Mechanisms of neural circuit dynamics in working memory

 描述（由申请人提供）：工作记忆，暂时保存多条信息进行心理操作的能力，是几乎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。以秒为单位的时间尺度上的证据积累，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试验台。该提案将建立在啮齿动物的证据积累范式，允许定量，时间精确的工作记忆和决策参数化。该范例将通过头部固定的啮齿动物在虚拟现实系统中的行为来实现（目标1），提供机械稳定性，使得能够使用双光子钙成像来观察与新皮层、基底神经节和小脑中的工作记忆相关的神经活动（目标3）。大脑活动也将受到干扰，使用个体发育来探测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，我们将通过相关的系列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，开发用于探测细胞类型和连接在工作记忆中的作用的方法（目的4）。这个为期三年的项目将产生一个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。在随后的几年里，这一目录将通过目标4中开发的解剖学和生理学方法进行机械研究。这个项目的长期目标是达到一个完整的，全脑的理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，这些模型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.