Understanding the Neurobiological Correlates of Ethanol's Aversive Actions

描述(由申请人提供)：饮酒倾向可以被认为是乙醇的有益(促进使用)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酗酒并患上酒精使用障碍。此外，酒精依赖与对酒精令人厌恶的特性的耐受性增加有关，这可能会促进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促使用特性及其与成瘾的关系上，但很少有人研究酒精的使用限制特性及其在成瘾过程中的作用的神经生物学相关性。然而，最近发现了中脑的一个区域，即被盖旋转内侧核(RMTg)，它通过对多巴胺神经元的显著抑制控制，参与了负奖赏预测错误和对厌恶刺激的行为反应。有趣的是，参与发出环境刺激显著信号的PRL皮质向RMTG发送了一个非常密集的投射。目前的提议将检验一个新的假设，即PRL皮质通过其向RMTG的投射传递关于条件性环境刺激的厌恶特性的信息-包括与酒精的厌恶行为有关的信息-。进一步假设，RMTG对厌恶信号的调制在调节饮酒过程中发挥着重要作用，RMTG对酒精厌恶特性的正常加工会因长期酒精暴露而改变。一组创新性的研究被提出，以检验RMTG在调节酒精厌恶特性中的作用。目的1用逆行追踪结合免疫组织化学方法检测乙醇诱导的条件性味觉厌恶(CTA)后Fos的诱导，以确定PRL-RMTg通路是否参与了酒精厌恶行为的信号传递。这些研究还将利用体内光遗传学来抑制RMTg投射的PRL神经元，以检验抑制这一途径在乙醇诱导的CTA发展中的作用。目的2利用体内光遗传学方法结合操作者行为研究抑制PRL-RMTg通路对寻求酒精和饮酒行为的影响。目的3确定酒精依赖对RMTG神经元对PRL皮质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促成成瘾过程的神经生物学机制的理解差距。

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.