Habits and cues in alcohol drinking: Dynamic striatal activity

描述（由申请人提供）：酒精中毒是一种慢性疾病，通常持续数十年。习惯形成背后的学习过程可能会导致持续饮酒，并使行为难以改变。习惯（由条件线索驱动的行为，不依赖于结果）与目标导向行为（依赖于结果或药物的行为）驱动饮酒的程度可能会影响复发的易感性。大鼠的操作性条件反射范式可以产生强大的目标导向或习惯性行为，可以模拟习惯对饮酒的贡献，并允许在这些行为期间直接测量大脑功能。背内侧纹状体（DMS）是目标导向行为的基础，而背外侧纹状体（DLS）是习惯形成的关键，这两个区域都参与了复发的动物模型。多巴胺的输入对于线索和药物之间的联系是必不可少的，并且对突触可塑性、神经元活动和行为具有深刻的和区域特异性的影响。提示-动作习惯中的关键多巴胺信号可能是多巴胺（或瞬变）的快速变化，这种变化可能是对显著刺激的反应，只能用快速扫描循环伏安法测量。此外，背侧纹状体中的中型多刺神经元可以通过放电率的短期变化来编码奖励相关的线索和动作，这可能是多巴胺依赖的。这个建议将测试的总体假设，亚秒多巴胺的释放和正在进行的神经元活动不同，在DMS与DLS，与DMS优先活跃在目标导向的酒精强化，和DLS优先活跃在习惯性酒精强化和线索诱导的复发。我们将使用国家的最先进的，实时记录技术在大鼠：快速扫描循环伏安法，揭示多巴胺瞬变，并在多电极阵列的细胞外记录，以评估合奏活动的MSN。此外，我们将在目标导向和习惯性饮酒（目标1和2）以及复发样行为（目标3和4）期间进行化学和生理测量的组合，以提供迄今为止酒精相关习惯形成的背侧纹状体编码的最完整的图片。机制研究将调查多巴胺释放在与习惯性饮酒和复发相关的生理事件中的功能作用。这些创新研究的数据将提供关于背侧纹状体如何差异编码目标导向与习惯性饮酒的重要信息。总的来说，这些研究有可能确定习惯性饮酒导致大脑和行为过程变化的新机制，这些机制对酒精滥用和酒精中毒的发展和治疗都具有根本的重要性。 公共卫生相关性：习惯性饮酒和线索诱发的复发是酒精中毒的主要因素。我们将在习惯性饮酒和线索诱导复发的大鼠模型中研究多巴胺的释放和神经活动。

DESCRIPTION (provided by applicant): Alcoholism is a chronic disorder, typically spanning several decades. The learning processes underlying habit formation may contribute to continued alcohol drinking and render the behavior resistant to change. The degree to which habits (actions driven by conditioned cues and independent of outcome) versus goal-directed behaviors (actions dependent on the outcome or drug) drive alcohol drinking may influence susceptibility to relapse. Operant conditioning paradigms in rats, which can produce robust goal-directed or habitual behavior, can model the contribution of habit to alcohol drinking and allow direct measurement of brain function during these behaviors. The dorsomedial striatum (DMS) underlies goal-directed behavior while the dorsolateral striatum (DLS) is crucial for habit formation, and both areas are involved in animal models of relapse. Dopamine input is essential to the association between cues and drugs, and has profound and region-specific effects on synaptic plasticity, neuronal activity and behavior. The critical dopamine signal in cue-action habits may be fast changes in dopamine (or transients) that can occur in response to salient stimuli and that can only be measured with fast scan cyclic voltammetry. In addition, medium spiny neurons in the dorsal striatum can encode reward-related cues and actions by short-term changes in firing rates, which may be dopamine- dependent. This proposal will test the overall hypothesis that subsecond dopamine release and ongoing neuronal activity differ in DMS versus DLS, with the DMS preferentially active during goal-directed alcohol reinforcement, and the DLS preferentially active during habitual alcohol reinforcement and cue-induced relapse. We will use state-of-the-art, real-time recording techniques in rats: fast scan cyclic voltammetry to reveal dopamine transients, and extracellular recording at multielectrode arrays to evaluate ensemble activity of MSNs. Moreover, we will make this combination of chemical and physiological measurements during goal- directed and habitual alcohol drinking (Aims 1 and 2) as well as relapse-like behavior (Aims 3 and 4), to provide the most complete picture to date of dorsal striatal encoding of alcohol-related habit formation. Mechanistic studies will investigate the functional role of dopamine release in the physiological events associated with habitual drinking and relapse. The data resulting from these innovative studies will provide important information about how the dorsal striatum differentially encodes goal-directed versus habitual alcohol drinking. Overall, these studies have the potential to identify novel mechanisms by which habitual alcohol drinking leads to changes in brain and behavioral processes that are of fundamental importance to both the development and treatment of alcohol abuse and alcoholism. PUBLIC HEALTH RELEVANCE: Habitual alcohol drinking and cue-induced relapse are major factors to alcoholism. We will examine dopamine release and neural activity in rat models of habitual alcohol drinking and cue-induced relapse.