Decision-Making Dysfunction and Chronic Cocaine

决策功能障碍和慢性可卡因

• 批准号: 9236327
• 负责人: Jane R Taylor
• 金额: $ 33.08万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236327
• 关键词: Ablation; Amygdaloid structure; Anatomy; Animal Model; Area; Behavior; Behavior Control; Behavioral; Behavioral Mechanisms; Biological Psychiatry; Brain; Cell Adhesion Molecules; Chronic; Cocaine; Complex; Computer Analysis; Computer Simulation; Corpus striatum structure; Data; Decision Making; Development; Drug Addiction; Drug Exposure; Drug usage; Functional disorder; Goals; Habits; Human; Impairment; Incentives; Individual; Individual Differences; Investigation; Knowledge; LoxP-flanked allele; Mediating; Modeling; Molecular; Monkeys; Motivation; Neural Cell Adhesion Molecules; Neurobiology; Neuronal Plasticity; Neurons; Neurosciences; Nucleus Accumbens; Pattern; Performance; Pharmaceutical Preparations; Pharmacology; Process; Psychological reinforcement; Rattus; Research; Reversal Learning; Role; Structure; Task Performances; Techniques; Tracer; Viral; Work; addiction; base; cocaine exposure; cortico-limbic circuits; drug of abuse; flexibility; innovation; neurobehavioral; novel; novel therapeutics; resilience; stem; targeted treatment; tool

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.

尽管许多人偶尔会滥用药物，但很少有人会染上毒瘾。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吸毒行为 预先存在的决策过程。我们是最早提出前额功能障碍介导的人之一 自上而下的成瘾行为控制，这一观点现已得到广泛认可，我们提供了 支持证据表明决策缺陷、激励动机和习惯以及神经行为 成瘾动物模型的可塑性受到影响。尽管如此，一种更加机械化、电路驱动的方法 需要剖析决策功能障碍的个体差异与 由于长期接触毒品而容易上瘾。我们将使用尖端的病毒工具 表征大鼠异常决策策略之间的神经生物学关系 成瘾样行为的发展和持续。这里我们重点关注眶额皮质（OFC）的作用 在决策中对不同皮质下目标（OFC-杏仁核和OFC-伏隔核）的预测 制作过程。将使用新任务来评估大鼠适应行为变化的能力 强化意外事件或根据行动强化的抽象表示做出选择 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的 OFC 和计算模型，我们将隔离 OFC- 成瘾脆弱性背后的依赖电路和机制。在目标 1 中，我们将确定精确的 通过结合改造预测可卡因吸食行为的脆弱性的决策过程 具有复杂计算分析的行为任务。在目标 2 中，我们将描述特定角色的作用 OFC 电路在决策行为中使用一种新颖的方法来预测对可卡因吸食行为的脆弱性 特定于电路的逆转录病毒消融方法，用于识别和去除特定的自上而下的 OFC 电路。最后，在 目标3，我们将研究神经细胞粘附分子（NCAM）介导的可塑性的作用及其 OFC 回路内的促塑性修饰形式、聚唾液酸化 NCAM (PSA-NCAM)，在决策过程中 使用病毒工具预测对可卡因吸食行为的脆弱性。总体而言，这项工作的结果应该 提供了关于自上而下、OFC-皮层下控制的选择性丧失的作用的创新视角 决策过程和成瘾的脆弱性。这些研究有可能启发 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。