Paraventricular thalamic nucleus: Role of orexin and opioids in ethanol intake

描述(申请人提供)：酒精中毒，也被称为酒精使用障碍，是一种慢性衰弱障碍，特征是过量摄入酒精并损害社会和职业功能。虽然大多数关于调节这种疾病的脑机制的研究都集中在下丘脑或中脑边缘区域，但最近的证据集中在一个相对研究较少的区域-丘脑室旁核(PVT)，它在调节内分泌平衡的下丘脑和调节情绪的边缘核之间提供了一个重要的中继点。利用间歇性获取模型导致在与药物相关的水平上自愿消耗乙醇，我计划检验这一总体假设，即饮酒可刺激下丘脑神经肽增食欲素(OX)作用于PVT，主要作用于增食欲素2而不是增食素1受体(而不是其受体上的黑色素浓缩激素)，并且特定地在前而不是后亚区发挥作用，并且这一作用反过来会增加局部阿片脑啡肽(ENK)的水平，从而促进进一步的酒精摄入。鉴于这一系列事件可能对促进无序的酒精使用至关重要，我建议在目标1中，研究饮酒后发生的神经化学事件，从下丘脑的ox转录到PVT前部的ENK释放。在目标2中，我将检查这些神经化学变化的行为结果，测试在PVT内注射OX和ENK对饮酒和情绪行为的影响，以及这些行为是否可能因内源性多肽水平的升高而自然增加。在目标3中，我将研究这种OX到ENK连接的分子机制，并研究这对于促进酒精饮酒是必要的可能性。总而言之，通过使用各种技术，如原代神经元培养、原位杂交和行为评估测试，这些研究应该会提供关于相对研究较少的核团PVT及其可能参与酒精摄入的重要新信息。除了这项工作应该发表的出版物外，这项工作将使我能够整合分子、细胞和行为发现，这项拨款计划的资金将给我在研究和职业发展方面的必要培训，以获得作为一名科学家的独立性。我要再加一份 参加高级课程，参加洛克菲勒大学的研讨会和讲习班，并通过三机构合作网络，同时参加国家社会会议。我将得到我的赞助人莎拉博士的专家指导 莱博维茨和我的顾问委员会，再加上洛克菲勒大学的丰富资源，将使我能够学习新的实验方法，并在我的研究问题上获得新的视角。因此，在进行创新研究的过程中，我将获得成功过渡到独立研究科学家的职位所需的技能，并为酒精研究领域做出重大贡献。

DESCRIPTION (provided by applicant): Alcoholism, also known as alcohol use disorder, is a chronic debilitating disorder characterized by excessive ingestion of alcohol and impairment in social and occupational functioning. While most investigations of brain mechanisms mediating this disorder have studied the hypothalamus or mesolimbic regions, recent evidence focuses attention on a relatively understudied area, the paraventricular nucleus of the thalamus (PVT), which provides an important relay point between the homeostasis-regulating hypothalamus and emotion-regulating limbic nuclei. Utilizing the intermittent access model that leads to voluntary consumption of ethanol at pharmacologically-relevant levels, I plan to test th overall hypothesis that ethanol drinking stimulates the hypothalamic neuropeptide orexin (OX) to act in the PVT, primarily at the orexin 2 rather than orexin 1 receptor (and rather than melanin-concentrating hormone at its receptor) and specifically in the anterior rather than posterior subregion, and that this action, in turn, increases local levels of the opioid enkephali (ENK) to promote further ethanol intake. With this sequence of events possibly being critically important in promoting disordered alcohol use, I propose, in Aim 1, to investigate the neurochemical events that occur following ethanol drinking, from OX transcription in the hypothalamus to ENK release in the anterior PVT. In Aim 2, I will examine the behavioral results of these neurochemical changes, testing the effects of OX and ENK injection in the PVT on ethanol drinking and emotional behaviors and the possibility that these behaviors are naturally increased by elevated endogenous peptide levels. In Aim 3, I will then look at molecular mechanisms of this OX-to-ENK connection and examine the possibility that this is necessary for promoting ethanol drinking. Collectively, by using techniques as varied as primary neuronal culture, in situ hybridization, and behavioral assessment tests, these studies should provide significant new information on a relatively understudied nucleus, the PVT, and its potentially major involvement in ethanol intake. In addition to the publications that should come out of this work, which will allow me to integrate molecular, cellular, and behavioral findins, the funding of this grant proposal will give me the necessary training in both researh and career development to attain independence as a scientist. I will additionally take part in advanced coursework and attend seminars and workshops at The Rockefeller University and through the Tri-Institutional Collaboration Network, while participating in national society meetings. I will receive expert mentorship from my sponsor, Dr. Sarah Leibowitz, as well as my advisory committee which, together with the abundant resources at The Rockefeller University, will allow me to learn new experimental methods and gain new perspectives on my research questions. Thus, in the process of conducting innovative new research, I will gain the skills necessary to successfully transition into a position as an independent research scientist and to make a significant contribution to the field of alcohol research.