Circuit-level neurodevelopmental trajectories of decision-making computations across adolescence

Project Summary Adolescence is one of the most critical periods of neurodevelopment. The brain undergoes a profound reorganization during this stage, including the formation and stabilization of neural circuits that control decision- making. We, and others, hypothesize that age-related improvements in decision-making are driven by changes in brain circuits that encode specific decision-making mechanisms. Direct evidence supporting this hypothesis, however, has been limited. The prefrontal cortex in particular undergoes an intense restructuring during adolescence and brain imaging studies have observed robust changes in the orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC). The OFC and ACC are altered in individuals with mental illness, which is thought to be the mechanism underlying decision-making deficits that emerge in these clinical populations. When and how these alterations occur is not known, but emerging evidence suggests developmental changes in subcortical projections to the OFC and ACC may be involved. Here, we propose to use in vivo calcium imaging and optogenetic techniques coupled with computational modeling, to longitudinally assess circuit and neuronal activity in behaving rats at multiple adolescent ages to determine how developmental changes in OFC and ACC networks mediate improvements in decision-making. In Aim 1 we will determine how encoding of attention and reward-prediction errors in amygdala and ventral tegmental area (VTA) projections to the OFC improves across adolescence in rats using a reversal-learning task. We will then use a new transsynaptic tracing approach in Aim 2 to demonstrate that attention and reward prediction errors controlled by amygdala and VTA projections are integrated into OFC neurons to determine the degree to which action values are updated and strengthened during adolescence. Finally, Aim 3 studies will investigate the role of OFC projections to the ACC in integrating value updating with current action value estimates that guide adaptive decision making. Together, these studies will provide key insights into the developmental mechanisms that guide complex decision making. Our normative data will provide a framework for identifying and understanding the neurodevelopmental mechanisms of mental illness, and inspire future translational studies.