Cytoskeletal determinants of goal-directed decision-making

描述(申请人提供)：可卡因依赖是一个重大的持续公共卫生问题，部分原因是没有有效的药物治疗，康复后复发的可能性仍然很高。众所周知，可卡因会导致前额叶皮质长期、持续的变化，前额叶皮质是负责决策策略和奖励评估的大脑区域。这些变化甚至发生在树突的水平上，树突是神经元之间的主要通信点。可卡因诱导的前额叶皮质树突棘的改变可能是可卡因成瘾和复发的一个促成因素。人类和啮齿动物都可以学会将特定的行动与其结果联系起来。这些行动被认为是“目标导向的”，这意味着它们的表现对行动及其结果之间关系的变化很敏感。随着重复或接触滥用药物，如可卡因，目标导向的反应可以从对结果敏感转变为自动的，或“习惯性”，其定义是对行动-结果关系的变化不敏感。在实验模型中，在习惯形成后恢复目标导向决策被证明是特别具有挑战性的，但这是一项关键的研究任务，因为尽管习惯的发展可以服务于适应目的，但以牺牲目标导向决策为代价发生的习惯行为被认为在成瘾病因中发挥了作用。这项建议旨在确定目标导向行为的细胞机制，并恢复因接触可卡因而养成习惯的小鼠的目标导向决策。我将把重点放在ROCK上，它是肌动蛋白细胞骨架的关键调节器，控制着树突棘依赖收缩的重塑。我已经证明，岩石抑制剂HA-1077可以恢复经过广泛训练的小鼠的目标导向决策，否则这些小鼠就会养成刺激反应的习惯。相比之下，接触可卡因会让人养成习惯。这些发现提出了一种挑衅性的可能性，即靶向细胞骨架调节因子，如ROCK，可能在治疗可卡因依赖和防止复发方面有用。我建议：1)使用HA-1077逆转可卡因诱导的习惯，并阻断对可卡因的习惯性反应。2)使用活体多光子显微镜实时定量前额叶皮质树突棘对可卡因暴露的形态反应。接下来，我将隔离HA-1077干预的影响，期望HA-1077将逆转暴露于可卡因的结构性后果。可卡因诱导的前额叶皮质树突棘的改变是否是成瘾病因的一个因素在该领域引起了激烈的争论，尤其是 由于很少有研究小组配备工具来模拟可卡因诱导的适应不良决策，并同时分离细胞结构改变。我将利用这些工具来全面解决当前知识中的这一差距。

DESCRIPTION (provided by applicant): Cocaine dependence is a significant ongoing public health concern, in part because there is no effective pharmacological treatment, and the likelihood of relapse after recovery remains high. Cocaine is known to cause long-term, persistent changes in the prefrontal cortex, a brain region responsible for decision-making strategies and reward valuation. These changes occur even at the level of dendritic spines, the primary communication points between neurons. Cocaine-induced alteration of prefrontal cortical dendritic spines may thus be a contributing factor to cocaine addiction and relapse. Both humans and rodents can learn to associate specific actions with their outcomes. These actions are considered 'goal-directed,' meaning their performance is sensitive to changes in the relationship between the action and its outcome. With repetition or exposure to drugs of abuse such as cocaine, goal-directed responding can shift from being outcome-sensitive to being automatic, or 'habitual', which is defined by insensitivity to changes in the action-outcome relationship. Restoring goal-directed decision-making after habit formation in experimental models has proven particularly challenging, but it is a critical research imperative because although the development of habits can serve adaptive purposes, habitual behaviors that occur at the expense of goal-directed decision-making are thought to play a role in addiction etiology. This proposal aims to identify the cellular mechanisms of goal-directed behavior and to restore goal-directed decision-making in mice that have developed habits due to cocaine exposure. I will focus on ROCK, a key regulator of the actin cytoskeleton that controls contractile-dependent remodeling of dendritic spines. I have shown that the ROCK inhibitor HA-1077 restores goal-directed decision-making in extensively trained mice that otherwise engage in stimulus-response habits. By contrast, cocaine exposure induces habits. These findings raise the provocative possibility that targeting cytoskeletal regulators such as ROCK may be useful in the treatment of cocaine dependence and prevention of relapse. I propose to: 1) Reverse cocaine-induced habits, as well as block habitual responding for cocaine, using HA-1077. 2) Use in vivo multiphoton microscopy to quantify, in real time, the morphological response of prefrontal cortical dendritic spines to cocaine exposure. I will next isolate the effects of HA-1077 intervention with the expectation that HA-1077 will reverse the structural consequences of cocaine exposure. Whether cocaine-induced alterations of prefrontal cortical dendritic spines are a contributing factor to addiction etiology represents a lively debate in the field, especially since few research groups are equipped with the tools to both model cocaine-induced maladaptive decision-making and to isolate cytostructural modifications in tandem. I will harness these tools to comprehensively address this gap in current knowledge.