Analysis of Edinger Westphal Nucleus Activity Following Alcohol

酒精后 Edinger Westphal 核活动的分析

基本信息

批准号：
8883070
负责人：
Monique Leana George
金额：
$ 4.31万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8883070
关键词：
Acute Affect Affinity Alcohol consumption Alcoholism Alcohols Animal Model Area Attenuated Behavioral Model Binding Brain CRF receptor type 1 CRF receptor type 2 Cell Nucleus Cells Chronic Consumption Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Data Designer Drugs Development Disease Electrophysiology (science)Ethanol FOS gene Genetic Goals Heavy Drinking Hour Individual Injection of therapeutic agent Intake Knock-out Knockout Mice Laboratories Lead Lesion Ligands Light Literature Mus Neurons Neuropeptides Oral Outcome Pattern Peptides Pharmaceutical Preparations Process Regulation Relapse Research Rewards Rodent Role Self Administration Self-Administered Societies Source Stress System Techniques Technology Testing Work alcohol effect alcohol reward alcohol use disorder base biological adaptation to stress cost extracellular genetic approach in vivo neural circuit neuroadaptation preference public health relevance receptor relating to nervous system research study response

项目摘要

DESCRIPTION (provided by applicant): Alcoholism is a progressive disorder with detrimental consequences for both the affected individual and society as a whole. Transition into compulsive alcohol use is hypothesized to occur due to alcohol-induced adaptations with in several neural circuits, including the corticotropin-releasing factor (CRF) system, a network of neuropeptide ligands and receptors that orchestrate the stress response. Although previous literature has implicated the CRF system in excessive ethanol (EtOH) intake, the complexity of the CRF system and its multiple ligands and receptors has limite understanding of this process. One such ligand, Urocortin1 (Ucn-1), is known to bind to both CRF-1 and CRF-2 receptors with a higher affinity than CRF itself. In light of this, our lab has provided converging lines of evidence highlighting the contribution of Ucn-1 in excessiv ethanol (EtOH) consumption and sensitivity. In fact, it has been determined that the primary source for Ucn1, the "centrally projecting Edinger Westphal nucleus" (EWcp) is the only region that, across multiple strains and species of rodents, shows consistently enhanced c-Fos expression following oral self-administration of alcohol. In further support of this notion, electrolytic lesions of the EWcp and genetic deletion of Ucn1 attenuates EtOH consumption. Additionally, genetic deletion of CRF-2 receptors or Ucn-1 attenuates the conditioned rewarding effects of EtOH. These findings clearly indicate that EWcp-Ucn1 neurons contribute to alcohol consumption, however these strategies (lesion and global knockout) have caveats that can be avoided with more precise techniques. Thus, the goal of the current proposal is to utilize in vivo electrophysiology and pharmacosynthetic technology to characterize the role of EWcp-Ucn1 neurons in alcohol self-administration and reward. Based on previous data and my own preliminary research, I hypothesize that alcohol activates EWcp neurons, which in turn promotes alcohol consumption and conditioned reward.

描述（由申请人提供）：酒精中毒是一种进行性疾病，对受影响的个人和整个社会都有不利影响。假设由于酒精诱导的适应性在几个神经回路中的适应性，包括皮质激素释放因子（CRF）系统，这是一个神经肽配体和受体网络，这些神经蛋白释放因子（CRF）在几个神经回路中都会过渡到强迫性饮酒。尽管以前的文献已牵涉到过度乙醇（ETOH）摄入中的CRF系统，但CRF系统及其多个配体和受体的复杂性对这一过程有限制的理解。已知一种这样的配体Urocortin1（UCN-1）与CRF-1和CRF-2受体的结合，其亲和力高于CRF本身。鉴于此，我们的实验室提供了融合的证据线，强调了UCN-1在多余的乙醇（ETOH）消耗和敏感性中的贡献。实际上，已经确定，UCN1的主要来源是“中央投射的Edinger Westphal Nucleus”（EWCP）是唯一一个在多种菌株和啮齿动物物种中显示出在口腔自我导致酒精后持续增强的C-FOS表达的区域。为了进一步支持这一概念，EWCP的电解病变和UCN1的遗传缺失减弱了ETOH的消耗。另外，CRF-2受体或UCN-1的遗传缺失减弱了ETOH的条件奖励作用。这些发现清楚地表明，EWCP-UCN1神经元有助于饮酒，但是这些策略（病变和全球敲除）具有更精确的技术可以避免的警告。因此，当前建议的目的是利用体内电生理学和药物合成技术来表征EWCP-UCN1神经元在酒精自我给药和奖励中的作用。根据以前的数据和我自己的初步研究，我假设酒精激活了EWCP神经元，这反过来促进了酒精消耗和条件奖励。