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

描述（由申请人提供）：酒精中毒，也被称为酒精使用障碍，是一种慢性衰弱障碍，其特征是过量摄入酒精和社会和职业功能受损。虽然大多数关于调节这种疾病的脑机制的研究都研究了下丘脑或中边缘区域，但最近的证据将注意力集中在一个相对未被研究的区域，即丘脑室旁核（PVT），它在调节体内平衡的下丘脑和调节情绪的边缘核之间提供了重要的中继点。利用间歇性进入模型，导致在药理学相关水平上自愿消耗乙醇，我计划测试总体假设，即乙醇饮酒刺激下丘脑神经肽食欲素（OX）在PVT中起作用，主要是在食欲素2而不是食欲素1受体（而不是在其受体上的黑色素集中激素），特别是在前亚区而不是后亚区，并且这种作用，反过来，增加局部阿片类脑啡肽（ENK）水平，以促进进一步的乙醇摄入。由于这一系列事件可能对促进酒精使用紊乱至关重要，我建议，在第1章中，研究酒精饮用后发生的神经化学事件，从下丘脑的OX转录到前pvt的ENK释放。在第2章中，我将研究这些神经化学变化的行为结果。测试在PVT内注射OX和ENK对乙醇饮酒和情绪行为的影响，以及这些行为因内源性肽水平升高而自然增加的可能性。在目标3中，我将研究这种ox - enk连接的分子机制，并研究这种连接对于促进乙醇饮用是必要的可能性。总的来说，通过使用不同的技术，如原代神经元培养、原位杂交和行为评估测试，这些研究应该为相对未被充分研究的细胞核PVT及其在乙醇摄入中的潜在主要作用提供重要的新信息。除了这项工作应该出版的出版物，这将使我能够整合分子，细胞和行为的发现，这项拨款提案的资金将使我在研究和职业发展方面获得必要的培训，以获得作为科学家的独立性。我还会把

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.