Pivotal role of thalamic hypocretin transmission during EtOH seeking and relapse

丘脑下丘脑分泌素传输在乙醇寻找和复发过程中的关键作用

• 批准号: 10436851
• 负责人: Remi Martin-Fardon
• 金额: $ 43.54万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436851
• 关键词: Abstinence; Acute; Affect; Alcohol consumption; Amygdaloid structure; Animals; Anti-Anxiety Agents; Area; Arousal; Behavior; Brain imaging; Brain region; Cell Nucleus; Chronic; Corpus striatum structure; Cues; Data; Dependence; Development; Dorsal; Energy Metabolism; Ethanol; Ethanol dependence; Etiology; FOS gene; Food; Functional disorder; Gene Expression; Gene Silencing; Goals; Hippocampus (Brain); Human; Hypothalamic structure; Impairment; Individual; Laboratory Finding; Lateral; Measures; Medial; Mediating; Messenger RNA; Milk; Molecular; Nature; Neurobiology; Neurons; Nucleus Accumbens; Palate; Peptides; Pharmaceutical Preparations; Physiological Processes; Prefrontal Cortex; Prevalence; Prevention; Production; RRM1 gene; Rattus; Recording of previous events; Regulation; Relapse; Research; Rewards; Rodent; Role; Signal Transduction; Source; Specific qualifier value; Stress; Structure; Structure of paraventricular nucleus of thalamus; Structure of terminal stria nuclei of preoptic region; System; Testing; Thalamic structure; Therapeutic; Time; Ventral Tegmental Area; Viral Vector; alcohol abstinence; alcohol relapse; alcohol seeking behavior; alcoholism prevention; antagonist; behavior test; biological adaptation to stress; brain dysfunction; craving; disorder later incidence prevention; drug of abuse; experimental study; feeding; hypocretin; improved; insight; interest; knock-down; neural circuit; neurotransmission; new therapeutic target; novel; prepro-orexin; prevent; problem drinker; receptor; recruit; reinforcer; relating to nervous system; response; small hairpin RNA; therapeutic target; transmission process; vector

A central problem in the treatment of ethanol (EtOH) addiction is the prevalence of relapse to EtOH use even after protracted intervals of forced or self-imposed abstinence. Advances have been made in elucidating the neurocircuitry that mediates craving and EtOH seeking, which provides insights into the neurobiological basis of relapse. Functional brain imaging in humans and studies that use c-fos expression as a marker of neural activation in rodents implicate interconnected cortical and limbic brain regions in response to drug cue-, drug priming-, and stress-induced reinstatement. Major components of this circuitry include the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (BNST), ventral tegmental area (VTA), nucleus accumbens (NAC), hippocampus, thalamus (THAL), and dorsal striatum. The hypocretin (Hcrt) system regulates a wide range of physiological processes, including feeding, energy metabolism, and arousal, and is recruited by drugs of abuse, including EtOH. Of interest for the present proposal, recent studies have demonstrated a critical role of Hcrt in the modulation of stress and a possible anxiolytic effect of Hcrt receptor (Hcrt-r) antagonism. Hcrt neurons, located only in the hypothalamus, project to the major components of the neurocircuitry that mediates EtOH seeking and innervates densely the paraventricular nucleus of the thalamus (PVT). Recent evidence suggests that the PVT participates in the modulation of reward function in general and drug-directed behavior in particular. Furthermore, it has been shown that PVT is an important contributor in the regulation of stress, a critical factor that can induce intense craving and trigger relapse in abstinent individuals. Earlier findings demonstrated selective recruitment of the LH/DMH/PFA-PVT during EtOH seeking, and preliminary data suggest that a history of EtOH dependence dysregulates the Hcrt/Hcrt-r system. Thalamic impairments are a key feature of EtOH-related brain dysfunction in alcoholics, remaining to be determined are the extent to which a history of EtOH dependence dysregulates Hcrt and whether this dysfunction will predict maladaptive compulsive EtOH-seeking (relapse) that is precipitated by stress vs. normal (food-seeking) behavior. This proposal will test the hypothesis that a history of EtOH dependence dysregulates Hcrt and its interaction with the PVT, and that this dysfunction will predict compulsive EtOH seeking (relapse) precipitated by stress. Furthermore, using local gene silencing, this proposal will test the hypothesis that the permanent decrease in Hcrt production via a viral vector will prevent Hcrt transmission dysregulation in the PVT during dependence and therefore prevent exacerbated response to stress during EtOH abstinence. This project is likely to highlight a previously unrecognized mechanism in the etiology of compulsive EtOH seeking during abstinence; ultimately leading to the identification of novel therapeutic targets for the prevention of EtOH relapse.

治疗乙醇 (EtOH) 成瘾的一个核心问题是，即使使用乙醇，乙醇成瘾的复发率仍然很高。 经过长时间的强迫或自我禁欲之后。在阐明问题方面已取得进展 介导渴望和乙醇寻求的神经回路，提供了对神经生物学基础的见解 的复发。人类功能性脑成像以及使用 c-fos 表达作为神经标志物的研究 啮齿类动物的激活涉及相互关联的皮质和边缘脑区域对药物提示的反应 启动和压力诱导的恢复。该电路的主要组成部分包括内侧前额叶 皮质 (mPFC)、基底外侧杏仁核 (BLA)、杏仁核中央核 (CeA)、纹状体床核 终末肌 (BNST)、腹侧被盖区 (VTA)、伏隔核 (NAC)、海马、丘脑 (THAL)、 和背侧纹状体。下丘脑分泌素 (Hcrt) 系统调节多种生理过程，包括 喂养、能量代谢和唤醒，并且是由滥用药物（包括乙醇）招募的。感兴趣的是 根据目前的建议，最近的研究表明 Hcrt 在调节压力和 抗焦虑作用可能与Hcrt受体（Hcrt-r）拮抗作用。 Hcrt 神经元仅位于下丘脑， 投射到神经回路的主要组成部分，介导乙醇寻找并密集地神经支配 丘脑室旁核（PVT）。最近的证据表明，PVT 参与了 一般奖励功能的调节，特别是药物导向行为的调节。此外，已经 研究表明，PVT 是压力调节的重要贡献者，压力调节是导致强烈压力的关键因素。 渴望并引发禁欲者的复发。早期的研究结果表明，选择性招募 寻找 EtOH 期间的 LH/DMH/PFA-PVT，初步数据表明有 EtOH 依赖史 Hcrt/Hcrt-r 系统失调。丘脑损伤是乙醇相关脑功能障碍的一个关键特征 在酗酒者中，仍有待确定的是乙醇依赖史在多大程度上失调 Hcrt 以及这种功能障碍是否会预测适应不良的强迫性 EtOH 寻求（复发），即 由压力与正常（寻求食物）行为引发。该提案将检验以下假设：历史 EtOH 依赖性会导致 Hcrt 及其与 PVT 的相互作用失调，并且这种功能障碍将预示 压力引发的强迫性乙醇寻找（复发）。此外，利用局部基因沉默，这 该提案将检验以下假设：通过病毒载体永久减少 Hcrt 产量将阻止 依赖期间 PVT 中的 Hcrt 传输失调，从而防止对药物的反应加剧 乙醇戒断期间的压力。该项目可能会凸显一个以前未被认识到的机制 禁欲期间强迫性寻求乙醇的病因；最终导致小说的识别 预防乙醇复发的治疗目标。