Neural Circuits that Regulate Risk Seeking

对认知行为的适应性控制，以应对未来奖励不确定性的变化 这是生存的根本。与不确定性相关的适应不良行为，如 适应不良的风险寻求或回避，在广泛的精神障碍中都可以观察到。但是，到目前为止， 不确定性中介的风险寻求或风险规避的神经机制尚不清楚。而且，从解剖学上讲 针对许多风险相关行为状态的靶向治疗尚未开发出来。的首要目标是 目前的更新是揭示风险决策的神经和行为机制 不确定性。目标1将揭示单个神经元在以下条件下调节危险决策的机制 不确定性。我们以前的工作表明，腹侧苍白球(VP)在发生危险之前传递危险信号 决定。这引发了至关重要的新问题。VP如何计算其风险信号？它的作用是什么？ 做决定？我们假设VP计算风险的主观价值，以管理风险- 决策中的报酬权衡，决策由VP的主要接受者控制 投射-外侧缰核(LHB)。目标1将(I)在风险的主要机械描述中进行测试 并评估风险的主观价值如何受不同形式的回报不确定性和 通过奖赏计时，(Ii)确定VP神经元的活动是否是控制决策的必要和充分的 通过这些机制在不确定性下进行决策，以及(Iii)确定VP是否以及如何与风险决策相关 活动反映在LHB中。初步数据表明，风险决策是由于主观因素的改变而产生的 Vp中不确定性敏感神经元介导的风险价值，以及总体主观表征 价值最终通过LHB引导选择，位于VP的下游。目标2将阐明行为 和神经机制，通过这些机制，风险容忍度和基于价值的决策 由时间调停。我们发现猴子的行为与人类的决策非常相似：猴子 当他们能够及早解决由此产生的不确定性而不是不得不忍受时，他们更愿意接受风险 这种不确定性和这种风险耐受性反映在VP和LHB神经元上。我们 假设在计算上控制该风险容忍度所需的定时信息被编码为 中缝背核(DRN)--VP和LHB的调制输入。目标2将(I)描述神经元如何在 DRN处理支配风险容忍度的与时间和不确定性相关的变量，以及(Ii)瞬时 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 神经元以一种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。 这些目标提供了一个前所未有的机会来(I)了解高风险决策的机制和 (Ii)研究与精神疾病密切相关的大脑区域的神经元活动，这些区域尚未在 在最接近人类的动物模型中进行决策。

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.