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，美国12岁以上人口中有一半以上是目前的EtOH饮酒者。如此高水平消耗的主要驱动因素是EtOH本质上是一种积极强化刺激，这是由于其药理作用强烈激活腹侧被盖区（VTA）内的中边缘多巴胺（DA）神经元，导致伏隔核（NAc）的DA短暂爆发。虽然EtOH的强化作用本身并不有害，但EtOH的自我强化性质可能导致慢性滥用，从而深刻改变神经回路并产生与酒精使用障碍相关的精神病理。目前尚不清楚EtOH是如何从积极的强化因素转变为有害地塑造行为的刺激因素的。NAc主要由gaba能投射介质棘神经元组成，表达DA D1Rs （D1R MSNs）或DA D2Rs （D2R MSNs）。NAc内的D1R激活是酒精相关行为发展的关键中介，我最近发现，小鼠对EtOH的单一挑战持续增强NAc D1R msn上的突触选择性传递。本提案的研究目标是表征和确定这种新型etoh诱导可塑性的分子机制。Ron实验室之前的工作已经证实，EtOH激活了哺乳动物雷帕霉素靶蛋白1 (mTORC1)，这是一种调节与可塑性有关的突触蛋白的局部树突翻译的激酶。此外，NAc内mTORC1的激活介导了酒精相关行为的发展。初步结果表明，NAc中D1R的激活增加了由mTORC1调节翻译的蛋白（GluA1， PSD95和HOMER）的水平。因此，我假设，ettoh诱导的NAc内的DA爆发和伴随的D1R/mTORC1通路的激活驱动了这种形式的持久突触可塑性，最终成为持久的神经奖励痕迹的基础。目的1将验证etoh诱导的D1R激活触发D1R msn内产生突触可塑性的突触后改变的假设。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

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.