Cellular mechanisms for dopaminergic control of learning in prefrontal cortex

描述（由申请人提供）：前额皮质对许多高阶执行功能至关重要，包括决策、注意力和工作记忆。前额叶执行控制和决策功能障碍涉及成瘾的各个方面，包括成瘾的建立、表达和复发。为了做出决定，前额叶皮层需要有关当前感觉和运动状态的信息，这些信息通过远距离皮层内输入传递，以及有关奖励状态的信息，通过多巴胺能输入传递。事实上，多巴胺被假设为皮质内连接的主要调节器，并且对前额叶回路中的联想学习模型至关重要。然而，这种调控是如何在细胞水平上发生的尚不清楚。本研究的目的是确定多巴胺调节前额叶回路皮层内加工的细胞机制，特别关注多巴胺如何调节皮层内突触输入的学习规则。我们将结合电生理学、双光子成像和光遗传学来研究多巴胺能调节机制、它们通过内源性多巴胺信号的募集、它们的时间过程以及药物使用的功能障碍。这项研究的结果将为PFC网络如何正常运作以及如何受到药物使用的挑战提供见解。

DESCRIPTION (provided by applicant): Prefrontal cortex is critical for many high-order executive functions, including decision making, attention, and working memory. Dysfunctions in prefrontal executive control and decision making have been implicated in all aspects of addiction, including addiction establishment, expression, and relapse. To make decisions, prefrontal cortex requires information about current sensory and motor states, conveyed via long-range intracortical inputs, and information about reward states, conveyed via dopaminergic inputs. Indeed, dopamine is hypothesized to be a major regulator of intracortical connectivity, and is critical for models of associative learning in prefrontal circuits. Yet how this regulation occurs at the cellular level is unclear. The objective of this proposal is to identify cellular mechanisms by which dopamine regulates intracortical processing in prefrontal circuits, with particular focus on how dopamine can modulate learning rules at intracortical synaptic inputs. We will use a combination of electrophysiology, 2-photon imaging, and optogenetics to examine dopaminergic regulatory mechanisms, their recruitment by endogenous dopamine signaling, their time course, and dysfunction with drug use. Results of this study will provide insight into how PFC networks function normally and when challenged by drug use.