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

基本信息

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
项目类别：
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

项目摘要

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，这种反应的一个标志是激活大脑中的免疫反应。大脑的主要免疫细胞小胶质细胞很容易适应重复的刺激，这可以增强或增强。随着时间的推移，小胶质细胞的反应会减弱。然而，表征这些效应的临床前研究结果非常明显。混合取决于物种、剂量、长期酒精度和时间。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然而，由于有限，目前还无法在灵长类动物中评估这些机制。这个分两阶段的提案将测量小胶质细胞对急性免疫挑战的反应的非侵入性工具。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）将表征反复酒精暴露下的小胶质细胞动力学。优于目前的 PET 靶标，因为它仅在小胶质细胞上表达。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使用该成像工具提供关键工具。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渐增加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，这些发现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小胶质细胞动态过程及其对饮酒行为的影响。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。