Neural Circuits that Regulate Risk Seeking

调节风险寻求的神经回路

• 批准号: 10563222
• 负责人: Ilya E. Monosov
• 金额: $ 39.74万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563222
• 关键词: Anatomy; Animal Model; Animals; Anxiety; Area; Attitude; Basal Ganglia; Behavior; Behavior assessment; Behavioral; Behavioral Mechanisms; Brain; Brain Stem; Cognition; Data; Decision Making; Disease; Dorsal; Drug Addiction; Electric Stimulation; Emotions; Event; Future; Globus Pallidus; Goals; Grant; Habenula; Human; Lateral; Link; Mediating; Mental Depression; Mental disorders; Monkeys; Motivation; Neurons; Outcome; Output; Pattern; Population; Primates; Process; Punishment; Research; Resolution; Rewards; Risk; Risk Behaviors; Signal Transduction; Testing; Time; Uncertainty; Variant; Work; basal forebrain; clinically relevant; cognitive control; discounting; dorsal raphe nucleus; experimental study; maladaptive behavior; motivated behavior; neural circuit; neuromechanism; neuronal circuitry; neuroregulation; response; transmission process

Adaptive control of cognitive behaviors in response to changes in uncertainty about future rewards is fundamental for survival. It is not surprising that uncertainty-related maladaptive behaviors, such as maladaptive risk seeking or avoidance, are observed in a wide range of psychiatric disorders. But, to date, the neural mechanisms of uncertainty-mediated risk seeking or risk avoidance are unclear. And, anatomically targeted treatments for many risk-related behavioral states have not been developed. The overarching goal of the current renewal is to uncover the neuronal and behavioral mechanisms of risky decision making under uncertainty. Aim 1 will uncover the mechanisms by which single neurons regulate risky decisions under uncertainty. Our previous work showed that the ventral pallidum (VP) transmits a risk signal before risky decisions. This raised crucial new questions. How does VP compute its risk signal? What is its function in decision making? We hypothesize that VP computes the subjective value of risk in order to govern risk- reward tradeoffs in decision making, and that decision making is controlled by a major recipient of VP projections - the lateral habenula (LhB). Aim 1 will (i) test among leading mechanistic accounts of risky behavior and assess how the subjective value of risk is governed by distinct forms of reward uncertainty and by reward timing, (ii) determine whether VP neurons' activity is necessary and sufficient to control decision making under uncertainty via these mechanisms, and (iii) determine whether and how VP risky decision related activity is reflected in the LHb. Preliminary data indicate that risky decisions arise due to a change in subjective value of risk mediated by uncertainty-sensitive neurons in the VP, and that representations of total subjective value ultimately guide choice through the LhB, downstream of VP. Aim 2 will shed light on the behavioral and neuronal mechanisms through which risk tolerance and value-based decision making are mediated by time. We found that monkeys' behavior closely resembled human decision making: monkeys are more willing to accept risks when they can resolve the resulting uncertainty early instead of having to live with the uncertainty for a prolonged time, and this risk tolerance was reflected in VP and LhB neurons. We hypothesize that timing information that is computationally necessary to control this risk tolerance is encoded in dorsal raphe nucleus (DRN) – a modulatory input to VP and LhB. Aim 2 will (i) characterize how neurons in DRN process the timing- and uncertainty-related variables that govern risk tolerance and (ii) transiently manipulate population activity in the DRN to assess the impact on decisions. Preliminary data show that DRN neurons encode information about time and uncertainty in a manner that is sufficient to control risk tolerance. The Aims offer an unprecedented opportunity to (i) understand the mechanisms of risky decision-making and (ii) study the neuronal activity in brain areas tightly linked to psychiatric disorders that have not been studied in during decision making in the closest animal model to human beings.

对认知行为的自适应控制对未来奖励的不确定性变化的反应是 生存的基础。不奇怪的是，与不确定性相关的适应不良行为，例如 在多种精神病患者中观察到不良适应性风险寻求或避免。但是，迄今为止， 不确定性介导的寻求风险或避免风险的神经机制尚不清楚。而且，从解剖学上 尚未开发针对许多与风险有关的行为状态的有针对性治疗。总体目标 当前的续约是揭示有风险决策的神经元和行为机制 不确定。 AIM 1将发现单个神经元调节风险决定的机制 不确定。我们以前的工作表明，腹侧颗粒（VP）在风险之前传输风险信号 决定。这提出了至关重要的新问题。 VP如何计算其风险信号？它的功能是什么 决策？我们假设VP计算风险的主题价值以管理风险 - 奖励决策中的权衡，该决策由副总裁的主要接受者控制 预测 - 外侧Habenula（LHB）。 AIM 1将（i）在风险的领先机理中测试 行为和评估风险的主观价值如何受到不同形式的奖励不确定性和 通过奖励时机，（ii）确定VP神经元的活动是否必要且足以控制决策 通过这些机制在不确定性下进行，（iii）确定副总裁是否以及如何与风险决定有关 活动反映在LHB中。初步数据表明，由于主观变化而引起的风险决定 VP中对不确定性敏感神经元介导的风险价值以及总主观的表示 价值最终通过VP下游的LHB进行指导选择。 AIM 2将阐明行为 和神经元机制，风险承受能力和基于价值的决策是 由时间介导。我们发现猴子的行为与人类的决策非常相似：猴子是 当他们能够尽早解决最终的不确定性时，更愿意接受风险 长时间的不确定性，这种风险公差反映在VP和LHB神经元中。我们 假设控制这种风险公差在计算上是必需的计算信息已编码 背侧raphe核（DRN） - 对VP和LHB的调节输入。 AIM 2将（i）表征神经元如何 DRN处理处理风险容忍度的时间和不确定性相关变量，并且（ii）暂时 操纵DRN中的人口活动，以评估对决策的影响。初步数据显示DRN 神经元以足以控制风险容忍度的方式编码有关时间和不确定性的信息。 目的为（i）了解风险决策和 （ii）研究大脑区域的神经元活动与尚未研究的精神疾病紧密相关 在最接近人类动物模型的决策过程中。