Cytoskeletal determinants of goal-directed decision-making

描述（由申请人提供）：可卡因依赖是一个持续存在的重大公共卫生问题，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，可卡因会导致前额皮质长期持续的变化，前额皮质是大脑中负责决策策略和奖励评估的区域。这些变化甚至发生在树突棘的水平上，树突棘是神经元之间的主要通讯点。因此，可卡因引起的前额叶皮层树突棘的改变可能是可卡因成瘾和复发的一个因素。人类和啮齿类动物都能学会将特定的行为与结果联系起来。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与其结果之间关系的变化很敏感。随着药物滥用的重复或暴露，如可卡因，目标导向的反应可以从结果敏感转变为自动或“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的决策被证明是特别具有挑战性的，但这是一项至关重要的研究，因为尽管习惯的发展可以服务于适应性目的，但以牺牲目标导向决策为代价的习惯行为被认为在成瘾病因学中发挥作用。该建议旨在确定目标导向行为的细胞机制，并恢复因可卡因暴露而养成习惯的小鼠的目标导向决策。我将重点关注ROCK，肌动蛋白细胞骨架的关键调节因子，控制树突棘的收缩依赖性重塑。我已经证明，ROCK抑制剂HA-1077可以在经过广泛训练的小鼠中恢复目标导向的决策，否则它们就会养成刺激反应习惯。相比之下，可卡因会诱发习惯。这些发现提出了一种具有挑衅性的可能性，即靶向细胞骨架调节剂（如ROCK）可能有助于治疗可卡因依赖和预防复发。我建议：1)使用HA-1077来逆转可卡因引起的习惯，并阻断对可卡因的习惯性反应。2)利用体内多光子显微镜实时定量观察可卡因暴露后前额叶皮层树突棘的形态学反应。接下来，我将分离HA-1077干预的效果，期望HA-1077能扭转可卡因暴露的结构性后果。可卡因引起的前额叶皮层树突棘的改变是否是成瘾病因学的一个促成因素，在该领域存在激烈的争论

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.