The Role of Orbitofrontal Cortex in Risky Decision-Making

(7)项目摘要/摘要 物质使用障碍是一种以病理性冒险行为为特征的慢性难治性疾病， 这导致了尽管有后果的风险，仍在不断地寻求毒品。这项提议利用了一个大鼠模型。 了解有助于做出高风险决策的神经元活动。高风险的决策任务 (RDT)提供小额、安全的奖励和伴随不断上升的风险的大奖励之间的选择 轻微的脚部电击。虽然风险承担的平均水平随着惩罚风险的增加而下降，但RDT显示 风险偏好的广泛变异性，包括持续偏爱大回报的老鼠亚群 尽管有很高的惩罚风险。了解Risk患者这种自然变异的神经机制 决策可能有助于开发针对异常决策过程的治疗方法 实质上是滥用者。驱动高风险决策的功能性活动的一个可能的轨迹是眶前叶 皮质(OFC)，这一领域涉及几种基于风险的决策方式以及对 物质使用。本提案中的实验将评估OFC加工过程中的差异如何驱动个体 在高风险决策过程中，通过测量和操纵OFC活动来实现风险承担的差异。目标一 将利用活体单个单位电生理学来测量OFC在危险期间的功能神经元活动 决策。活动将在一个专门设计的RDT版本中进行测量，该版本将解析为 决策过程中的不同阶段：决策前的审议和决策后的结果 期待。为了确定OFC如何预测风险承担中的个人偏向，事件引发的OFC活动将 比较不同风险偏好水平的大鼠之间的差异。目标二将利用光遗传抑制来 在风险决策中抑制不同时期的OFC活动。这将确定 OFC在驱动冒险行为中的作用，并确定OFC对冒险行为的调制是否作为风险的函数而不同- 偏好。上面概述的实验将测量和操作OFC活动在 研究不足的与成瘾相关的高风险决策形式，这可能导致新的生物标志物和/或 对成瘾患者对惩罚风险的长期不敏感进行精确治疗。此外，这一点 建议书将提供强大的培训部分，包括关键技术技能、复杂的数据分析和 信号处理、多个高影响力出版物的机会以及来自以下团队的强大指导 处于不同职业阶段的调查人员。

(7) Project Summary/Abstract Substance use disorder is a chronic, intractable disease characterized by pathological risk-taking behavior, which engenders ongoing drug seeking despite the risk of consequences. This proposal harnesses a rat model to understand the neuronal activity that contributes to risky decision-making. The Risky Decision-Making Task (RDT) offers choice between a small, safe reward and a large reward accompanied by an escalating risk of mild foot shock. While risk-taking on average decreases with increasing risk of punishment, the RDT reveals wide variability in risk preference, including a subpopulation of rats that consistently prefer the large reward despite high risk of punishment. Understanding the neuronal mechanisms of this natural variability in risky decision-making may contribute to development of treatments that target aberrant decision-making processes in substance abusers. A likely locus of the functional activity driving risky decision-making is the orbitofrontal cortex (OFC), an area implicated in several modalities of risk-based decision-making as well as vulnerability to substance use. Experiments in this proposal will assess how differences in OFC processing drive individual differences in risk-taking by measuring and manipulating OFC activity during risky decision-making. Aim one will utilize in vivo single-unit electrophysiology to measure functional neuronal activity in OFC during risky decision-making. Activity will be measured during a specially designed version of RDT that parses apart distinct epochs within the decision-making process: pre-decision deliberation, and post-decision outcome anticipation. To determine how OFC predicts individual biases in risk-taking, event-evoked OFC activity will be compared between rats with different levels of risk preference. Aim two will utilize optogenetic inhibition to suppress OFC activity during different epochs within risky decision-making. This will identify the causal role of OFC in driving risk-taking, and determine if OFC modulation of risk-taking diverges as a function of risk- preference. The experiments outlined above will both measure and manipulate OFC activity during an understudied form of addiction-relevant risky decision-making, which may lead to novel biomarkers and/or precise treatments for the chronic insensitivity to risk of punishment observed in addiction. In addition, this proposal will offer a strong training component including critical technical skills, complex data analysis and signal processing, the opportunity for multiple high impact publications, and strong mentorship from a team of investigators at various career stages.