Distinct patterns of outcome valuation and amygdala-prefrontal cortex synaptic remodeling in adolescence and adulthood.

Adolescent behavior is typified by increased risk-taking, reward- and novelty-seeking, as well as an augmented need for social and environmental stimulation. This behavioral phenotype may result from alterations in outcome valuation or reward learning. In the present set of experiments, we directly compared adult and adolescent animals on tasks measuring both of these processes. Additionally, we examined developmental differences in dopamine D1-like receptor (D1R), dopamine D2-like receptor (D2R), and polysialylated neural cell adhesion molecule (PSA-NCAM) expression in animals that were trained on an effortful reward valuation task, given that these proteins play an important role in the functional development of the amygdala-prefrontocortical (PFC) circuit and mesocorticolimbic dopamine system. We found that adolescent animals were not different from adults in appetitive associative learning, but exhibited distinct pattern of responses to differences in outcome values, which was paralleled by an enhanced motivation to invest effort to obtain larger rewards. There were no differences in D2 receptor expression, but D1 receptor expression was significantly reduced in the striatum of animals that had experiences with reward learning during adolescence compared to animals that went through the same experiences in adulthood. We observed increased levels of PSA-NCAM expression in both PFC and amygdala of late adolescents compared to adults that were previously trained on an effortful reward valuation task. PSA-NCAM levels in PFC were strongly and positively associated with high effort/reward (HER) choices in adolescents, but not in adult animals. Increased levels of PSA-NCAM expression in adolescents may index increased structural plasticity and represent a neural correlate of a reward sensitive endophenotype

Post-training depletions of basolateral amygdala serotonin fail to disrupt discrimination, retention, or reversal learning.

In goal-directed pursuits, the basolateral amygdala (BLA) is critical in learning about changes in the value of rewards. BLA-lesioned rats show enhanced reversal learning, a task employed to measure the flexibility of response to changes in reward. Similarly, there is a trend for enhanced discrimination learning, suggesting that BLA may modulate formation of stimulus-reward associations. There is a parallel literature on the importance of serotonin (5HT) in new stimulus-reward and reversal learning. Recent postulations implicate 5HT in learning from punishment. Whereas, dopaminergic involvement is critical in behavioral activation and reinforcement, 5HT may be most critical for aversive processing and behavioral inhibition, complementary cognitive processes. Given these findings, a 5HT-mediated mechanism in BLA may mediate the facilitated learning observed previously. The present study investigated the effects of selective 5HT lesions in BLA using 5,7-dihydroxytryptamine (5,7-DHT) vs. infusions of saline (Sham) on discrimination, retention, and deterministic reversal learning. Rats were required to reach an 85% correct pairwise discrimination and single reversal criterion prior to surgery. Postoperatively, rats were then tested on the (1) retention of the pretreatment discrimination pair, (2) discrimination of a novel pair, and (3) reversal learning performance. We found statistically comparable preoperative learning rates between groups, intact postoperative retention, and unaltered novel discrimination and reversal learning in 5,7-DHT rats. These findings suggest that 5HT in BLA is not required for formation and flexible adjustment of new stimulus-reward associations when the strategy to efficiently solve the task has already been learned. Given the complementary role of orbitofrontal cortex in reward learning and its interconnectivity with BLA, these findings add to the list of dissociable mechanisms for BLA and orbitofrontal cortex in reward learning

Solving the Credit Assignment Problem With the Prefrontal Cortex

In naturalistic multi-cue and multi-step learning tasks, where outcomes of behavior are delayed in time, discovering which choices are responsible for rewards can present a challenge, known as the credit assignment problem. In this review, I summarize recent work that highlighted a critical role for the prefrontal cortex (PFC) in assigning credit where it is due in tasks where only a few of the multitude of cues or choices are relevant to the final outcome of behavior. Collectively, these investigations have provided compelling support for specialized roles of the orbitofrontal (OFC), anterior cingulate (ACC), and dorsolateral prefrontal (dlPFC) cortices in contingent learning. However, recent work has similarly revealed shared contributions and emphasized rich and heterogeneous response properties of neurons in these brain regions. Such functional overlap is not surprising given the complexity of reciprocal projections spanning the PFC. In the concluding section, I overview the evidence suggesting that the OFC, ACC and dlPFC communicate extensively, sharing the information about presented options, executed decisions and received rewards, which enables them to assign credit for outcomes to choices on which they are contingent. This account suggests that lesion or inactivation/inhibition experiments targeting a localized PFC subregion will be insufficient to gain a fine-grained understanding of credit assignment during learning and instead poses refined questions for future research, shifting the focus from focal manipulations to experimental techniques targeting cortico-cortical projections

