How does neuromodulation shape the fluidity of spatial working memory?

摘要/项目摘要 空间导航需要工作记忆才能灵活更新位置的内部表示 当一个人在世界上行走时，在休息期间也要稳定地记住自己的位置。尽管 工作记忆对广泛的认知过程至关重要，我们目前缺乏基本的 了解工作记忆电路如何平衡灵活性和稳定性之间的基本张力。 这一差距是由三个主要挑战造成的：(1)定义包含内部表示的完整网络 在工作记忆中；(2)因果测试网络在不同网络之间转换的流畅性 表示；以及(3)关于如何在生物物理学中调制转移概率的概念框架 水平。这项建议将通过研究多巴胺如何调节细胞内 一个易于处理的实验系统的内部空间表征：果蝇的中心复合体。 我们已经开发了方法来测量多巴胺能调制如何塑造突触、细胞和网络 基因识别的神经元的动力学，这些神经元编码空间方向。首先，我们将测量多巴胺何时 利用在虚拟现实中行走的苍蝇大脑的全细胞电生理学来调制导航电路。 然后，我们将通过使用光遗传学来探索多巴胺水平如何塑造网络动力学 多巴胺改变了覆盖空间表示的简易性。最后，我们将使用特定单元格类型 多巴胺受体与体内电生理学和钙成像的扰动以确定如何改变 突触和固有属性塑造了网络的流动性。最终目标是生物物理级的描述 神经调节如何塑造在线工作记忆处理。由于口译和翻译的困难， 这些实验扰乱了分布在大型哺乳动物大脑中的种群活动 以前是遥不可及的。通过使用果蝇，我们可以专注于一个紧凑的导航电路，它只由 数百个神经元，具有已知的连通性和无与伦比的遗传通路。尽管有明确的 苍蝇和哺乳动物的差异、多巴胺信号和空间编码特性(头部方向 网络)在物种之间是惊人的保守的。这些相似之处表明，我们在 果蝇将与其他动物的认知过程相关。对工作记忆的机械性理解 流动性对于自上而下设计治疗认知障碍的治疗策略至关重要。

ABSTRACT / PROJECT SUMMARY Spatial navigation requires working memory for the ability to flexibly update an internal representation of position as one moves through the world, yet also stably hold “in mind” one’s position during periods of rest. Despite the critical importance of working memory for a wide range of cognitive processes, we currently lack basic understanding of how working memory circuits balance the fundamental tension between flexibility and stability. This gap is due to three major challenges: (1) defining a complete network that holds internal representations during working memory; (2) the ability to causally test how fluidly networks can transition between distinct representations; and (3) a conceptual framework for how transition probabilities are modulated at a biophysical level. This proposal will overcome these challenges by investigating how dopamine modulates the stability of internal spatial representations in a tractable experimental system: the central complex of the fruit fly, Drosophila. We have developed methods to measure how dopaminergic modulation shapes synaptic, cellular, and network dynamics of genetically identified neurons that code for spatial orientation. First, we will measure when dopamine modulates navigational circuits using whole-cell electrophysiology from the brains of flies walking in virtual reality. Then we will define how dopamine levels shape network dynamics by using optogenetics to explore how dopamine alters the ease of overwriting spatial representations. Finally, we will use cell-type specific perturbations of dopamine receptors with in vivo electrophysiology and calcium imaging to define how changes to synaptic and intrinsic properties shape network fluidity. The ultimate goal is a biophysical-level description of how neuromodulation shapes working memory processing online. Due to the difficulty of interpreting and perturbing population activity that is distributed across large mammalian brains, these experiments have been previously out of reach. By using Drosophila, we can focus on a compact navigational circuit comprised of only a few hundred neurons with known connectivity and unmatched genetic access. Although there are clear differences between flies and mammals, dopamine signaling and spatial coding properties (head direction networks) are strikingly conserved across species. These similarities argue that the principles we discover in the fruit fly will be relevant to cognitive processing in other animals. A mechanistic understanding of working memory fluidity is essential for the top-down design of therapeutic strategies to treat cognitive disorders.