Mechanisms of neural circuit dynamics in working memory

 描述（由申请人提供）：工作记忆，即暂时保存多条信息以进行心理操作的能力，几乎是所有认知能力的核心。工作记忆与多种神经活动动力学密切相关，例如持续性神经活动、活动斜坡和活动序列。这些动力学的神经回路机制仍不清楚。该提案将应用虚拟现实、行为自动监测、活体显微镜、个体发生和神经回路重建等先进技术来解决工作记忆理解的基本问题。在数秒的时间尺度上积累的证据是一种对决策至关重要的工作记忆，将被用作研究工作记忆的测试平台。该提案将建立在啮齿动物证据积累范式的基础上，该范式允许对工作记忆和决策进行定量、时间精确的参数化。该范例将通过在虚拟现实系统中表现的头部固定啮齿动物来实现（目标 1），提供机械稳定性，从而能够使用双光子钙成像来观察与新皮质、基底神经节和小脑中的工作记忆相关的神经活动（目标 3）。还将利用个体遗传学来扰乱大脑活动，以探究大脑区域和特定细胞类型在记忆形成和稳定中的作用（目标 2）。最后，我们将开发通过相关串行电子显微镜和光学显微镜以及群体对单个细胞或细胞群的个体发育刺激的反应成像来探测细胞类型和连接在工作记忆中的作用的方法（目标4）。这个为期三年的项目将产生与许多大脑区域的工作记忆相关的神经回路动力学类型的目录。在接下来的几年中，该目录将通过目标 4 中开发的解剖学和生理学方法进行机械研究。该项目的长期目标是对与工作记忆相关的活动动力学的细胞和环路机制有一个完整的、全脑的理解。这种理解预计将以新一代模型的形式出现，其中包含分布在大脑区域的认知变量，以及明确表示神经回路动态的模型。这一成就将是对认知神经基础的机械理解迈出的关键一步。

 DESCRIPTION (provided by applicant): Working memory, the ability to temporarily hold multiple pieces of information for mental manipulation, is central to virtually all cognitive abiliies. Working memory has been closely associated with multiple kinds of neural activity dynamics, such as persistent neural activity, activity ramps, and activity sequences. The neural circuit mechanisms of these dynamics remain unclear. This proposal will apply advanced technologies such as virtual reality, automated monitoring of behavior, in vivo microscopy, ontogenetic, and neural circuit reconstruction to solve fundamental problems in the understanding of working memory. The accumulation of evidence over time scales of seconds, a type of working memory critical for decision-making, will be used as a test bed for studying working memory. The proposal will build upon a rodent evidence-accumulation paradigm that allows quantitative, temporally precise parameterization of working memory and decision-making. The paradigm will be implemented with head-fixed rodents behaving in a virtual reality system (Aim 1), providing mechanical stability that enables the use of two-photon calcium imaging to observe neural activity related to working memory in the neocortex, basal ganglia, and cerebellum (Aim 3). Brain activity will also be perturbed using ontogenetic to probe the roles of brain regions and specific cell types in the formation and stabilization of memory (Aim 2). Finally, we will develop methods for probing the roles of cell types and connectivity in working memory through correlative serial electron microscopy and light microscopy as well as imaging of population responses to ontogenetic stimulation of single cells or groups of cells (Aim 4). This three-year project will produce a catalog of the types of neural circuit dynamics that are related to working memory across many brain regions. In subsequent years, this catalog will be mechanistically investigated by the anatomical and physiological methods developed in Aim 4. The long-term goal of this project is to arrive at a complete, brain-wide understanding of the cellular and circut mechanisms of activity dynamics related to working memory. The understanding is expected to take the form of a new generation of models containing cognitive variables distributed across brain regions, as well as models that explicitly represent neural circuit dynamics. This achievement will be a crucial step towards a mechanistic understanding of the neural basis of cognition.