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

项目 2：乙醇自我管理脆弱性的潜在机制：群养猴子的行为和大脑成像研究

• 批准号: 10310701
• 负责人: Paul W. Czoty
• 金额: $ 39.86万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-10 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310701
• 关键词: Abstinence; Address; Alcohol consumption; Animal Model; Animals; Area; Behavioral; Brain; Brain imaging; Brain region; Cerebrovascular Circulation; Chronic; Consultations; Consumption; Cues; Data; Ethanol; Functional Magnetic Resonance Imaging; Grant; Hour; Human; Human Subject Research; Image; Individual Differences; Intervention; Knowledge; Laboratory Animals; Macaca fascicularis; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; Modeling; Monkeys; Neurobiology; Pattern; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Population; Positioning Attribute; Prevention strategy; Preventive; Procedures; Public Health; Relapse; Resistance; Rest; Rodent; Scanning; Schedule; Self Administration; Social Hierarchy; Stimulant; Stress; Structure; Study Subject; Testing; Time; Translations; Vulnerable Populations; alcohol abstinence; alcohol availability; alcohol effect; alcohol exposure; alcohol reinforcement; alcohol research; alcohol seeking behavior; alcohol sensitivity; alcohol use disorder; base; behavioral study; chronic alcohol ingestion; cost; drinking; drug of abuse; effective therapy; experimental study; forest; gray matter; human subject; imaging modality; imaging study; insight; nonhuman primate; novel; relating to nervous system; resilience; secondary analysis; social; social group; social stress; therapy design; translational approach; treatment effect; white matter

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.

项目摘要 酒精使用障碍（AUD）仍然是一个昂贵的公共卫生问题，缺乏广泛有效的药物 和预防战略。这个项目的首要科学前提，就像其他的唤醒一样， 森林转化酒精研究中心（WF-TARC），是神经基板，有助于 对澳元的脆弱性和弹性尚未完全了解。使用非人灵长类动物（NHP）受试者的研究 具有特定的优势，使其成为全面的转化方法的关键部分， 解决这个问题，包括实验控制的可能性，不可能在人类受试者和 与啮齿类动物相比，人类的神经生物学更相似。群居的猴子形成线性社会 等级制度;社会等级已被证明会影响对滥用药物的敏感性，下属表现出 易受兴奋剂和乙醇（EtOH）滥用相关影响的脆弱性。该工作组的项目2将 利用这种不同社会阶层的敏感性差异来确定行为和大脑机制， 是发展澳元的基础。行为学研究将描述诱导中与等级相关的差异 的EtOH饮用，EtOH消费超过一年的22小时每天访问和EtOH寻求行为 在禁欲期间，使用一种非常良好的NHP EtOH自我给药模型， 在人类中饮酒我们还将确定是否主导和从属猴子的敏感性不同， 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 磁共振成像将表征显性之间的结构和功能差异， 下属，并确定具体的变化，发生在灰色和白色物质的完整性，脑血 在长期乙醇饮用和随后的禁欲过程中的流动和功能连接。重要的是这些 NHP研究在WF-TARC的翻译结构中占据关键地位，支持向前和 反向翻译，以告知和扩展啮齿动物和人类项目的发现。NHP成像研究将 专注于将在人类受试者中成像和研究的相同大脑区域和节点， 在啮齿类动物中操作。对成像数据的二次分析将把这种关注扩展到整个大脑。采取 本项目的研究结果，特别是与其他项目产生的数据相结合， WF-TARC的组成部分，将提供人群之间大脑差异的全面说明 对澳元的抵抗力和脆弱性。这些知识将最终帮助从业人员直接预防 为最能从中受益的群体做出努力，并为更有效的药物确定新的目标。 针对最弱势群体。