Neuroimaging Adaptive Microglia Processes During Extended Alcohol Drinking

项目总结 急性酒精会在大脑中引发免疫反应。这种反应的一个特点是激活了 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，小胶质细胞的反应减弱。然而，表征这些效应的临床前研究结果是高度的 根据品种、剂量、酒精的慢性和时间的不同而混合。重要的是要确定适应性的特征 反复酒精暴露中的小胶质细胞过程，因为先天神经免疫因子与 不断升级的酒精饮酒。然而，由于有限，这些机制还不能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反应的非侵入性工具。这项分两个阶段的提案将 首次开发一种新的针对集落刺激因子1的正电子发射断层扫描(PET)放射性示踪剂 受体(CSF1R)，将表征重复酒精暴露的小胶质细胞动力学。CSF1R是 比目前的PET靶标更有优势，因为它只在小胶质细胞上表达。这款CSF1R PET 将评估放射性示踪剂的合适成像特性和对急性酒精挑战的敏感性。 对这些属性的确认将为第二阶段提供一个关键工具。第二阶段将使用此成像工具 在三个时间点测量非人类灵长类动物对酒精的急性免疫反应：酒精幼稚， 第一次酒精刺激后一周，4个月后酒精自我给药。收集到的数据将 描述在饮酒开始和增加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。这些发现将使这一领域向前推进 提供了一种新的成像工具，已经成熟，可以翻译成人体研究，同时测试以下重要假设 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。结果将会是 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 有酒精使用障碍的人和未来酒精使用障碍的高危人群。

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.