Monoaminergic neuromodulation of cortical circuits underlying economic investment decisions

我们试图做出最有利于我们目标的决定。然而，在复杂的环境中，未来结果的来源和时间都不确定。因此，人类和其他动物必须根据获得积极结果的风险来调整他们对有限资源的投资--无论是时间、努力还是金钱。眶额皮层（OFC）通过计算不确定结果的价值来帮助这些经济投资决策。然而，OFC动态计算价值的机制在很大程度上仍然未知。神经元释放单胺能神经调节剂，如多巴胺和5-羟色胺，向包括眶额皮层在内的许多大脑区域传播价值信号，因此可以做出经济投资决策。然而，它仍然是难以捉摸的（i）多巴胺和5-羟色胺如何控制眶额皮层神经元和网络，从而调整经济投资决策和（ii）如果和如何眶额皮层电路，反过来，通知神经调节中心的价值不确定的结果。我的建议的目标是确定单胺能神经调节剂与皮层网络相互作用的机制，以实现经济投资决策。具体来说，我的研究将解决：（1）什么是支持经济投资决策的OFC网络架构？(2)单胺能神经调节剂如多巴胺和5-羟色胺是如何控制OFC网络来调整经济投资决策的？(3)什么是皮质神经调节反馈机制，通知神经调节信号？我将通过将大鼠中基于模型的行为方法与最先进的光遗传学，电生理学和计算工具相结合来解决这些问题。这将使我们能够记录大量的神经元，同时测量和控制单胺能神经调节剂（如多巴胺和5-羟色胺）的皮质释放，以确定它们对皮质网络的因果影响。此外，逆行病毒策略和光遗传学工具的组合将允许选择性地测量和操纵皮质投射神经元到神经调节中心，从而确定它们对投资决策的因果作用。这些实验将产生新的机制洞察皮层电路架构的经济决策。我的提议将揭示皮层神经元和网络的神经调节控制原理，从而阐明单胺能神经调节在决策中的功能作用。

We attempt to make decisions that best serve our goals. Yet in complex environments, both the source and timing of future outcomes is uncertain. Humans and other animals must therefore adjust their investments of limited resources – whether time, effort, or money – according to the risk in obtaining positive outcomes. Orbitofrontal cortex (OFC) contributes to these economic investment decisions by computing the value of uncertain outcomes. However, the mechanisms by which OFC dynamically computes value remain largely unknown. Neurons releasing monoaminergic neuromodulators such as dopamine and serotonin broadcast value signals to many brain regions including OFC and could therefore enable economic investment decisions. However, it remains elusive (i) how dopamine and serotonin control OFC neurons and networks thereby adjusting economic investment decisions and (ii) if and how OFC circuits, in turn, inform neuromodulatory centers about the value of uncertain outcomes. The goal of my proposal is to determine the mechanisms by which monoaminergic neuromodulators interact with cortical networks to enable economic investment decisions. Specifically, my research will address: (1) what is the network architecture in OFC that supports economic investment decisions? (2) How do monoaminergic neuromodulators such as dopamine and serotonin control OFC networks to adjust economic investment decisions? (3) What are the cortico-neuromodulatory feedback mechanisms that inform neuromodulatory signals? I will address these questions by combining a model-based behavioral approach in rats with state-of-the-art optogenetic, electrophysiological and computational tools. This will allow us to record a large number of neurons and simultaneously measure and control cortical release of monoaminergic neuromodulators such as dopamine and serotonin to determine their causal impact on cortical networks. In addition, a combination of retrograde viral strategies and optogenetic tools will allow to selectively measure and manipulate cortical projection neurons to neuromodulatory centers thereby determining their causal role for investment decisions. These experiments will yield novel mechanistic insight into the cortical circuit architecture for economic decisions. My proposal will reveal principles of neuromodulatory control of cortical neurons and networks that will delineate the functional roles of monoaminergic neuromodulation for decision-making.