Monoaminergic neuromodulation of cortical circuits underlying economic investment decisions

我们试图做出最符合我们目标的决定。然而，在复杂的环境中，未来结果的来源和时间都是不确定的。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、精力还是金钱。眼眶额叶皮质(OFC)通过计算不确定结果的价值，为这些经济投资决策做出贡献。然而，OFC动态计算价值的机制在很大程度上仍不清楚。释放单胺能神经调节剂的神经元，如多巴胺和5-羟色胺，向包括OFC在内的许多大脑区域广播价值信号，因此可以做出经济投资决策。然而，(I)多巴胺和5-羟色胺如何控制OFC神经元和网络，从而调整经济投资决策，以及(Ii)OFC回路是否以及如何反过来向神经调节中心告知不确定结果的价值，仍是一个令人费解的问题。我的建议的目标是确定单胺能神经调节剂与皮质网络相互作用的机制，以支持经济投资决策。具体地说，我的研究将解决：(1)OFC中支持经济投资决策的网络结构是什么？(2)多巴胺和5-羟色胺等单胺能神经调节剂如何控制OFC网络以调整经济投资决策？(3)通知神经调节信号的皮质神经调节反馈机制是什么？我将通过将大鼠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，同时测量和控制皮质单胺能神经调节剂如多巴胺和5-羟色胺的释放，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工具的组合将允许有选择地测量和操纵皮质投射神经元到神经调节中心，从而确定它们在投资决策中的因果作用。这些实验将产生对大脑皮层电路结构的新的机械洞察，以做出经济决策。我的提案将揭示皮层神经元和网络的神经调节控制原理，这些原理将描绘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.