Neural Circuits that Regulate Risk Seeking

调节风险寻求的神经回路

• 批准号: 10298264
• 负责人: Ilya E. Monosov
• 金额: $ 40.36万
• 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/10298264
• 关键词: Anatomy; Animal Model; Animals; Anxiety; Area; Attitude; Basal Ganglia; Behavior; 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; Light; 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; base; clinically relevant; cognitive control; discounting; dorsal raphe nucleus; experimental study; maladaptive behavior; motivated behavior; neural circuit; neuromechanism; neuronal circuitry; neuroregulation; response

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.

针对未来奖励的不确定性变化而对认知行为进行适应性控制是 与不确定性相关的适应不良行为是生存的基础，这并不奇怪。 但迄今为止，在多种精神疾病中都观察到了适应不良的风险寻求或回避。 不确定性介导的风险寻求或风险规避的神经机制尚不清楚。 许多与风险相关的行为状态的针对性治疗尚未制定。 当前的更新是揭示风险决策的神经和行为机制 目标 1 将揭示单个神经元在不确定性下调节风险决策的机制。 我们之前的工作表明，腹侧苍白球（VP）在有风险之前传递风险信号。 这提出了重要的新问题：VP 如何计算其风险信号？ 我们让 VP 计算风险的主观价值以管理风险- 决策中的奖励权衡，并且决策由 VP 的主要接受者控制 预测 - 外侧缰核 (LhB) 目标 1 将 (i) 测试主要的风险机制解释。 行为并评估风险的主观价值如何受到不同形式的奖励不确定性的控制 通过奖励计时，(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做出决策，以及 (iii) 确定 VP 风险决策是否相关以及如何相关 初步数据表明，由于主观的变化而产生了风险决策。 VP 中不确定性敏感神经元介导的风险值，以及总主观的表征 价值最终通过 LhB 指导选择，VP 的下游将阐明行为。 以及风险承受能力和基于价值的决策的神经机制 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由此产生的不确定性而不是忍受时，他们更愿意接受风险 长时间的不确定性，这种风险承受能力反映在 VP 和 LhB 神经元上。 保持控制这种风险承受能力所需的计算时间信息被编码在 中缝背核 (DRN) – VP 和 LhB 的调节输入将 (i) 描述神经元的特征。 DRN 处理控制风险承受能力的时间和不确定性相关变量，并且 (ii) 瞬时 操纵 DRN 中的群体活动来评估对决策的影响。 神经元以足以控制风险承受能力的方式编码有关时间和不确定性的信息。 这些目标提供了前所未有的机会：（i）了解风险决策的机制和 (ii) 研究与精神疾病密切相关的大脑区域的神经活动，这些区域尚未在 在最接近人类的动物模型中做出决策时。