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: 10200612
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200612
• 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; 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复发的流行率甚至 强迫或自我强制禁欲的持久间隔。阐明了 介导渴望和寻求ETOH的神经记录，从而提供了对神经生物学基础的见解 复发。人类的功能性脑成像和使用C-FOS表达作为神经标记的研究 啮齿动物的激活暗示互连的皮质和边缘脑区域响应药物提示，药物 启动和应力诱导的恢复。该电路的主要组成部分包括内侧前额叶 皮层（MPFC），基底外侧杏仁核（BLA），杏仁核的中央核（CEA），质质的床核 末端（BNST），腹侧对盖区（VTA），伏隔核（NAC），海马，丘脑（thal），（thal），（thal）， 和背纹状体。低载素（HCRT）系统调节了广泛的生理过程，包括 喂养，能量代谢和唤醒，并由包括ETOH在内的滥用药物招募。感兴趣的 本提案最近的研究表明，HCRT在调节压力和A中的关键作用 HCRT受体（HCRT-R）拮抗作用可能的抗焦虑作用。 HCRT神经元，仅位于下丘脑， 向介导ETOH寻求并密切支配的神经记录的主要组成部分的项目 丘脑（PVT）的旁脑核。最近的证据表明，PVT参与 尤其是对奖励功能的调节，尤其是指导行为。此外，已经 表明PVT是压力调节的重要因素，这是可能引起强烈的关键因素 避免个人的渴望和触发复发。较早的发现证明了选择性招募 LH/DMH/PFA-PVT在寻求ETOH期间，初步数据表明ETOH依赖的历史 失调HCRT/HCRT-R系统。丘脑损伤是ETOH相关脑功能障碍的关键特征 在酗酒者中，剩余的确定是EtOH依应史的史的程度 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） 由压力与正常（寻求食物）行为引起。该提议将检验以下假设 EtOH依应依赖性失调及其与PVT的相互作用，并且这种功能障碍将预测 强迫性EtoH寻求（复发）由压力沉淀。此外，使用局部基因沉默，这 提案将检验以下假设，即通过病毒载体的HCRT产生永久减少将阻止 依赖期间，PVT中的HCRT传播失调，因此阻止了对 EtoH戒酒期间的压力。该项目可能会突出以前未认识到的机制 在禁欲期间寻求强迫性ETOH的病因；最终导致了新颖的识别 预防ETOH复发的治疗靶标。