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

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。人们认为，大脑内部的功能障碍 支持目标导向决策的神经系统可能会导致不适应的奖赏行为 这要么夸大了，要么难以控制，比如强迫性寻求毒品和暴饮暴食，或者 变得虚弱到不健康的程度，如在各种精神病症和 神经退行性疾病(如阿尔茨海默病和精神分裂症)。我们对生物多样性研究的新进展 需要支持自适应决策的神经系统，这样我们才能更好地定位 神经功能的特殊异常，会引起病理性的奖赏寻求。当前项目 将使用一种综合的方法来提供解剖上截然不同的决策功能的新测试 内侧(MOFC)和外侧(LOFC)眶前皮质相互连接的通路 丘脑内侧背侧(MDTHAL)。我们的行为方法将利用经过充分验证的线索分析-和 大鼠基于价值的决策。本研究将探讨奖励预测线索对动作选择的影响。 使用特定于结果的巴甫洛夫-工具性迁移任务，在该任务中， 暗示特定奖励结果(例如，蔗糖溶液)的可用性的提示会使大鼠有选择地偏向 追求这一结果，而不是不同但同样有价值的结果(例如，颗粒颗粒)。为了探寻价值- 基于决策，我们将使用结果特定的奖励贬值任务，在任务中，老鼠展示他们的 能够灵活地抑制他们的工具性动作或巴甫洛夫条件化方法的表现 当期望的报酬因特定的饱腹感而贬值时的反应。在目标1中，我们将病毒式地表达 HM4Di，一种GI偶联的DREADD(由设计师药物独占激活的设计师受体)，在mOFC中， LOFC，或MDTHAL，使我们能够确定这些区域中抑制神经元的方式(通过系统性hM4Di 激活)或连接这些区域的特定路径(通过局部hM4Di激活)影响基于线索的 决策(巴甫洛夫式--工具性转移)。在目标2中，我们将使用相同的基本化学发生 研究基于价值的决策所需的神经回路的方法(工具性和 巴甫洛夫报酬贬值)。这些实验将共同为创新提供严格的测试 关于这些未被研究的更广泛的通路的行为功能的假设 眶丘脑网络。鉴于有证据表明，这些通路中的功能障碍导致了 我们相信，这项工作将产生广泛的科学影响，并将为 为我们未来研究不良适应决策的神经机制奠定基础。

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.