Towards a Complete Description of the Circuitry Underlying Sharp Wave-Mediated Memory Replay

全面描述锐波介导的记忆重放背后的电路

• 批准号: 9769888
• 负责人: GYORGY BUZSAKI
• 金额: $ 264.38万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769888
• 关键词: Address; Affect; Animals; Area; Behavior; Behavioral; Brain; Cell Nucleus; Cells; Cognition; Cognitive; Communities; Comorbidity; Computer Simulation; Dendrites; Event; Hippocampus (Brain); Interneurons; Invertebrates; Learning; Medial; Mediating; Memory; Memory Disorders; Methods; Modeling; Molecular; Monitor; Neurons; Neurosciences; Optics; Output; Pathway interactions; Pattern; Play; Positioning Attribute; Process; Property; Pyramidal Cells; Research; Resources; Role; Route; Signal Transduction; Speed; System; Technology; Testing; Work; awake; biophysical model; brain cell; cell type; cognitive function; dentate gyrus; entorhinal cortex; experimental study; granule cell; insight; memory consolidation; nervous system disorder; network architecture; neuropsychiatric disorder; novel strategies; relating to nervous system; segregation; spatial memory; supercomputer; therapy design; voltage; way finding

Although neuroscience has provided a great deal of information about how neurons work, the fundamental question of how neurons function together in a network to produce cognition has been difficult to address. Our group has been at the forefront of developing methods that allow large scale monitoring of identified neurons, monitoring of voltage signals by optical means and elucidation of subcellular events in dendrites, all of which can now be done in awake behaving animals. We propose to use these methods to provide a deep understanding of how the neurons of the hippocampal region generate the sharp-wave ripple (SPW- R). This remarkable signal has been shown to depend on prior learning and to produce high-speed replay of memory sequences (e.g. a path along a track). The function of this signal is memory consolidation; disruption of SPW-Rs results in strong deficits in memory-guided behavior. Because much is known about the hippocampal cell types involved and their network connections, understanding the SPW-R is a tractable target for the first major effort to elucidate the cellular/network mechanism of a mammalian brain signal at an analytical level comparable to that achieved in the study of simple invertebrate systems. Project 1 is aimed at understanding the external and intra-hippocampal pathways that control the initiation of SPW-Rs. Project 2 deals with the events that occur during the SPW-R, including the timing of activity in identified cell types and understanding the fundamental network architecture by which memory sequences are produced. Project 3 deals with how the information that is replayed during the SPW-R is encoded. We will attempt to create an artificial memory and then determine whether the memory is replayed during a SPW-R; we will also interfere with molecular mechanisms of memory storage to determine whether we can erase the memories that are replayed during the SPW-R. Project 4 builds upon recent work indicating that differentially projecting CA1 pyramidal cells have distinct properties and will test the possibility that SPW- Rs in distinct output channels may carry different information and affect different behaviors. In Project 5 we will develop the first non-reduced computational model of the hippocampus, incorporating information about cell types and connections. This will be a major new resource for our group and the research community that will permit unprecedentedly close interplay between experiment and computation. To the extent that the model can account for the experimental observations, we can use it to understand underlying network principles and design interventional experiments to validate this understanding. To the extent that the model cannot explain results, it will help point us to aspects of network function that require further elucidation. Taken together, Projects 1-5 provide a tractable path to a major breakthrough in understanding how a cognitively important brain signal is generated.

尽管神经科学提供了大量关于神经元如何工作的信息，但基本原理 神经元如何在网络中共同发挥作用以产生认知的问题一直难以解决。 我们的团队一直处于开发方法的最前沿，这些方法可以对已识别的物质进行大规模监测 神经元，通过光学手段监测电压信号并阐明树突中的亚细胞事件， 所有这些现在都可以在清醒的动物身上完成。我们建议使用这些方法来提供 深入了解海马区神经元如何产生尖波波纹（SPW- R）。这一非凡的信号已被证明依赖于先前的学习并产生高速重放 记忆序列（例如沿着轨道的路径）。该信号的作用是巩固记忆； SPW-R 的破坏会导致记忆引导行为的严重缺陷。因为很多人都知道 所涉及的海马细胞类型及其网络连接，了解 SPW-R 是 阐明哺乳动物大脑细胞/网络机制的首次重大努力的易处理目标 信号的分析水平与简单无脊椎动物系统研究中达到的水平相当。 项目 1 旨在了解控制启动的外部和海马内通路 SPW-R。项目 2 处理 SPW-R 期间发生的事件，包括活动的时间安排 识别细胞类型并了解记忆序列的基本网络架构 被生产。项目 3 涉及如何对 SPW-R 期间重放的信息进行编码。我们 将尝试创建人工记忆，然后确定该记忆是否在某个过程中重放 SPW-R；我们还将干扰记忆存储的分子机制，以确定我们是否可以 擦除 SPW-R 期间重播的记忆。项目 4 以最近的工作为基础，表明 差异投影 CA1 锥体细胞具有独特的特性，将测试 SPW- 的可能性 不同输出通道中的R可能携带不同的信息并影响不同的行为。在项目5中我们 将开发第一个非简化的海马计算模型，其中包含信息 关于细胞类型和连接。这将成为我们小组和研究的主要新资源 社区将允许实验和计算之间前所未有的密切相互作用。至 模型可以解释实验观察的程度，我们可以用它来理解 底层网络原理并设计介入实验来验证这种理解。至 尽管模型无法解释结果，但它将帮助我们指出网络功能中需要的方面 进一步阐明。总而言之，项目 1-5 为在 了解具有认知意义的重要大脑信号是如何产生的。