Decision-Making Dysfunction and Chronic Cocaine

虽然许多人偶尔滥用药物，但很少有人会上瘾。的可能性 一个人从偶尔吸毒到强迫吸毒的转变可能取决于异常的 预先存在的决策过程。我们是最早提出前额叶功能障碍 成瘾中自上而下的行为控制，这是一个现在被广泛认可的观点，我们已经提供了 支持证据表明，决策缺陷，激励动机和习惯，以及神经行为 可塑性在成瘾动物模型中受到影响。尽管如此，一个更机械的，电路驱动的方法， 需要剖析决策功能障碍的个体差异之间的精确关系， 由于长期接触毒品而容易上瘾。我们将使用最先进的病毒工具 描述大鼠异常决策策略之间的神经生物学关系， 成瘾行为的发展和持续。在这里，我们集中在眶额皮质（OFC）的作用， 在决策过程中，向不同的皮质下目标（OFC到杏仁核和OFC到丘脑核）的投射， 制作过程。将使用新的任务来评估大鼠适应行为变化的能力 强化偶然性或基于行动强化的抽象表征做出选择 意外事件我们假设，通过使用依赖于 为了更好地描述决策过程，我们将隔离OFC- 依赖的电路和机制，成瘾脆弱性的基础。在目标1中，我们将确定精确的 决策过程，预测脆弱性可卡因服用行为相结合的改造， 行为任务与复杂的计算分析。在目标2中，我们将描述特定的 OFC电路的决策行为，预测脆弱性可卡因服用行为使用一种新的 回路特异性逆转录病毒消融方法，以识别和去除特定的自上而下的OFC回路。最后在 目的3：探讨神经细胞粘附分子（NCAM）介导的神经细胞可塑性及其在神经细胞损伤中的作用。 在决策过程中，OFC回路内的前体修饰形式，聚唾液酸化NCAM（PSA-NCAM） 利用病毒工具预测可卡因吸食行为的脆弱性。总的来说，这项工作的结果应 提供了一个创新的角度上的作用，选择性损失的自上而下，OFC-皮层下的控制， 决策过程和成瘾的脆弱性。这些研究有可能激发 开发新的治疗策略，为生物精神病学开辟新的研究领域， 神经科学，并为人类成瘾产生高度转化的结果。

Although many people use drugs of abuse occasionally, few people develop a drug addiction. The likelihood that an individual transitions from occasional to compulsive patterns of drug use may depend upon aberrant pre-existing decision-making processes. We were among the first to argue that prefrontal dysfunction mediates top-down behavioral control in addiction, a perspective that is now widely recognized, and we have provided supporting evidence that decision-making deficits, incentive motivation and habits, and neurobehavioral plasticity are impacted in animal models of addiction. Nonetheless, a more mechanistic, circuit-driven approach is needed to dissect the precise relationship between individual differences in decision-making dysfunction and vulnerability to addiction from the consequence of chronic drug exposure. We will use cutting-edge viral tools to characterize the neurobiological relationship between aberrant decision-making strategies in rats on the development and persistence of addiction-like behavior. Here we focus on the role of orbitofrontal cortex (OFC) projections to distinct subcortical targets (OFC-to-amygdala and OFC-to-nucleus accumbens) in decision- making processes. Novel tasks will be used that assess the ability of rats to adapt behavior to changing reinforcement contingencies or make choices based on abstract representations of action-reinforcement contingencies. We hypothesize that by using highly-translational behavioral tasks that are dependent upon the OFC and computational models to better characterize decision-making processes, we will isolate the OFC- dependent circuitry and mechanisms that underlie addiction vulnerability. In Aim 1, we will identify precise decision-making processes that predict vulnerability to cocaine-taking behaviors by combining retro-fitted behavioral tasks with sophisticated computational analyses. In Aim 2, we will characterize the role of specific OFC circuits in decision-making behaviors that predict vulnerability to cocaine-taking behavior using a novel circuit-specific, retroviral ablation approach to identify and remove specific top-down OFC circuits. Finally, in Aim 3, we will investigate the role of plasticity mediated by neural cell adhesion molecule (NCAM) and its proplastic modified form, polysialylated NCAM (PSA-NCAM) within OFC circuits, in decision-making processes that predict vulnerability to cocaine-taking behaviors using viral tools. Overall, results from this work should provide an innovative perspective on the role of selective loss of top-down, OFC–subcortical control on decision-making processes and vulnerability to addiction. These studies have the potential to inspire the development of novel therapeutic strategies, open new areas of investigation for biological psychiatry and neuroscience, and produce highly translational results for human addiction.