Mechanisms of neural circuit dynamics in working memory

 描述(申请人提供)：工作记忆，一种暂时保存多条信息以进行精神操作的能力，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，如持续性神经活动、活动斜波和活动序列。这些动力学的神经回路机制仍不清楚。这项提议将应用虚拟现实、行为自动监测、活体显微镜、个体发育和神经回路重建等先进技术来解决工作记忆理解中的基本问题。在几秒的时间尺度上积累的证据将被用作研究工作记忆的试验台。秒是一种对决策至关重要的工作记忆。该提案将建立在啮齿动物证据积累范例的基础上，该范例允许对工作记忆和决策进行定量的、时间上精确的参数化。该模式将在虚拟现实系统(目标1)中使用头部固定的啮齿动物来实施，提供机械稳定性，使双光子钙成像能够使用双光子钙成像来观察新皮质、基底节和小脑中与工作记忆相关的神经活动(目标3)。大脑活动也将受到干扰，使用个体发育来探索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，我们将开发方法，通过相关的连续电子显微镜和光学显微镜以及对单个细胞或细胞组的个体发育刺激的群体反应的成像，探索细胞类型和连接性在工作记忆中的作用(目标4)。这个为期三年的项目将制作一份与大脑许多区域的工作记忆相关的神经回路动力学类型的目录。在接下来的几年里，这个目录将用Aim 4中开发的解剖学和生理学方法进行机械研究。这个项目的长期目标是全面、全面地了解与工作记忆相关的活动动力学的细胞和电路机制。这种理解预计将采取新一代模型的形式，该模型包含分布在大脑各区域的认知变量，以及明确表示神经回路动力学的模型。这一成就将是对认知的神经基础进行机械化理解的关键一步。

 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.