Alcohol and D1R- and mTORC1-dependent plasticity

描述（由申请人提供）：酒精（EtOH）消费是全球普遍存在的社会和文化规范，根据最近的SAMSHA全国药物使用和健康调查，超过一半的12岁以上的美国人口目前是EtOH饮用者。如此高水平的消耗的主要驱动力是EtOH本质上是一种积极的强化刺激，这是由于其药理作用，强烈激活腹侧被盖区（VTA）内的中脑边缘多巴胺（DA）神经元，导致多巴胺在丘脑核（NAc）中的短暂爆发。虽然EtOH的强化作用本身不是有害的，但EtOH的自我强化性质可导致慢性滥用，这深刻地改变了神经回路并产生与酒精使用障碍相关的精神病理学。乙醇是如何从一个积极的刺激物转变为一个有害的行为刺激物的，这是未知的。NAc主要由表达DA D1 R（D1 R MSNs）或DA D2 R（D2 R MSNs）的GABA能投射中型多刺神经元组成。NAc内的D1 R激活是酒精相关行为发展的关键介质，我最近发现，小鼠对乙醇的单一挑战持续增强NAc D1 R MSNs上的选择性突触传递。本提案中研究的目标是表征和确定这种新型EtOH诱导可塑性的分子机制。罗恩实验室以前的工作已经确定，乙醇激活哺乳动物雷帕霉素复合物1（mTORC 1），一种激酶，调节局部树突翻译的选择突触蛋白参与可塑性。此外，NAc内的mTORC 1激活介导了酒精相关行为的发展。初步结果表明，NAc中D1 R的激活增加了蛋白质（GluA 1，PSD 95和HOMER）的水平，这些蛋白质的翻译受mTORC 1的调节。因此，我假设EtOH诱导的DA在NAc内的爆发和伴随的D1 R/mTORC 1通路的激活驱动了这种形式的持久的突触可塑性，最终成为持久的神经奖赏痕迹的基础。目的1将测试EtOH诱导的D1 R激活触发突触后改变，在D1 R MSNs内产生突触可塑性的假设。我还将确定这些EtOH诱导的适应的持续时间和纹状体亚区特异性。目标2将调查：1）如果 mTORC 1在NAc D1 R MSN中被EtOH特异性激活，2）EtOH是否诱导GluA 1、PSD 95和HOMER的翻译，以及3）mTORC 1激活是否是EtOH诱导的兴奋性突触强度增强所必需的。总的来说，我的研究将揭示一种新的突触可塑性形式，这种形式可能是乙醇奖励效应的持久神经痕迹的基础。

DESCRIPTION (provided by applicant): Alcohol (EtOH) consumption is a ubiquitous societal and cultural norm globally, and according to the most recent SAMSHA National Survey on Drug Use and Health, just over half of the United States population over 12 years old are current EtOH drinkers. The primary driver for such high levels of consumption is that EtOH is intrinsically a positively reinforcing stimulus, which is due to its pharmacological action that strongly activates mesolimbic dopamine (DA) neurons within the ventral tegmental area (VTA) leading to a transient burst of DA in the nucleus accumbens (NAc). While the reinforcing effects of EtOH are not detrimental per se, the self- reinforcing nature of EtOH can lead to chronic abuse, which profoundly alters neural circuits and produces psychopathology associated with alcohol-use disorders. It is unknown as to how EtOH transitions from a positive reinforcer to a stimulus that deleteriously shapes behavior. The NAc is primarily composed of GABAergic projection medium spiny neurons that express either DA D1Rs (D1R MSNs) or DA D2Rs (D2R MSNs). D1R activation within the NAc is a critical mediator of the development of alcohol-related behavior, and I recently found that a single challenge of mice to EtOH persistently enhances synaptic transmission selectively on NAc D1R MSNs. The goal of the research in this proposal is to characterize and determine the molecular mechanism underlying this novel form of EtOH-induced plasticity. Previous work from the Ron Lab has established that EtOH activates mammalian target of rapamycin complex 1 (mTORC1), a kinase that regulates local dendritic translation of select synaptic proteins involved in plasticity. Moreover, mTORC1 activation within the NAc mediates the development of alcohol-related behaviors. Preliminary results suggest that activation of D1R in the NAc increases the levels of proteins (GluA1, PSD95 and HOMER) whose translation is regulated by mTORC1. I therefore hypothesize that the EtOH-induced DA burst within the NAc and the concomitant activation of the D1R/mTORC1 pathway drives this form of long-lasting synaptic plasticity that ultimately underlies the enduring neural trace of reward. Aim 1 will test the hypothesis that EtOH-induced D1R activation triggers postsynaptic alterations that generate synaptic plasticity within D1R MSNs. I will also determine the duration and striatal subregion specificity of these EtOH-induced adaptations. Aim 2 will investigate: 1) if mTORC1 is activated by EtOH specifically in NAc D1R MSNs, 2) if EtOH induces the translation of GluA1, PSD95 and HOMER, and 3) whether mTORC1 activation is necessary for the EtOH-induced enhancement of excitatory synaptic strength. Collectively, my studies will shed light on a novel form of synaptic plasticity that may underlie the enduring neural trace for the rewarding effects of EtOH.