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，其特点是越来越冲动，因此危险的决定。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，如酒精或非法药物的实验，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风险和冲动决策的相对增加。具体而言，眶额前额叶皮层（OFC）已被证明在延迟折扣任务中的处理价值期望中发挥核心作用。延迟折扣任务是一个强大的翻译模型，用于量化冲动，其中受试者在较小的奖励和较大的奖励之间进行选择。对小而快的奖励的偏好高于对大而晚的奖励的偏好表明了冲动的选择。不成熟的眶额皮层是否会通过类似的机制来处理决策，这是未知的。最近的证据表明，多巴胺能神经支配的眶额皮层起着重要的作用，在介导延迟折扣的选择和药物治疗哌甲酯（MPH; ADHD药物）减少青少年的冲动行为。因此，本论文的研究目标是评估，在整个生命周期，如何OFC编码的线索，预测奖励的可用性和接收的即时和延迟奖励。该建议还将描述OFC在青春期延迟折扣表现中的作用。为此，第一个目标将调查在青少年和成年期的奖励幅度辨别和延迟折扣任务中OFC活动的神经生理学变化。第二个目标是在执行延迟折扣任务之前，在青少年和成年大鼠中检测OFC，以确定OFC活动是否是MPH对冲动控制的影响所必需的。结合起来，这些方法提供了一个强大的定量和机制评估的影响，冲动行为在整个发展。了解整个发展过程中与抑制控制相关的动态过程对研究人员来说是一个重大挑战，对青少年公共卫生具有重要意义。

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.