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

尽管神经科学提供了大量关于神经元如何工作的信息，但基本的 神经元如何在网络中共同作用以产生认知的问题一直很难解决。 我们的团队一直处于开发方法的前沿，这些方法允许对已识别的 神经元，用光学手段监测电压信号和阐明树突中的亚细胞事件， 所有这一切现在都可以在清醒状态下的动物身上完成。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纹波(SPW- r)。这一显着的信号已被证明依赖于先前的学习并产生高速重播 存储序列(例如，沿着轨道的路径)。这个信号的功能是巩固记忆； SPW-Rs的中断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是一种 为阐明哺乳动物大脑的细胞/网络机制的第一次重大努力提供了易处理的目标 信号的分析水平可与简单无脊椎动物系统的研究相媲美。 项目1旨在了解控制启动的海马体外和海马体内通路 SPW-R。项目2处理在防止外空军备竞赛期间发生的事件，包括#年活动的时间安排。 识别单元类型并了解内存序列所依据的基本网络体系结构 都被生产出来。项目3涉及如何对在SPW-R期间重放的信息进行编码。我们 将尝试创建人工记忆，然后确定是否在 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期间重播的记忆。项目4建立在最近的工作基础上，表明 差异投射的CA1锥体细胞具有不同的特性，将测试SPW- 不同输出通道中的RS可能携带不同的信息，影响不同的行为。在项目5中，我们 将开发第一个包含信息的海马体非简化计算模型 关于细胞类型和连接。这将是我们团队和研究的主要新资源 这将允许实验和计算之间空前密切的相互作用。发送到 在模型能够解释实验观测的程度上，我们可以用它来理解 基础网络原理和设计干预实验来验证这一理解。发送到 在模型不能解释结果的程度上，它将帮助我们找到需要 进一步澄清。总而言之，项目1-5提供了一条容易处理的道路，在以下方面取得重大突破 理解认知上重要的大脑信号是如何产生的。

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.