Neuroimaging Adaptive Microglia Processes During Extended Alcohol Drinking

长期饮酒期间的神经影像适应性小胶质细胞过程

• 批准号: 10511295
• 负责人: Ansel Hillmer
• 金额: $ 12.41万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10511295
• 关键词: Acute; Alcohol consumption; Alcohols; Animals; Attenuated; Binding; Brain; Brain imaging; Cells; Chronic; Complex; Conflict (Psychology); Data; Development; Dose; Future; Goals; Human; Image; Imaging Device; Immune; Immune response; Immune signaling; Immune system; In Vitro; Lead; Link; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Measures; Mediating; Microglia; Neuroimmune; Persons; Phase; Population; Positron-Emission Tomography; Primates; Process; Property; Proteins; Rodent; Self Administration; Signaling Protein; Specificity; Stimulus; Testing; Time; Translating; alcohol exposure; alcohol response; alcohol sensitivity; alcohol use disorder; alcohol use initiation; base; drinking; drinking behavior; experience; high risk; imaging properties; in vivo; in vivo evaluation; neuroimaging; nonhuman primate; novel; pre-clinical; predicting response; process repeatability; radiotracer; response; tool; translation to humans

PROJECT SUMMARY Acute alcohol triggers an immune response in the brain. A hallmark of this response is the activation of the brain's primary immune cells, microglia. Microglia readily adapt to repeated stimuli, which can enhance or attenuate microglia responses over time. However, preclinical findings characterizing these effects are highly mixed depending on species, dose, alcohol chronicity, and timing. It is important to characterize adaptive microglia processes during repeated alcohol exposures because innate neuroimmune factors are linked with escalating alcohol drinking. Yet, these mechanisms cannot be evaluated yet in primates due to limited noninvasive tools that measure microglia responses to acute immune challenges. This 2-phase proposal will first develop a novel positron emission tomography (PET) radiotracer specific for the colony stimulating factor 1 receptor (CSF1R) that will characterize microglia dynamics from repeated alcohol exposures. CSF1R is advantageous over current PET targets because it is expressed exclusively on microglia. This CSF1R PET radiotracer will be evaluated for suitable imaging properties and sensitivity to an acute alcohol challenge. Confirmation of these properties will provide a key tool for the second phase. Phase 2 will use this imaging tool to measure the acute immune response to alcohol in nonhuman primates at three time points: alcohol naïve, a week after initial alcohol challenge, and after 4 months alcohol self-administration. The data collected will characterize adaptive microglia processes occur during alcohol initiation and escalating drinking, and determine the relationship of these process with drinking behaviors. The findings will advance the field by providing a new imaging tool ripe for translation to human studies while testing important hypotheses regarding dynamic microglia processes from alcohol exposure and their effects on drinking behaviors. The results will have clear translational implications for future human studies evaluating adaptive microglia processes in people with alcohol use disorder and populations with high risk for future alcohol use disorder.

项目概要 急性酒精会引发大脑的免疫反应。这种反应的一个特点是激活 大脑的主要免疫细胞，小胶质细胞。小胶质细胞很容易适应重复的刺激，这可以增强或 随着时间的推移减弱小胶质细胞的反应。然而，表征这些效应的临床前发现高度 根据物种、剂量、酒精长期性和时间进行混合。表征适应性很重要 小胶质细胞在反复酒精暴露过程中的过程，因为先天神经免疫因素与 饮酒量不断增加。然而，由于有限，这些机制还无法在灵长类动物中进行评估 测量小胶质细胞对急性免疫挑战的反应的非侵入性工具。这个分两阶段的提案将 首先开发出一种针对集落刺激因子 1 的新型正电子发射断层扫描 (PET) 放射性示踪剂 受体（CSF1R），它将表征反复酒精暴露下的小胶质细胞动力学。 CSF1R 是 优于目前的 PET 靶标，因为它仅在小胶质细胞上表达。这个CSF1R PET 将评估放射性示踪剂的适当成像特性和对急性酒精挑战的敏感性。 这些属性的确认将为第二阶段提供关键工具。第 2 阶段将使用此成像工具 测量非人类灵长类动物在三个时间点对酒精的急性免疫反应：未饮酒、酒精中毒 首次酒精挑战后一周，以及自我饮酒 4 个月后。收集的数据将 描述在饮酒开始和逐步饮酒过程中发生的适应性小胶质细胞过程，以及 确定这些过程与饮酒行为的关系。研究结果将推动该领域的发展 提供一种成熟的新成像工具，可以转化为人类研究，同时测试有关的重要假设 酒精暴露引起的动态小胶质细胞过程及其对饮酒行为的影响。结果将 对评估适应性小胶质细胞过程的未来人类研究具有明确的转化意义 患有酒精使用障碍的人和未来酒精使用障碍高风险的人群。