic; Pathway interactions; Peripheral; 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; Rodent Model; Role; Signal Transduction; Single Nucleotide Polymorphism; Site; Slice; Stress; Structure; Surveys; System; Systems Biology; Techniques; Testing; Trauma; Traumatic Shock; United States; Viral Vector; Withdrawal Symptom; addiction; alcohol comorbidity; alcohol exposure; alcohol use disorder; antagonist; anxiety-like behavior; anxiety-related disorders; behavior change; behavioral outcome; behavioral phenotyping; candidate marker; clinical anxiety; cohort; comorbidity; cytokine; drinking; gamma-Aminobutyric Acid; hypothalamic-pituitary-adrenal axis; improved; innovation; interleukin-18 binding protein; interleukin-18 receptor; knock-down; male; neuroinflammation; neuropsychiatric disorder; next generation sequencing; novel; pharmacologic; receptor; receptor expression; relapse risk; resilience; response; ribosome profiling; stress disorder; synaptic function; systemic inflammatory response; 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.

压力是酒精使用障碍（AUDs）的一个危险因素。一般来说，患有焦虑症的人，比如