Project 2: Mechanisms underlying vulnerability to ethanol self-administration: behavioral and brain imaging studies in group-housed monkeys

项目总结 酒精使用障碍(AUD)仍然是一个代价高昂的公共健康问题，缺乏广泛有效的药物 以及预防的策略。这个项目的主要科学前提，就像《觉醒》中的其他项目一样 森林转化酒精研究中心(WF-TARC)，是神经底物对 对澳元的脆弱性和复原力还没有完全了解。非人灵长类(NHP)受试者的研究 具有特定的优势，使其成为全面、可转换的方法的关键部分 解决这个话题，包括在人类受试者中不可能的实验控制的可能性和一个 与啮齿动物相比，它与人类的神经生物学更相似。群居猴子形成线性社会 等级制度；社会等级已被证明影响对滥用药物的敏感性，下属表现出 易受兴奋剂和乙醇滥用相关影响的影响(乙醇)。WF-TARC的项目2将 利用这种社会阶层之间的差异敏感性来确定行为和大脑机制 开发AUD的潜在漏洞。行为研究将表征归纳中与职级相关的差异 酒精饮用量、一年以上每天饮用酒精22小时及酒精寻觅行为 在戒酒期间使用一种极具特色的NHP Etoh长期自我给药模式 在人类中饮酒。我们还将确定主猴和从属猴对 AUD的慢性治疗潜在药物。在这些实验的同时，大脑成像研究使用 磁共振成像将表征优势种和非优势种之间的结构和功能差异 并确定在灰质和白质完整性、脑血液中发生的具体变化 长期饮用乙醇和随后戒酒期间的流动和功能连接。重要的是，这些 NHP研究在WF-TARC的翻译结构中占有关键地位，支持向前和 向后翻译以通知和扩展啮齿动物和人类项目的研究结果。NHP成像研究将 将重点放在相同的大脑区域和节点上，这些区域和节点将在受试者身上成像并进行研究和 在啮齿动物身上被操控。对成像数据的二次分析将把这一重点扩展到整个大脑。已被占用 总而言之，本项目的研究结果，特别是结合其他项目产生的数据 WF-TARC的组成部分，将全面说明不同人群之间的大脑差异 对澳元具有抵抗力和脆弱性的人。这一知识最终将帮助实践者指导预防 向受益最大的群体努力，并将为更有效的药物确定新的靶点 针对最脆弱的人群。

PROJECT SUMMARY Alcohol use disorder (AUD) persists as a costly public health problem that lacks widely effective medications and strategies for prevention. The overarching scientific premise of this Project, like the others of the Wake Forest Translational Alcohol Research Center (WF-TARC), is that the neural substrates that contribute to vulnerability and resilience to AUD are not fully understood. Studies using nonhuman primate (NHP) subjects have specific advantages that make them a critical part of a comprehensive, translational approach to addressing this topic, including the possibility of experimental control not possible in human subjects and a greater similarity to humans' neurobiology compared to rodents. Group-housed monkeys form linear social hierarchies; social rank has been shown to influence sensitivity to abuse drugs, with subordinates showing vulnerability to the abuse-related effects of stimulants and ethanol (EtOH). Project 2 of the WF-TARC will exploit this differential sensitivity across social ranks to determine the behavioral and brain mechanisms that underlie vulnerability to develop AUD. Behavioral studies will characterize rank-related differences in induction of EtOH drinking, EtOH consumption over one year of 22 hours-per-day access and EtOH seeking behavior during abstinence using an extremely well-characterized NHP EtOH self-administration model of long-term drinking in humans. We will also determine whether dominant and subordinate monkeys differ in sensitivity to chronic treatment potential medications for AUD. In parallel to these experiments, brain imaging studies using magnetic resonance imaging will characterize the structural and functional differences between dominants and subordinates, and determine the specific changes that occur in grey and white matter integrity, cerebral blood flow and functional connectivity during long-term EtOH drinking and subsequent abstinence. Importantly, these NHP studies occupy a critical position in the translational structure of the WF-TARC, supporting forward and backwards translation to inform and extend findings in rodent and human projects. NHP imaging studies will focus on the same brain regions and nodes that will be imaged in human subjects and studied and manipulated in rodents. Secondary analyses on imaging data will expand this focus to the entire brain. Taken together, the results of the studies in this Project, particularly in combination with data generated in other components of the WF-TARC, will provide a comprehensive account of brain differences between populations that are resistant versus vulnerable to AUD. This knowledge will ultimately help practitioners direct preventive efforts to groups who will most benefit from them, and will identify new targets for more effective medications targeted to the most vulnerable populations.