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: 10704077
• 负责人: Ansel Hillmer
• 金额: $ 33.48万
• 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/10704077
• 关键词: Acute; Alcohol consumption; Alcohols; Animals; Attenuated; Binding; Brain; Brain imaging; Cells; Chronic; Complex; Data; Development; Dose; Future; Goals; Human; Image; Imaging Device; Immune; Immune response; Immune signaling; Immune system; In Vitro; Lead; Link; Macrophage Colony-Stimulating Factor Receptor; Measures; Mediating; Microglia; Neuroimmune; Persons; Phase; Population; Positron-Emission Tomography; Primates; Process; Property; Proteins; Reporting; Rodent; Self Administration; Signaling Protein; Specificity; Stimulus; Testing; Time; Translating; alcohol exposure; alcohol response; alcohol sensitivity; alcohol use disorder; alcohol use initiation; drinking; drinking behavior; experience; high risk; imaging properties; in vivo; in vivo evaluation; neuroimaging; nonhuman primate; novel; pre-clinical; predicting response; 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.

项目摘要 急性酒精会触发大脑的免疫响应。这种反应的标志是激活 脑的原发性免疫细胞，小胶质细胞。小胶质细胞容易适应重复的刺激，可以增强或 随着时间的流逝，小胶质细胞反应减弱。但是，表征这些效果的临床前发现高度 取决于物种，剂量，酒精慢性和时机的混合。表征适应性很重要 重复酒精暴露期间的小胶质细胞过程，因为先天神经免疫性因子与 不断饮酒。但是，由于有限 测量小胶质细胞对急性免疫挑战的反应的无创工具。这个2相建议将 首先开发一种新型的正电子发射断层扫描（PET）刺激因子1 接收器（CSF1R）将表征来自反复酒精暴露的小胶质细胞动力学。 CSF1R是 优于当前宠物靶标，因为它仅在小胶质细胞上表达。这个CSF1R宠物 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。 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 在三个时间点测量非人类隐私中酒精的急性免疫反应：幼稚，一个 初始酒精挑战后的一周，四个月后酒精自我管理。收集的数据将 表征自适应小胶质细胞过程在酒精启动和饮酒升级期间发生，并且 确定这些过程与饮酒行为的关系。这些发现将通过 在测试有关重要假设的同时，提供了一种新的成像工具，以使其翻译成人类研究 酒精暴露及其对饮酒行为的影响的动态小胶质细胞过程。结果将 对未来的人类研究具有明确的翻译意义，评估自适应小胶质细胞过程 患有饮酒障碍和人群的人患有未来饮酒障碍的人。