Physiological Effects of Ethanol on Neural Circuits Mediating Habit Formation

乙醇对介导习惯形成的神经回路的生理影响

• 批准号: 7591506
• 负责人: Henry Yin
• 金额: $ 17.79万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591506
• 关键词: Acute; Affect; Alcohol consumption; Alcohol dependence; Alcohols; Animals; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain; Cells; Chronic; Cognitive deficits; Corpus striatum structure; Development; Dorsal; Electrodes; Electrophysiology (science); Ethanol; Ethanol dependence; Exposure to; Goals; Habits; Knowledge; Lead; Learning; Mediating; Methods; Mus; Operant Conditioning; Outcome; Physiological; Physiological Processes; Procedures; Process; Property; Public Health; Range; Research; Rewards; Role; Self Administration; Slice; Structure; Synaptic Transmission; System; Testing; Work; addiction; alcohol effect; alcohol exposure; alcohol seeking behavior; awake; in vivo; innovation; neglect; neural circuit; novel; patch clamp; relating to nervous system; research study; skills; transmission process; vapor

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.

描述（由申请人提供）：拟议研究的目的是了解乙醇暴露对负责控制目标行动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。尽管在介导乙醇对大脑作用的药理学靶标方面取得了很多进展，但对神经系统水平上乙醇成瘾产生的适应性知之甚少。到目前为止，关于乙醇对目标指导行为的影响的大多数研究都集中在酒精自我管理范式上。相当忽视的是乙醇如何影响正常奖励引导行为的神经系统的问题。要了解负责乙醇上瘾特性的神经自助性机制，我们必须首先了解它如何影响奖励引导行为的正常机制。更具体地说，几乎没有研究乙醇对纹状体的影响，乙醇对自愿行为控制的关键结构，由于最近的研究而与习惯形成和成瘾有关。因此，关于乙醇如何改变纹状体依赖性学习和行为并不了解。在此提案中，假设暴露于乙醇（使用乙醇蒸气腔室程序）可以在纹状体中篡夺正常的学习过程，这些学习过程从事技能和习惯形成的自动化，从而对随后控制奖励指导行为的控制产生重大影响。因此，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）确定在仪器学习过程中，在醒着的行为小鼠中，先前的乙醇暴露对纹状体神经活动的影响。 3）使用全细胞贴片夹记录确定先前的乙醇暴露对纹状体突触传递的影响。该提案采用一种创新和综合的方法来研究大脑对乙醇的作用，通过将体内和体内电生理学方法与工具学习研究中的强大测定相结合。拟议的实验的结果将有助于我们了解介导目标指导作用和习惯形成的采集和控制的皮质 - 纹状体回路中的神经适应机制。这种机制可以为治疗酒精成瘾提供新的目标。 公共卫生相关性：最近的工作提出了背纹状体在习惯形成中的关键作用。结果，不同纹状体区域的参与现在已成为研究的重点。但是，尚不清楚酒精如何影响形成的神经回路。拟议的研究的结果将大大提高我们对酒精暴露的理解，如何利用通常从事习惯形成的可塑性机制，以促进改变自愿行为的控制。这种知识可能会导致更好的治疗选择，这些方案专门针对导致习惯性和强迫性酒精行为发展的生理过程。