Dysregulation of thalamic hypocretin transmission following ethanol dependence

 描述（由申请人提供）：下丘脑泌素（Hcrt）系统长期以来被认为调节广泛的生理过程，包括进食、能量代谢和唤醒。最近，一致的观察表明，Hcrt在大多数滥用药物的强化特性中发挥重要作用。因此，Hcrt神经元主要来自外侧下丘脑（LH），投射到涉及唤醒，压力和奖励调节的大脑结构。虽然Hcrt神经元已被证明大量项目的丘脑室旁核（PVT），最近的证据表明，PVT可能是一个关键的中继Hcrt编码的奖励相关的LH和腹侧和背侧纹状体之间的通信。虽然这个丘脑区域不被认为是“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中的Hcrt传输-涉及一般的奖励功能的调节，特别是药物导向行为的几个方面。重要的是，我们实验室的研究结果表明，在乙醇寻求过程中，PVT会选择性激活，我们的初步数据表明，酒精依赖史导致LH中Hcrt下调，Hcrtr 1上调，（编码Hcrt受体1）这项建议旨在研究慢性脆弱性复发的神经生物学基础，通过关注PVT中的Hcrt传递作为一种新的神经传导机制，这可能是导致乙醇寻求的强迫性的原因。具体而言，该提议将（i）确定Hcrt传递在乙醇寻求行为中PVT中的作用，以及（ii）测试以下假设：在非依赖大鼠中使用LH中的局部基因沉默敲低Hcrt将模拟后依赖大鼠的表型。总的来说，计划的实验将提供新的见解，具体参与LH→PVT Hcrt传输酒精寻求行为，并可能会突出一个以前未被认识到的神经传递系统在戒酒期间强迫性酒精寻求的病因，并证明靶向hyprocretin系统酒精中毒和复发预防。

 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.