Dysregulation of thalamic hypocretin transmission following ethanol dependence

乙醇依赖后丘脑下丘脑分泌素传输失调

• 批准号: 9110011
• 负责人: Remi Martin-Fardon
• 金额: $ 22.86万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110011
• 关键词: Abstinence; Alcohol dependence; Animals; Arousal; Behavior; Brain; Chronic; Code; Communication; Corpus striatum structure; Data; Development; Dorsal; Dose; Down-Regulation; Drug Addiction; Energy Metabolism; Ethanol dependence; Etiology; Future; Gene Silencing; Goals; Hypothalamic structure; Laboratories; Lateral; Mediating; Messenger RNA; Molecular; Nature; Neurobiology; Neurons; Peptides; Pharmaceutical Preparations; Phenotype; Physiological Processes; Production; Property; RRM1 gene; Rattus; Recording of previous events; Regulation; Relapse; Rewards; Role; Signal Transduction; Stress; Structure; Structure of paraventricular nucleus of thalamus; System; Testing; Thalamic structure; Therapeutic; Up-Regulation; Work; alcohol seeking behavior; alcoholism prevention; base; design; disorder later incidence prevention; drug of abuse; feeding; hypocretin; improved; insight; knock-down; neurotransmission; novel; orexin A receptor; prevent; problem drinker; public health relevance; relating to nervous system; research study; response; small hairpin RNA; therapeutic target; transmission process; vector

 DESCRIPTION (provided by applicant): The hypocretin (Hcrt) system has long been known to regulate a wide range of physiological processes, including feeding, energy metabolism, and arousal. More recently, concordant observations have demonstrated an important role for Hcrt in the reinforcing properties of most drugs of abuse. Accordingly, Hcrt neurons, which predominantly arise from the lateral hypothalamus (LH), project to brain structures implicated in the regulation of arousal, stress, and reward. Although Hcrt neurons have been shown to massively project to the paraventricular nucleus of the thalamus (PVT), recent evidence suggests that the PVT may be a key relay of Hcrt-coded reward-related communication between the LH and both the ventral and dorsal striatum. While this thalamic region was not thought to be part of "drug addiction circuitry," an increasing amount of evidence indicates that the PVT-particularly Hcrt transmission in the PVT-is implicated in the modulation of reward function in general and several aspects of drug-directed behaviors in particular. Importantly, findings from our laboratory demonstrated selective activation of the PVT during ethanol seeking, and our preliminary data suggest that a history of ethanol dependence produces a downregulation of Hcrt in the LH and upregulation of Hcrtr1 (encoding Hcrt receptor 1) in the PVT. This proposal is designed to study the neurobiological basis of chronic vulnerability to relapse by focusing on Hcrt transmission in the PVT as a novel neural substrate that may be responsible for the compulsive nature of ethanol seeking. Specifically, this proposal will (i) establish the role of Hcrt transmission in the PVT in ethanol-seeking behavior and (ii) test the hypothesis that knocking down Hcrt using local gene silencing in the LH in nondependent rats will mimic the phenotype of postdependent rats. Overall, the planned experiments will provide novel insights into the specific involvement of LH→PVT Hcrt transmission in alcohol-seeking behavior and will likely highlight a previously unrecognized neurotransmission system in the etiology of compulsive alcohol seeking during abstinence and justify targeting the hyprocretin system for alcoholism and relapse prevention.

 描述（由申请人提供）：人们早就知道下丘脑分泌素（Hcrt）系统可以调节广泛的生理过程，包括进食、能量代谢和唤醒，最近的一致观察结果表明，Hcrt 在强化方面发挥着重要作用。因此，Hcrt 神经元主要产生于外侧下丘脑 (LH)，投射到与觉醒、压力和情绪调节有关的大脑结构。虽然 Hcrt 神经元已被证明大量投射到丘脑室旁核 (PVT)，但最近的证据表明，PVT 可能是 LH 与腹侧和背侧之间 Hcrt 编码的奖励相关通信的关键中继。虽然这个丘脑区域不被认为是“药物成瘾回路”的一部分，但越来越多的证据表明PVT，尤其是Hcrt在纹状体中的传播。 PVT 与一般奖励功能的调节有关，特别是药物导向行为的几个方面。重要的是，我们实验室的研究结果表明，PVT 在寻求乙醇过程中选择性激活，并且我们的初步数据表明，乙醇依赖的历史。导致 LH 中的 Hcrt 下调和 PVT 中的 Hcrtr1（编码 Hcrt 受体 1）上调。该提案旨在通过重点研究慢性易复发性的神经生物学基础。 PVT 中的 Hcrt 传输作为一种新的神经基质，可能导致乙醇寻求的强迫性质。具体来说，该提案将 (i) 确定 PVT 中 Hcrt 传输在乙醇寻求行为中的作用，并 (ii) 测试该行为。假设在非依赖大鼠的 LH 中使用局部基因沉默来敲除 Hcrt 将模仿依赖后大鼠的表型总体而言，计划的实验将为 LH→PVT Hcrt 传递的具体参与提供新的见解。寻求酒精的行为，并且可能会强调在禁酒期间强迫性寻求酒精的病因学中以前未被认识的神经传递系统，并证明针对酗酒和预防复发的下丘脑分泌素系统是合理的。