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.

尽管神经科学已经提供了大量关于神经元如何工作的信息，但神经元的基本功能仍然是神经元的功能。 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，这些方法可以大规模监测已识别的 神经元，通过光学手段监测电压信号和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一个 深入了解海马区神经元如何产生尖波涟漪（SPW）， R）。这一显著的信号已被证明依赖于先前的学习，并产生高速重放 存储器序列（例如，沿着轨道的路径沿着）。这个信号的功能是记忆巩固; SPW-R的破坏导致记忆引导行为的严重缺陷。因为我们知道 参与的海马细胞类型及其网络连接，了解SPW-R是一个 第一个主要努力阐明哺乳动物大脑的细胞/网络机制的易处理的目标 在分析水平上的信号与在简单无脊椎动物系统的研究中获得的信号相当。 项目1旨在了解控制启动的外部和海马内通路 的SPW-R。项目2涉及在《战略和工作计划》-恢复期间发生的事件， 识别细胞类型并理解记忆序列的基本网络结构 是生产出来的。项目3处理如何在SPW-R期间重放的信息被编码。我们 将尝试创建一个人工记忆，然后确定是否在一个 我们还将干扰记忆存储的分子机制，以确定我们是否可以 擦除在SPW-R期间重放的记忆。项目4以最近的工作为基础， 差异投射的CA 1锥体细胞具有不同的特性，并将测试SPW- 不同输出通道中的Rs可能携带不同的信息并影响不同的行为。在项目5中， 将开发第一个海马体的非简化计算模型， 关于细胞类型和连接。这将是我们小组和研究的一个主要新资源 这个社区将允许实验和计算之间前所未有的密切相互作用。到 只要模型能解释实验观察结果，我们就可以用它来理解 基本的网络原理，并设计干预实验来验证这种理解。到 尽管该模型无法解释结果，但它将帮助我们了解网络功能的各个方面， 进一步说明。综合起来，项目1-5提供了一个易于处理的途径，以实现重大突破， 了解一个重要的认知大脑信号是如何产生的。