Benefit, Burdens and Brain Correlates of Heightened Reward Sensitivity in Adolescence

Increased exploration, risk-taking and reward-seeking are the hallmarks of adolescence. These and related behaviors prepare the young to transition from the parent’s nest to independent living. Adolescence is also a period of heightened structural and functional brain reorganization, particularly within the mesocorticolimbic dopamine system, frontal cortex, striatum and amygdala - an interconnected network of brain regions that supports reward-directed behavior. The goal of this dissertation to further our understanding of ways in which the adolescent brain interacts with rewards. In Chapter 2, I present the results of a set of experiments demonstrating that adolescent rats do not differ from adults in a simple form of stimulus-reward learning but are willing to invest greater effort to obtain larger rewards. While previous studies have focused on the role of neurodevelopmental changes in the dopamine system and within the striatum in heightened reward seeking in adolescence, our data suggest that synaptic remodeling within the frontal cortex and amygdala may also contribute to enhanced reward sensitivity. Chapter 3 explores the long-term consequences of prescription drug exposure during the adolescent period of heightened reward sensitivity in rats. The data suggest that adolescent exposure to both fluoxetine and methylphenidate impairs learning and cognitive flexibility in adulthood in male rats long after the drug administration has been terminated. Adolescent methylphenidate exposure has the direst consequences, impairing both the initial learning and reversal of reward contingencies. The data also reveal sex differences: while females take longer to learn the task, they are also less vulnerable to the negative effects of drug exposure. In Chapter 5, I compare adult and adolescent humans in their approaches to solving the credit assignment problem (i.e., the problem of discovering which choices are responsible for rewards, introduced in Chapter 4). The data provide preliminary evidence for enhanced contingent credit assignment in adolescence. While adults integrate information about their previous decisions and past outcomes to guide their subsequent choices, adolescents are more narrowly focused on the most recent choice-reward history. In Chapter 6, I discuss the implications of the present work and offer cautious advice on drug abuse prevention and improvements in pedagogical practice

Distinct patterns of outcome valuation and amygdala-prefrontal cortex synaptic remodeling in adolescence and adulthood.

Adolescent behavior is typified by increased risk-taking, reward- and novelty-seeking, as well as an augmented need for social and environmental stimulation. This behavioral phenotype may result from alterations in outcome valuation or reward learning. In the present set of experiments, we directly compared adult and adolescent animals on tasks measuring both of these processes. Additionally, we examined developmental differences in dopamine D1-like receptor (D1R), dopamine D2-like receptor (D2R), and polysialylated neural cell adhesion molecule (PSA-NCAM) expression in animals that were trained on an effortful reward valuation task, given that these proteins play an important role in the functional development of the amygdala-prefrontocortical (PFC) circuit and mesocorticolimbic dopamine system. We found that adolescent animals were not different from adults in appetitive associative learning, but exhibited distinct pattern of responses to differences in outcome values, which was paralleled by an enhanced motivation to invest effort to obtain larger rewards. There were no differences in D2 receptor expression, but D1 receptor expression was significantly reduced in the striatum of animals that had experiences with reward learning during adolescence compared to animals that went through the same experiences in adulthood. We observed increased levels of PSA-NCAM expression in both PFC and amygdala of late adolescents compared to adults that were previously trained on an effortful reward valuation task. PSA-NCAM levels in PFC were strongly and positively associated with high effort/reward (HER) choices in adolescents, but not in adult animals. Increased levels of PSA-NCAM expression in adolescents may index increased structural plasticity and represent a neural correlate of a reward sensitive endophenotype

Complementary contributions of basolateral amygdala and orbitofrontal cortex to value learning under uncertainty.

We make choices based on the values of expected outcomes, informed by previous experience in similar settings. When the outcomes of our decisions consistently violate expectations, new learning is needed to maximize rewards. Yet not every surprising event indicates a meaningful change in the environment. Even when conditions are stable overall, outcomes of a single experience can still be unpredictable due to small fluctuations (i.e., expected uncertainty) in reward or costs. In the present work, we investigate causal contributions of the basolateral amygdala (BLA) and orbitofrontal cortex (OFC) in rats to learning under expected outcome uncertainty in a novel delay-based task that incorporates both predictable fluctuations and directional shifts in outcome values. We demonstrate that OFC is required to accurately represent the distribution of wait times to stabilize choice preferences despite trial-by-trial fluctuations in outcomes, whereas BLA is necessary for the facilitation of learning in response to surprising events