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.

虽然许多人偶尔滥用毒品，但很少有人上瘾。这种可能性 一个人从偶然的药物使用模式转变为强制使用模式可能取决于异常 预先存在的决策过程。我们是第一批认为前额叶功能障碍在 上瘾的自上而下的行为控制，这一观点现在得到了广泛的认可，我们已经提供了 支持决策缺陷、激励动机和习惯以及神经行为的证据 在成瘾的动物模型中，可塑性受到影响。尽管如此，更机械化的、电路驱动的方法 需要分析决策障碍的个体差异和 长期药物暴露的后果对成瘾的脆弱性。我们将使用尖端的病毒工具 研究大鼠异常决策策略之间的神经生物学关系。 成瘾性行为的发展和持续。在这里，我们关注眶前叶皮质(OFC)的作用。 大脑皮质下不同靶点(OFC-杏仁核和OFC-伏隔核)的投射 制造过程。将使用新的任务来评估老鼠适应变化的行为的能力 加强应急或基于行动的抽象表示作出选择-加强 意外情况。我们假设，通过使用依赖于 为了更好地描述决策过程，我们将分离OFC- 依赖的电路和机制是成瘾脆弱性的基础。在目标1中，我们将确定准确的 结合回归分析预测吸食可卡因行为易感性的决策过程 具有复杂计算分析的行为任务。在目标2中，我们将描述特定的角色 使用一种新的方法预测吸食可卡因行为易感性的决策行为中的OFC回路 特定于电路的逆转录病毒消融方法，以识别和移除特定的自上而下的OFC电路。最后，在 目的：探讨神经细胞黏附分子(NCAM)及其受体在可塑性中的作用。 决策过程中OFC电路中的前塑性修饰形式聚唾液酸化NCAM(PSA-NCAM) 使用病毒工具预测吸食可卡因行为的脆弱性。总的来说，这项工作的结果应该是 提供了一个关于选择性失去自上而下、OFC-皮质下控制的作用的创新视角 决策过程和上瘾的脆弱性。这些研究有可能激励 开发新的治疗策略，开辟生物精神病学研究的新领域 神经科学，并为人类成瘾产生高度翻译的结果。