Interactions between orbitofrontal cortex and mediodorsal thalamus in cue- and value-based decision making

眶额皮层和内侧丘脑在基于线索和价值的决策中的相互作用

• 批准号: 10267685
• 负责人: Sean Bjorn Ostlund
• 金额: $ 19.63万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10267685
• 关键词: Address; Alzheimer' s Disease; Anatomy; Animals; Area; Attention; Behavior; Behavioral; Biological Assay; Clozapine; Collaborations; Communication; Coupled; Cues; Data; Decision Making; Dependence; Drug Addiction; Feedback; Food; Functional disorder; Future; Goals; Grain; Health; Hyperphagia; Lateral; Lead; Ligands; Measures; Medial; Mediating; Mental disorders; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Obsessive-Compulsive Disorder; Outcome; Oxides; Pathologic; Pathway interactions; Performance; Personal Satisfaction; Pharmaceutical Preparations; Play; Prefrontal Cortex; Proteins; Rattus; Reporter; Research; Research Personnel; Resources; Rewards; Rodent; Satiation; Schizophrenia; Short-Term Memory; Signal Transduction; Stimulus; Structure; Sucrose; Support System; Task Performances; Testing; Thalamic structure; Time; Training; Viral; Water; Work; addiction; base; cognitive process; designer receptors exclusively activated by designer drugs; expectation; experimental study; flexibility; improved; innovation; interest; learning outcome; motivated behavior; motivational processes; neural circuit; neuromechanism; novel; preference; relating to nervous system; response

Abstract Our health and well being depend on our ability to make adaptive decisions that take into account information about the expected value and availability of potential behavioral goals. It is believed that dysfunction within the neural systems that support goal-directed decision making can result in maladaptive reward-seeking behavior that is either exaggerated and difficult to control, such as with compulsive drug seeking and overeating, or becomes weakened to an unhealthy degree, such as with the apathy apparent in various psychiatric and neurodegenerative disorders (e.g., Alzheimer's disease and schizophrenia). Advances in our understanding of the neural systems that support adaptive decision making are needed so that we are better able to pinpoint the specific aberrations in neural function that give rise to pathological forms of reward seeking. The current project will use an integrative approach to provide novel tests of the decision-making functions of anatomically distinct pathways connecting the medial (MOFC) and lateral (LOFC) orbitofrontal cortices to each other and to the mediodorsal thalamus (MDTHAL). Our behavioral approach will make use of well-validated assays of cue- and value-based decision making in rats. The influence of reward-predictive cues on action selection will be probed using the outcome-specific Pavlovian-to-instrumental transfer task, in which noncontingent presentations of a cue that signals the availability of a specific reward outcome (e.g., sucrose solution) biases rats to selectively pursue that outcome instead of a different but equally valuable outcome (e.g., grain pellets). To probe value- based decision making, we will use outcome-specific reward devaluation tasks, in which rats demonstrate their capacity to flexibly suppress their performance of instrumental actions or Pavlovian conditioned approach responses when an expected reward is devalued through specific satiety. In Aim 1 we will virally express hM4Di, a Gi-coupled DREADD (Designer Receptors Exclusively Activated by Designer Drugs), in the MOFC, LOFC, or MDTHAL, allowing us to determine how inhibiting neurons in these areas (via systemic hM4Di activation) or specific pathways connecting these areas (via local hM4Di activation) impacts cue-based decision making (Pavlovian-instrumental transfer). In Aim 2 we will use the same basic chemogenetic approach to investigate the neural circuitry required for value-based decision making (instrumental and Pavlovian reward devaluation). Together these experiments will provide rigorous tests of innovative hypotheses regarding the behavioral functions of these understudied pathways within the broader orbitothalamic network. Given evidence that dysfunction within these pathways contributes to aberrations in reward-motivated behavior, we believe that this work will have a broad scientific impact, and will lay the groundwork for our own future research investigating neural mechanisms of maladaptive decisions.

摘要 我们的健康和幸福取决于我们做出考虑信息的适应性决策的能力 关于潜在行为目标的期望值和可用性。据信， 支持目标导向决策的神经系统可能导致不适应的寻求奖励行为 要么是夸大和难以控制，如强迫性药物寻求和暴饮暴食，或 变得虚弱到不健康的程度，例如在各种精神病和 神经变性病症（例如，阿尔茨海默氏病和精神分裂症）。我们对人类进化的认识 需要支持自适应决策的神经系统，以便我们能够更好地确定 神经功能的特殊畸变，导致病态的奖赏寻求。当前项目 将使用一种综合的方法来提供解剖学上不同的决策功能的新测试， 连接内侧（MOFC）和外侧（LOFC）眶额皮质彼此之间以及与 内侧背丘脑（MDTHAL）。我们的行为方法将利用经过充分验证的线索分析， 老鼠的价值决策本研究将探讨奖赏-预测线索对动作选择的影响 使用特定结果的巴甫洛夫到工具转移任务，其中非偶然的介绍， 发信号通知特定奖励结果的可用性的提示（例如，蔗糖溶液）使大鼠选择性地 追求该结果而不是不同但同样有价值的结果（例如，谷物颗粒）。去探索价值- 基于决策，我们将使用特定于结果的奖励贬值任务，在这些任务中，大鼠表现出他们的 灵活抑制工具性行为或巴甫洛夫条件反射的能力 当预期的奖励因特定的饱腹感而贬值时，在目标1中，我们将病毒表达 hM4Di，一种GI偶联的DREADD（仅由设计药物激活的设计受体），在MOFC中， LOFC或MDTHAL，使我们能够确定如何抑制这些区域中的神经元（通过系统性hM4Di 激活）或连接这些区域的特定途径（通过局部hM4Di激活）影响基于线索的 巴甫洛夫工具转移（Pavlovian-instrumental transfer）在目标2中，我们将使用相同的基本化学遗传学 研究基于价值的决策所需的神经回路的方法（工具和 巴甫洛夫奖励贬值）。这些实验将为创新性技术提供严格的测试。 关于这些未充分研究的通路的行为功能的假设在更广泛的 眶丘脑网络有证据表明，这些通路中的功能障碍会导致 奖励动机的行为，我们相信这项工作将产生广泛的科学影响，并将奠定 为我们自己未来研究适应不良决策的神经机制打下基础。