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，其特点是做出的决定越来越冲动，因此是危险的。虽然冲动行为的增加在发育的这个阶段是正常的，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。青少年前额叶皮质和皮质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相对增加的原因。具体地说，在延迟折扣任务中，前额叶皮质(OFC)的眶前区(OFC)在加工价值预期中起着核心作用。延迟折扣任务是一种稳健的转换模型，用于量化冲动，在该模型中，受试者在较小的-较早或较大-较晚的奖励之间进行选择。对较小--越早越大--较晚回报的偏好上升，表明他们冲动地做出了选择。目前尚不清楚一个不成熟的OFC是否会通过类似的机制处理决策。最近的证据表明，OFC的多巴胺能神经支配在调节延迟折扣选择和哌醋甲酯(一种ADHD药物)的药物治疗减少青少年的冲动行为方面发挥了重要作用。因此，本论文的研究目标是评估在整个生命周期内，OFC是如何编码预测奖励可用性以及即时和延迟奖励接收的线索的。这项建议还将说明OFC在青少年延迟折扣表现方面的作用。为此，第一个目标将研究青春期和成年期在奖励幅度辨别和延迟折扣任务过程中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，对青少年和成年大鼠的OFC进行药物灭活，以确定OFC活动是否对MPH对冲动控制的影响是必要的。这些方法结合在一起，为冲动行为在整个开发过程中的影响提供了强大的量化和机械性评估。对研究人员来说，理解整个发育过程中与抑制控制相关的动态过程是一个重大挑战，这对青少年公共健康具有重要意义。

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.