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

项目摘要 青春期是神经发育最关键的时期之一。大脑经历了一场深刻的 这一阶段的重组，包括控制决策的神经回路的形成和稳定。 制作。我们和其他人假设，与年龄相关的决策改进是由变化驱动的 在编码特定决策机制的大脑回路中。支持这一假设的直接证据， 然而，这一点一直受到限制。尤其是前额叶皮质，在 青春期和脑成像研究观察到眼眶额叶皮质(OFC)和 前扣带回皮质(ACC)。OFC和ACC在患有精神疾病的人身上发生了变化，这被认为是 这是在这些临床人群中出现决策缺陷的潜在机制。何时和 这些变化是如何发生的尚不清楚，但新出现的证据表明，皮质下的发育变化 可能涉及对OFC和ACC的预测。在这里，我们建议使用体内钙成像和 光遗传技术与计算建模相结合，纵向评估电路和神经元 不同青春期行为大鼠的活动以确定OFC和Acc的发育变化 网络促成了决策的改进。在目标1中，我们将确定注意的编码和 杏仁核和腹侧被盖区(VTA)投射到OFC的奖赏预测误差 使用反转学习任务的大鼠青春期。然后我们将在AIM中使用一种新的跨突触跟踪方法 2证明杏仁核和VTA投射控制的注意力和奖赏预测误差是 整合到OFC神经元中，以确定动作值更新和加强的程度 在青春期。最后，目标3研究将调查OFC对行政协调会的预测在整合过程中的作用 用当前行动价值估计进行价值更新，以指导适应性决策。总而言之，这些研究 将为指导复杂决策的发展机制提供关键见解。我们的规范 数据将为识别和理解心理疾病的神经发育机制提供一个框架。 疾病，并启发未来的翻译研究。

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.