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。 aud是一个 慢性复发障碍与失去控制和强迫性饮酒有关。出现 急性戒断期间的负面情绪状态及其在旷日持久期间的维护是 导致过量和强迫性饮酒的关键驱动力。识别神经记录 这涉及负面情绪状态和过度饮酒是理解的关键步骤 强迫饮酒的神经元原因。我们已经确定了几个关键的大脑区域 在急性饮酒期间招募，但尚不清楚这些电路在 节制的节制。此外，以前的研究经常因区域的预选而偏见 兴趣;因此，公正的全脑功能电路成像是检查整个的关键步骤 大脑并确定戒酒涉及的整个网络。 我将利用直接早期基因的全脑成像来识别被招募的大脑区域 在急性戒酒和持久的禁欲期间。一旦确定了这些大脑区域，它们就会 关于使用相关分析和图理论的功能关系相比。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） 和节制。这些关键组件或集线器一旦确定，将是针对的，有选择的 使用DAUN02/LACZ方法灭活，测试这些枢纽与负面的因果关系 依赖小鼠的情绪状态和强迫性饮酒。 这些研究将在我的K99阶段开始在Scripps研究所开始，并在 我在独立R00阶段的未来机构。在我的K99阶段，我将获得图表的培训 理论分析和DAUN02失活，以识别和破坏在功能网络中的关键节点 戒酒。在R00阶段，我将使用DAUN02灭活来继续这些项目，并进一步 探索功能性戒酒网络中关键节点破坏关键节点的方式 改变与酒精有关的行为。总的来说，这项工作将提供有关功能电路的见解 有助于酗酒，揭示新的目标和可检验的假设，用于未来的大脑成像研究 在人类中，并促进了AUD的新型治疗方法的发展，包括无创大脑的靶标 刺激。