Understanding the Neurobiological Correlates of Ethanol's Aversive Actions

描述（由申请人提供）：饮酒的倾向可以被认为是乙醇的奖励（使用促进）和厌恶（使用限制）属性之间的平衡。因此，经历酒精负面影响较少的人更有可能大量饮酒并发展酒精使用障碍。此外，酒精依赖与对酒精的厌恶特性的耐受性增加有关，这可能有助于成瘾者继续饮酒，并在戒酒期间复发。虽然大量的研究集中在酒精的使用促进特性及其在成瘾中的作用，但很少有人研究酒精的使用限制特性的神经生物学相关性及其在依赖性发展中的作用。然而，最近，中脑区域被称为吻内侧被盖核（RMTg）被确定和其特点是参与负性奖励预测错误和行为反应厌恶刺激通过其突出的抑制控制多巴胺神经元。有趣的是，参与环境刺激显著性信号传递的前边缘皮层（PrL）向RMTg发送非常密集的投射。本提案将测试一个新的假设，即PrL皮层中继信息的厌恶属性的条件环境刺激-包括相关的信息厌恶行动的酒精-通过其投影到RMTg。进一步假设，由RMTg的厌恶信号的调制在调制饮酒中起着重要作用，并且由RMTg的酒精的厌恶特性的正常处理被慢性酒精暴露改变。一组创新的研究，提出了审查的作用，RMTg在调解酒精的厌恶属性的作用。目的1将检查酒精诱导的条件性味觉厌恶（CTA）后，使用逆行追踪结合免疫组织化学Fos诱导，以确认参与的PrL-RMTg信号通路酒精的厌恶行动。这些研究还将使用体内光遗传学检查抑制该途径对乙醇诱导的CTA的发展的影响，以抑制RMTg投射PrL神经元。目的2将使用体内光遗传学方法结合操作行为来研究抑制PrL-RMTg通路对乙醇寻求和饮酒行为的影响。目的3研究酒精依赖对RMTg神经元对来自PrL皮质的输入的突触反应的影响。这些研究的结果将为RMTg在饮酒和依赖中的作用提供新的见解，并将有助于解决我们对成瘾过程神经生物学机制的理解中的差距。

DESCRIPTION (provided by applicant): The propensity to drink alcohol can be thought of as a balance between ethanol's rewarding (use-promoting) and aversive (use-limiting) properties. Accordingly, individuals who experience fewer negative effects of alcohol are more likely to drink heavily and develop alcohol use disorders. In addition, alcohol dependence is associated with increased tolerance to the aversive properties of alcohol, which is likely to facilitate continued drinking in addicts and relapse during abstinence. While a significant body of research has focused on the use- promoting properties of alcohol and their involvement in addiction, much less has been done to investigate the neurobiological correlates of alcohol's use-limiting properties and their role in the progression to dependence. Recently, however, a midbrain region known as the rostromedial tegmental nucleus (RMTg) was identified and characterized for its involvement in negative reward prediction error and the behavioral response to aversive stimuli through its prominent inhibitory control over dopamine neurons. Interestingly, the prelimbic (PrL) cortex, which is involved in signaling the salience of environmental stimuli, sends a very dense projection to the RMTg. The present proposal will test a novel hypothesis that the PrL cortex relays information about the aversive properties of conditioned environmental stimuli --- including information related to the aversive actions of alcohol --- via its projection to the RMTg. It is further hypothesized that modulation of aversive signals by the RMTg plays an important role in modulating alcohol drinking, and that the normal processing of aversive properties of alcohol by the RMTg is altered by chronic alcohol exposure. An innovative set of studies is proposed to examine the role of the role of the RMTg in mediating the aversive properties of alcohol. Aim 1 will examine Fos induction following ethanol-induced conditioned taste aversion (CTA) using retrograde tract tracing in combination with immunohistochemistry to confirm the involvement of the PrL-RMTg pathway in signaling alcohol's aversive actions. These studies will also examine the effect of inhibition of this pathway on the development of ethanol-induced CTA using in vivo optogenetics to inhibit RMTg-projecting PrL neurons. Aim 2 will investigate the effect of inhibition of the PrL-RMTg pathway on ethanol-seeking and drinking behavior using in vivo optogenetics procedures in combination with operant behavior. Aim 3 will determine the effect of alcohol dependence on the synaptic response of RMTg neurons to input from PrL cortex. The results of these studies will provide new insights into the role of the RMTg in alcohol drinking and dependence and will help to address the gap in our understanding of the neurobiological mechanisms that contribute to the addictive process.