Network wide analysis of brain activity involved in alcohol withdrawal

酒精戒断相关大脑活动的网络范围分析

• 批准号: 10249381
• 负责人: Adam J Kimbrough
• 金额: $ 24.9万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249381
• 关键词: Abstinence; Acute; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Anxiety; Award; Behavior; Behavioral Model; Behavioral Symptoms; Brain; Brain imaging; Brain region; Cells; Chronic; Cluster Analysis; Complex; Data; Development; Disease; Ethanol; Exhibits; FOS gene; Future; Human; Hyperalgesia; Image; Immediate-Early Genes; Immunohistochemistry; Institution; LacZ Genes; Lead; Learning; Light; Maintenance; Measures; Microscopy; Modeling; Mus; Neurons; Neurosciences; Pathway Analysis; Phase; Process; Relapse; Research; Research Institute; Research Project Grants; Techniques; Test Result; Testing; Training; United States; Withdrawal; Withdrawal Symptom; Work; acute symptom; addiction; alcohol abstinence; alcohol abuse therapy; alcohol behavior; alcohol testing; alcohol use disorder; drinking; driving force; emotional symptom; graph theory; imaging study; innovation; insight; interest; mathematical methods; negative emotional state; neural circuit; neural network; noninvasive brain stimulation; novel; prevent; preventable death; recruit; segregation; skills; vapor

Project Summary / Abstract Alcohol use disorder (AUD) is one of the leading causes of preventable death in the United States. AUD is a chronic relapsing disorder that is associated with loss of control and compulsive drinking. The emergence of negative emotional states during acute withdrawal and their maintenance during protracted abstinence are critical driving forces that lead to excessive and compulsive-like alcohol drinking. Identifying the neurocircuitry that is involved in negative emotional states and excessive alcohol drinking is a critical step to understanding the neuronal causes of compulsive alcohol drinking. We have already identified several key brain regions that are recruited during acute alcohol withdrawal, but still unknown is whether these circuits are different during protracted abstinence. Additionally, previous research has often been biased by the preselection of regions of interest; therefore, unbiased whole-brain functional circuitry imaging is a critical step to examine the entire brain and identify entire networks that are involved in alcohol withdrawal. I will utilize the whole-brain imaging of immediate early genes to identify brain regions that are recruited during acute alcohol withdrawal and protracted abstinence. Once these brain regions are identified, they will be compared with regard to functional relationships using correlational analyses and graph theory. These analyses will identify critical components (brain regions) of the functional network of acute alcohol withdrawal and protracted abstinence. These critical components or hubs, once identified, will be targeted and selectively inactivated using the Daun02/LacZ approach to test causal relationships between these hubs and negative emotional states and compulsive alcohol drinking in dependent mice. These studies will be started at The Scripps Research Institute during my K99 phase and completed at my future institution during my independent R00 phase. During my K99 phase, I will receive training in graph theory analyses and Daun02 inactivation to identify and disrupt critical nodes within the functional network of alcohol abstinence. During the R00 phase, I will use Daun02 inactivation to continue these projects and further explore the ways in which the disruption of critical nodes within the functional alcohol abstinence network changes alcohol-related behavior. Collectively, this work will provide insights into the functional circuitry that contributes to alcohol addiction, reveal novel targets and testable hypotheses for future brain imaging studies in human, and facilitate the development of novel treatments for AUD, including targets for noninvasive brain stimulation.

项目摘要/摘要 酒精使用障碍(AUD)是美国可预防死亡的主要原因之一。澳元是一种 与失控和强迫性饮酒有关的慢性复发性障碍。新技术的出现 急性戒断期间的负面情绪状态及其在长期戒断期间的维持 导致过度和强迫性饮酒的关键驱动力。识别神经回路 这涉及到消极的情绪状态和过度饮酒是了解 强迫性饮酒的神经元原因。我们已经确定了几个关键的大脑区域 在急性戒酒期间被招募，但仍不清楚这些回路在戒酒过程中是否不同 长期禁欲。此外，以前的研究经常被预先选择的区域所偏颇 因此，无偏全脑功能回路成像是检查整个 并识别与酒精戒断有关的整个网络。 我将利用即刻早期基因的全脑成像来识别被招募的大脑区域 在急性戒酒和长期戒酒期间。一旦这些大脑区域被识别出来，它们就会 利用相关分析和图论对函数关系进行了比较。这些 分析将确定急性酒精戒断功能网络的关键组成部分(大脑区域) 以及长期禁欲。一旦确定了这些关键组件或集线器，就会有针对性地有选择地实施 使用Daun02/LacZ方法停用，以测试这些中枢和负值之间的因果关系 依赖小鼠的情绪状态和强迫性饮酒。 这些研究将在我的K99阶段在斯克里普斯研究所开始，并于 在我独立的R00阶段，我未来的机构。在我的K99阶段，我将接受图形培训 理论分析和Daun02停用来识别和中断功能网络中的关键节点 戒酒。在R00阶段，我将使用Daun02停用来继续这些项目，并进一步 探索功能性戒酒网络中关键节点的中断方式 改变与酒精相关的行为。总而言之，这项工作将提供对功能电路的见解 导致酒精成瘾，为未来的脑成像研究揭示新的靶点和可测试的假说 并促进开发AUD的新治疗方法，包括非侵入性脑损伤的靶点 刺激。