How does neuromodulation shape the fluidity of spatial working memory?

神经调节如何塑造空间工作记忆的流动性？

• 批准号: 10472347
• 负责人: Yvette E Fisher
• 金额: $ 130.57万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472347
• 关键词: Alzheimer' s Disease; Animals; Attention deficit hyperactivity disorder; Biophysics; Brain; Calcium; Cells; Code; Cognition Disorders; Cognitive; Complex; Disease; Dopamine; Dopamine Receptor; Drosophila genus; Electrophysiology (science); Equilibrium; Genetic; Goals; Head; Image; Knowledge; Liquid substance; Mammals; Measures; Methods; Mind; Neurons; Population; Positioning Attribute; Probability; Property; Psyche structure; Rest; Schizophrenia; Shapes; Short-Term Memory; Signal Transduction; Space Perception; Synapses; System; Testing; Therapeutic; Update; Walking; cell type; cognitive process; design; experimental study; flexibility; fluidity; fly; improved; in vivo; innovation; memory process; neuroregulation; novel strategies; optogenetics; therapy design; virtual reality; way finding

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.

摘要/项目总结 空间导航需要工作记忆来灵活地更新位置的内部表示 当一个人在世界上移动时，在休息期间也要稳定地“记住”自己的位置。尽管 工作记忆对于广泛的认知过程至关重要，我们目前缺乏基本的 理解工作记忆回路如何平衡灵活性和稳定性之间的基本张力。 这一差距是由于三个主要的挑战：（1）定义一个完整的网络，持有内部表示 （2）因果测试网络如何在不同的工作记忆之间流畅地转换的能力; 表示;和（3）一个概念框架，如何过渡概率调制在生物物理 水平这项提案将通过研究多巴胺如何调节神经元的稳定性来克服这些挑战。 一个易处理的实验系统中的内部空间表征：果蝇的中心复合体。 我们已经开发出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，编码空间方向。首先，我们将测量多巴胺 使用在虚拟现实中行走的苍蝇大脑的全细胞电生理学来调节导航电路。 然后，我们将定义多巴胺水平如何塑造网络动态，通过使用光遗传学来探索如何 多巴胺改变了大脑空间表征的容易程度。最后，我们将使用特定于细胞类型的 多巴胺受体的扰动与体内电生理学和钙成像，以确定如何变化 突触和内在属性塑造网络流动性。最终目标是在生物医药学水平上描述 神经调节如何影响在线工作记忆处理。由于翻译的困难， 这些实验扰乱了分布在大型哺乳动物大脑中的种群活动， 以前遥不可及。通过使用果蝇，我们可以专注于一个紧凑的导航电路， 几百个神经元具有已知的连接性和无与伦比的遗传通路。虽然有明确的 果蝇和哺乳动物之间的差异，多巴胺信号和空间编码特性（头部方向 网络）在物种之间是惊人地保守的。这些相似之处表明，我们发现的原则， 果蝇与其他动物的认知过程有关。对工作记忆的机械理解 流动性对于治疗认知障碍的治疗策略的自上而下设计是必不可少的。