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乙醇暴露对负责控制目标导向行为和习惯形成的神经系统的影响。乙醇成瘾与广泛的行为和认知缺陷有关。虽然在介导乙醇对大脑作用的药理学靶点方面取得了很大进展，但在神经系统水平上对乙醇成瘾导致的适应知之甚少。迄今为止，大多数关于酒精对目标导向行为影响的研究都集中在酒精自我管理范式上。而被忽视的问题是，乙醇是如何影响神经系统的，这是正常的奖励引导行为的基础。为了理解乙醇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，很少有研究对乙醇对纹状体的影响进行研究，纹状体是控制自愿行为的关键结构，最近的研究结果表明，纹状体与习惯形成和成瘾有关。因此，对于乙醇如何改变依赖纹状体的学习和行为，我们所知不多。在这个提议中，假设暴露于乙醇（使用乙醇蒸气室程序）可以篡占正常的学习过程在纹状体参与技能和习惯形成的自动化，对随后的控制奖励引导行为有重大影响。因此，我们提出了三个具体目标：1)确定先前乙醇暴露对纹状体依赖性学习和行为的影响。2)确定事先乙醇暴露对工具学习过程中清醒行为小鼠纹状体神经活动的影响。3)采用全细胞膜片钳记录法测定乙醇暴露对纹状体突触传递的影响。本研究采用了一种创新和综合的方法来研究乙醇对大脑的作用，将体内和离体电生理方法与来自器乐学习研究的强大分析相结合。实验结果将有助于我们理解皮层纹状体回路中的神经适应机制，这些神经适应机制介导目标导向行为的获取和控制以及习惯的形成。这种机制可以为治疗酒精成瘾提供新的靶点。

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.