The role of orbitofrontal cortex during adolescent decisions

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 reward value 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. Evidence suggests that the OFC dopaminergic system plays an important role in mediating decision-making processes, including delay-discounting choices, and that pharmacological treatment with dopamine agonist, methylphenidate (MPH; an ADHD medication), can alter impulsive behavior in adolescents. Little is known about how altering the dopaminergic system during adolescence might affect OFC-dependent executive function. To this end, the first Aim investigated the neurophysiological changes in OFC activity during Reward Magnitude Discrimination and Delay Discounting tasks in both adolescence and adulthood. We found that there was no difference in rate of reward discrimination learning between adolescent and adult rats. Further, adolescent and adult rats discounted the larger reward similarly, even as the delay to reward progressively increased. Despite the behavioral similarity, reward and temporal processing during decision-making are neurologically different in adolescents compared to adults. The prominent type of neurons observed were responsive after reward delivery. In adolescents, these neurons resembled an immature version of those in adults – qualitatively similar, but quantitatively less discriminative. Adolescent OFC neurons had an overall lower firing rate compared to adults, however they demonstrated more variability in neural activity. We also found that transient OFC responses were not as well developed in adolescents. In adults, these neurons developed choice-dependent phasic responding during Magnitude Discrimination and consistently showed a larger post-reward modulation to LL rewards compared with SS, even when delays were lengthened. On the other hand, Adolescent OFC neurons only begin to display differences in SS and LL activity after the longest delays. Overall, this research provides novel insight into how OFC executes impulse control across development and further suggest that OFC activity during cognitive processing is still not fully mature in late adolescence. The second Aim measured the impact of adolescent MPH on OFC-dependent behaviors both ongoing and after discontinuation of the drug in adulthood. This research further assessed the possible dopaminergic mechanism by which MPH may affect behavior by examining changes in dopamine receptor mRNA expression in animals pre-exposed to MPH. We found that while MPH exposure during late adolescence may alter reward discrimination learning initially at high doses, it did not impact temporal discounting. Long-term, MPH enhanced learning performance and increased mRNA expression of dopamine D3 receptor subtype. However, exposure did not increase risk preference or disrupt behavioral flexibility in adulthood. Overall, these results indicate that MPH can have both immediate and lasting effect on OFC-dependent cognitive performance and dopaminergic function in rodents. Combined, these aims provide a powerful quantitative and mechanistic assessment of the impact of cognitive performance across development. Understanding the dynamic processing associated with choice behavior throughout development represents a significant challenge for researchers, with overarching implications for adolescent mental health.