CRCNS: Network Mechanisms Underlying Episodic Memory

描述(由申请人提供)：智力价值：尽管在理解情节记忆是如何存储在大脑中的方面已经取得了相当大的进步，但基本的问题仍然存在。我们将使用实验和计算相结合的方法来研究两个主要问题。目的1：海马体中序列回忆的网络机制：我们回忆一系列事件的能力是情节记忆的核心组成部分。海马体是情景记忆所必需的，来自该结构的电生理记录已经开始揭示其中的一些过程。在老鼠经历了一条空间路径后，它会在被称为尖波的短暂事件中回忆起沿这条路径的位置序列。最近的实验表明，这些波是巩固记忆所必需的。尖锐波是在海马区内产生的，但产生它们的特定海马亚区尚不清楚。根据一种假设，CA3单独产生尖锐的波。另一种假说(乒乓球假说)假设尖锐的波是由齿状回(DG)和CA3共同作用产生的。这一假说起源于Sompolinsky和Kleinfeld的工作，他们认为序列回忆中的每个循环需要两个子步骤：a)链接子步骤，其中代表一个项目的细胞刺激代表序列中下一个项目的细胞；b)自动关联子步骤，纠正每个链接步骤中产生的微小错误，从而避免串联错误。利斯曼提出了如何将其映射到海马电路：代表序列中第n项的CA3细胞激发DG中的n+1项(通过已知的反向投影)；然后，DG中的n+1项被发送到CA3进行纠错(模式完成)。这进而启动了下一个周期的TE。为了区分乒乓球假说和单独CA3假说，J.Leutgeb将同时记录来自Dentate和CA3的数据。她将确定齿状细胞和CA3细胞是否都在尖锐的波中激发，以及它们是否像乒乓球过程中预期的那样，在不同的伽马振荡阶段激发。为了测试CA3中准确的序列回忆是否需要齿状突起，Leutgeb将使用光遗传学方法。如果需要齿状突起，准确的序列回忆应该被人为地在齿状突起中诱导活动或通过 阻断齿状体内的活动。数据分析将在利斯曼实验室进行。目的2：海马体中的神经编码：两个关键实验为空间和感觉信息在海马体中如何编码提供了洞察力。O‘Keefe表明，一个序列中的不同空间位置代表在theta循环的不同阶段。莫泽实验室证明，感觉信息是通过“速率重新映射”来编码的：与一个位置相关的感觉信息是通过编码该位置的位置细胞的放电速率的变化来编码的。目前尚不清楚这些主要想法是否兼容：在速率重新映射过程中增加的尖峰数量可能会抹黑theta阶段，从而危及阶段编码。为了确定情况是否如此，利斯曼将分析Leutgeb将获得的现有数据集和新数据集。我们的工作假设是，速率重新映射增加了短脉冲中的尖峰数量；由于短脉冲中的尖峰具有几乎相同的theta阶段，因此相位编码不会显著退化。 更广泛的影响：了解记忆是神经科学的一个主要目标，因为在老龄化人口中记忆问题的发生率越来越高。这项拟议的实验将确定构成情节记忆基础的神经回路的一个关键组成部分。这可能使更有针对性的治疗策略成为可能。第二个贡献将是神经科学、伦理学和生存(脊椎)夏季项目的一份MatLab教程。这是一门由NIMH赞助的课程，旨在帮助来自代表性不足的少数群体和弱势群体的研究生和博士后发展知识和技能。利斯曼和勒特格布将讲授情节记忆的主要进展，并描述计算在这一努力中的重要性。接下来是为期一个月的关于计算平台matlab的教程。

DESCRIPTION (provided by applicant): Intellectual Merit: Although considerable progress has been made in understanding how episodic memory is stored in the brain, fundamental questions remain. We will use a combination of experimental and computational approaches to study two major questions. Aim 1: Network mechanisms of sequence recall in the hippocampus: Our ability to recall a sequence of events is a core component of episodic memory. The hippocampus is necessary for episodic memory, and electrophysiological recordings from this structure have begun to reveal some of the processes involved. After a rat experiences a spatial path, it recalls sequences of places along that path during brief events called sharp waves. Recent experiments show that these waves are necessary for memory consolidation. Sharp waves are generated intrahippocampally, but the specific hippocampal subregions that produce them are not known. According to one hypothesis, CA3 alone generates the sharp wave. Another hypothesis (the ping-pong hypothesis) posits that sharp waves are generated by the combined action of the dentate gyrus (DG) and CA3.This hypothesis has its origins in the work of Sompolinsky and Kleinfeld, who argued that each cycle in sequence recall requires two substeps: a) a chaining substep in which cells representing one item stimulate the cells representing the next item in the sequence and b) an autoassociative substep that corrects minor errors produced in each chaining step, thereby avoiding concatenation of error. Lisman proposed how this could be mapped onto hippocampal circuitry: CA3 cells that represent the nth item in the sequence excite the n+1 item in the DG (by the known backprojections); then, the n+1 item in DG is sent to CA3 for error correction (pattern completion). This, in turn, initiates te next cycle. To distinguish between the ping-pong and CA3-alone hypotheses, J. Leutgeb will record simultaneously from dentate and CA3. She will determine whether both dentate and CA3 cells fire during sharp waves and whether they fire at a different phase of gamma oscillations, as would be expected from a ping-pong process. To test whether accurate sequence recall in CA3 requires the dentate, Leutgeb will use optogenetic methods. If the dentate is required, accurate sequence recall should be disrupted by artificially inducing activity in the dentate or by blocking activity in the dentate. The data analysis will be done in the Lisman laboratory. Aim 2: Neural coding in the hippocampus: Two key experiments have provided insight into how spatial and sensory information are encoded in the hippocampus. O'Keefe showed that different spatial positions in a sequence are represented in different phases of a theta cycle. The Moser lab demonstrated that sensory information is encoded by "rate remapping": sensory information associated with a place is encoded by a change in the firing RATE of the place cells that encode that position. It is unclear whether these major ideas are compatible: the increased number of spikes during rate remapping might smear theta phase and thereby compromise phase coding. To determine whether this is the case, Lisman will analyze an existing data set and a new data set to be obtained by Leutgeb. Our working hypothesis is that rate remapping increases the number of spikes in a brief burst; since the spikes in a burst have nearly the same theta phase, phase coding would not be significantly degraded. Broader Impact: Understanding memory is a major goal of neuroscience because of the increasing incidence of memory problems in an aging population. The proposed experiment will identify a key component of the neural circuitry that underlies episodic memory. This may enable more targeted therapeutic strategies. A second contribution will be a MATLAB tutorial for the Summer Program in Neuroscience, Ethics and Survival (SPINES). This is an NIMH-sponsored course aimed at helping grad students and postdocs from under-represented minority and disadvantaged groups to develop knowledge and skills. Lisman and Leutgeb will lecture on major advances in episodic memory and describe how computation is important in this endeavor. This will be followed by a one-month tutorial on the computational platform MATLAB.