Dysregulation of thalamic hypocretin transmission following ethanol dependence

 描述(由申请人提供)：长期以来，下丘脑肌素(Hcrt)系统一直被认为可以调节广泛的生理过程，包括摄食、能量代谢和唤醒。最近，一致的观察结果表明，Hcrt在增强大多数滥用药物的特性方面发挥了重要作用。因此，主要来自下丘脑外侧核的Hcrt神经元投射到与觉醒、应激和奖赏调节有关的脑结构。虽然Hcrt神经元被大量投射到丘脑室旁核(PVT)，但最近的证据表明，PVT可能是LHCRT编码的奖赏相关信息在LH与腹侧和背侧纹状体之间的关键传递。虽然这一丘脑区域被认为不是“药物成瘾回路”的一部分，但越来越多的证据表明，PVT--特别是PVT中Hcrt的传递--与奖赏功能的调节有关，特别是药物引导行为的几个方面。重要的是，我们实验室的研究结果表明，在寻找乙醇的过程中，PVT被选择性地激活，我们的初步数据表明，酒精依赖的历史导致LH中Hcrt的下调和PVT中Hcrtr1(编码Hcrt受体1)的上调。这项建议旨在通过重点研究PVT中Hcrt的传递来研究慢性复发易感性的神经生物学基础，作为一种新的神经底物，可能与寻求酒精的强迫性质有关。具体地说，这一建议将(I)确定Hcrt在PVT中的传递在酒精寻求行为中的作用，以及(Ii)检验假设，即在非依赖大鼠的黄体生成素(Lh)中通过局部基因沉默来敲除Hcrt将模仿后依赖大鼠的表型。总体而言，计划中的实验将提供新的见解，以了解促黄体生成素-下丘脑室旁核转录因子-hcrt传递在酒精寻求行为中的具体参与，并可能突出之前未知的神经传递系统在戒酒期间强迫性酒精寻求的病因中的作用，并证明针对下丘脑泌素系统来预防酒精中毒和复发是合理的。

 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.