Neuroimaging Adaptive Microglia Processes During Extended Alcohol Drinking

项目摘要 急性酒精会引发大脑的免疫反应。这种反应的一个标志是激活了 大脑的主要免疫细胞小胶质细胞小胶质细胞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研究结果是高度相关的。 根据物种、剂量、酒精慢性和时间混合。重要的是要描述适应性 小胶质细胞在重复酒精暴露期间发生变化，因为先天神经免疫因素与 不断增加的酒精摄入量然而，这些机制还不能在灵长类动物中进行评估，由于有限的 非侵入性工具，测量小胶质细胞对急性免疫挑战的反应。这两个阶段的提案将 首先开发一种新的特异于殖民地刺激因子1的正电子发射断层扫描（PET）放射性示踪剂 受体（CSF1R），将表征小胶质细胞的动力学反复酒精暴露。CSF1R是 因为它仅在小胶质细胞上表达，所以它比当前的PET靶标更有利。CSF1R PET 将评价放射性示踪剂的适当成像特性和对急性酒精激发的敏感性。 这些特性的确认将为第二阶段提供一个关键工具。第二阶段将使用这种成像工具 在三个时间点测量非人灵长类动物对酒精的急性免疫反应：未接触酒精的， 在初始酒精挑战后一周，以及在4个月酒精自我给药后。收集的数据将 表征在酒精起始和逐步饮酒期间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。这些发现将推动该领域的发展， 提供了一个新的成像工具，成熟的翻译为人类研究，同时测试重要的假设， 酒精暴露的动态小胶质细胞过程及其对饮酒行为的影响。结果将 对未来评估适应性小胶质细胞过程的人类研究具有明确的翻译意义， 患有酒精使用障碍的人和未来酒精使用障碍的高风险人群。

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.