The Role of Orbitofrontal Cortex in Adolescent Impulsivity

描述（由申请人提供）：青春期是一个过渡阶段，其特点是决定越来越冲动，因此很危险。虽然在这个发展阶段，冲动行为的增加是正常的，但未能抑制不适当的行为，例如尝试酒精或非法药物，可能会导致有害的后果。青少年前额叶皮层和皮层下系统发育阶段的差异可能解释了这一时期冒险和冲动决策的相对增加。具体来说，前额皮质眶额区（OFC）已被证明在处理延迟贴现任务中的价值期望中发挥核心作用。延迟折扣任务是一个用于量化冲动性的稳健平移模型，在该模型中，被试在较小的早奖励和较大的晚奖励之间进行选择。相对于较大较晚的奖励，对较小较早奖励的偏好升高表明是冲动选择。尚不清楚不成熟的OFC是否会通过类似的机制来处理决策。最近的证据表明，OFC的多巴胺能神经支配在介导延迟折扣选择和哌醋甲酯药物治疗（MPH； ADHD药物）减少青少年冲动行为方面起着重要作用。因此，本论文研究的目标是评估，在整个生命周期中，OFC如何编码预测奖励可用性和收到即时和延迟奖励的线索。本研究还将描述OFC在青少年延迟折扣行为中的作用。为此，第一个目的将研究青少年和成年期在奖励大小歧视和延迟折扣任务中OFC活动的神经生理变化。第二个目的是在执行延迟折扣任务之前，从药理学上灭活青春期和成年大鼠的OFC，以确定OFC活动是否对MPH对冲动控制的影响是必要的。综合起来，这些方法为冲动行为在整个发展过程中的影响提供了强有力的定量和机制评估。了解在整个发育过程中与抑制控制相关的动态加工对研究人员来说是一个重大挑战，对青少年公共卫生具有总体意义。

DESCRIPTION (provided by applicant): Adolescence is a transitional stage hallmarked by decisions that are increasingly impulsive and consequently dangerous. While an increase in impulsive behavior is normal in this stage of development, failure to inhibit inappropriate behaviors, such as experimentation with alcohol or illicit drugs, can lead to detrimental consequences. Differences in the developmental stage of prefrontal cortical and subcortical systems in adolescents might explain the relative increase in risky and impulsive decisions during this period. Specifically, the orbitofrontal region of prefrontal cortex (OFC) has been shown to play a central role in processing value expectation in a delay discounting task. The delay discounting task is a robust translational model used to quantify impulsivity, in which subjects choose between smaller-sooner and larger-later rewards. Elevated preference for smaller-sooner over larger-later rewards indicates impulsive choice. It is unknown whether an immature OFC will process decisions through similar mechanisms. Recent evidence suggests that dopaminergic innervation of the OFC plays an important role in mediating delay-discounting choices and pharmacological treatment with methylphenidate (MPH; an ADHD medication) decreases impulsive behavior in adolescents. Therefore, the goal of this dissertation research is to assess, across the lifespan, how OFC encodes the cues that predict reward availability and the receipt of immediate and delayed rewards. This proposal will also characterize the role of the OFC in delay discounting performance in adolescence. To this end, the first Aim will investigate the neurophysiological changes in OFC activity during Reward Magnitude Discrimination and Delay Discounting tasks in both adolescence and adulthood. The second Aim will pharmacologically inactivate OFC in adolescent and adult rats prior to performing the Delay Discount task to determine whether OFC activity is necessary for MPH effects on impulse control. Combined, these approaches provide a powerful quantitative and mechanistic assessment of the impact of impulsive behavior across development. Understanding the dynamic processing associated with inhibitory control throughout development represents a significant challenge for researchers, with overarching implications for adolescent public health.