Physiological Effects of Ethanol on Neural Circuits Mediating Habit Formation

描述(由申请人提供)：拟议研究的目标是了解酒精暴露对负责控制目标导向行为和习惯养成的神经系统的影响。酒精成瘾与广泛的行为和认知缺陷有关。虽然在调节酒精对大脑作用的药理靶点方面已经取得了很大进展，但对于酒精成瘾在神经系统水平上导致的适应还知之甚少。到目前为止，关于酒精对目标定向行为的影响的研究大多集中在酒精自我给药范式上。更被忽视的问题是，酒精如何影响作为正常奖励引导行为基础的神经系统。为了理解导致酒精成瘾的神经适应机制，我们必须首先了解它是如何影响奖励引导行为的正常机制的。更具体地说，关于酒精对纹状体的影响的研究很少，纹状体是控制自愿行为的关键结构，最近的研究表明，纹状体与习惯养成和成瘾有关。因此，人们对乙醇如何改变纹状体依赖的学习和行为知之甚少。在这项建议中，假设暴露在乙醇中(使用乙醇蒸汽室程序)可以篡改纹状体内的正常学习过程，这些过程参与了技能和习惯形成的自动化，从而对随后的奖励引导行为的控制产生重大影响。因此，我们提出了三个具体目标：1)确定先前酒精暴露对纹状体依赖学习和行为的影响。2)研究预先酒精暴露对清醒行为小鼠工具性学习过程中纹状体神经活动的影响。3)采用全细胞膜片钳技术研究乙醇暴露对纹状体突触传递的影响。这项建议采用了一种创新的综合方法来研究酒精对大脑的作用，将体内和体外的电生理方法与仪器学习研究中的强大分析相结合。所提出的实验结果将帮助我们理解皮质纹状体回路中的神经适应机制，该机制调节目标定向动作和习惯形成的获得和控制。这种机制可以为酒精成瘾的治疗提供新的靶点。 公共卫生相关性：最近的研究表明，背侧纹状体在习惯养成中起着关键作用。因此，不同纹状体区域参与成瘾现在正成为研究的焦点。然而，目前还不清楚酒精如何影响潜在的习惯形成的神经回路。拟议中的研究结果将极大地促进我们对酒精暴露如何篡夺通常参与习惯形成的可塑性机制的理解，以促进改变对自愿行为的控制。这些知识可能会带来更好的治疗选择，专门针对导致习惯性和强迫性饮酒行为发展的生理过程。

DESCRIPTION (provided by applicant): The goal of the proposed research is to understand the effects of ethanol exposure on neural systems responsible for the control of goal-directed actions and habit formation. Ethanol addiction is associated with a wide range of behavioral and cognitive deficits. While much progress has been made on the pharmacological targets mediating ethanol action on the brain, little is known about the adaptations resulting from ethanol addiction at the level of neural systems. So far, the majority of research on the effects of ethanol on goal-directed behavior has focused on alcohol self-administration paradigms. Rather neglected is the question of how ethanol affects the neural systems underlying normal reward-guided behavior. To understand the neuroadapative mechanisms responsible for the addictive properties of ethanol, we must first understand how it affects the normal mechanisms underlying reward-guided behavior in general. More specifically, little research has been conducted on the effects of ethanol on the striatum, a key structure in the control of voluntary behavior that has been implicated in habit formation and addiction as a result of recent research. Consequently, not much is known about how ethanol can change striatum-dependent learning and behavior. In this proposal it is hypothesized that exposure to ethanol (using the ethanol vapor chamber procedure) can usurp normal learning processes in the striatum that are engaged in automatization of skills and habit formation to have significant impact on the subsequent control of reward- guided behavior. Accordingly, three specific aims are proposed: 1) To determine the effects of prior ethanol exposure on striatum-dependent learning and behavior. 2) To determine the effects of prior ethanol exposure on striatal neural activity in awake behaving mice during instrumental learning. 3) To determine the effects of prior ethanol exposure on striatal synaptic transmission ex vivo using whole-cell patch clamp recording. This proposal employs an innovative and integrative approach in studying ethanol actions on the brain, by combining in vivo and ex vivo electrophysiological methods with powerful assays from the study of instrumental learning. Results from the proposed experiments will help us understand the neuroadaptive mechanisms in the cortico-striatal circuits that mediate the acquisition and control of goal-directed actions and habit formation. Such mechanisms can provide novel targets for the treatment of alcohol addiction. PUBLIC HEALTH RELEVANCE: Recent work has suggested a critical role for the dorsal striatum in habit formation. As a consequence, the involvement of different striatal regions in addiction is now becoming a focus of research. However, it is not clear how alcohol affects the neural circuits underlying habit formation. Results from the proposed studies will significantly advance our understanding of how exposure to alcohol can usurp plasticity mechanisms normally engaged in habit formation to promote to alter the control of voluntary behavior. Such knowledge can potentially lead to better treatment options that are specifically targeted at the physiological processes responsible for the development of habitual and compulsive alcohol seeking behavior.