CRCNS: US-German Proposal: Mechanisms of Sequence Generation in the Hippocampus

项目总结（见说明）： 海马体在情景记忆的形成中是不可或缺的。有趣的是，啮齿动物海马中的神经元在多个时间尺度上表现出连续的活动;这种活动可能代表了要编码和存储在记忆中的情节的神经元基础。当动物处于给定神经元的“位置场”内时，神经元开始发放尖峰，而在位置场之外，发放率基本上为零。自从奥基夫和杜斯特洛夫斯基（1）发现它们以来，大量的研究随之而来，导致了以下观察结果。位置细胞相对于其余群体的尖峰活动提供了关于动物位置的信息的附加通道，特别是关于在5-12 Hz θ频率下的局部场电位的振荡。与后一种振荡相关的尖峰相位开始于θ的峰值，随着动物前进并最终离开位置场而减小。这种“相位进动”表明海马体中细胞之间的时间协调程度显著，并可能为每个θ周期内的简短序列模式提供基础。当动物休息或睡觉时，这些序列再次以正向和反向顺序被重新激活。大量神经元的连续尖峰脉冲发生在100-400 ms的时间窗口内，并伴随着称为尖波波纹的网络事件。总之，海马中的位置场活动导致观察到的时间序列：1）在行为时间尺度上，当动物跑过位置场序列时，2）在海马θ振荡的时间尺度上，当细胞在θ周期中以位置依赖的相位发射时，以及3）在尖波波纹的时间尺度上，当大量神经元以精细的时间结构发射时。本文概述的研究目标是揭示在统一框架内产生这些明显不同序列的机制。为此，所提出的工作采用了海马网络的最先进的计算建模，自由行为和睡眠大鼠的CA 1和CA 3区域中的大规模电生理学，以及行为和睡眠期间CA 3的光遗传学沉默的创新组合。

PROJECT SUMMARY (See instructions): The hippocampus is integral in the formation of episodic memory. Interestingly, neurons in the rodent hippocampus exhibit sequential activity on multiple timescales; such activity may represent the neuronal basis of episodes to be encoded and stored in memory. When the animal is within the "place field" of a given neuron, the neuron begins to spike, while outside of the place field, the firing rate is essentially zero. Since their discovery by O'Keefe and Dostrovsky (1) a wealth of research has followed, resulting in the following observations. The spiking activity of place-cells relative to that of the remaining population provides an additional channel of information regarding the animal's position, particularly in relation to oscillations in the local field potential at the 5-12 Hz theta frequency. The spiking phase relative to this latter oscillation begins at the peak of theta, and decreases as the animal advances and ultimately leaves the place-field. This "phase precession" demonstrates the remarkable degree of temporal coordination between cells in the hippocampus and may provide the basis for brief sequential patterns within each cycle of theta. These sequences are again reactivated when the animal is resting or sleeping, both in the forward and reverse order. The sequential spiking of large populations of neurons occur within a 100-400 ms time-window and are accompanied by network events called sharp-wave ripples. In summary, place-field activity in the hippocampus results in temporal sequences observed: 1) at the behavioral timescale, as animals run through sequences of place fields, 2) at the timescale of hippocampal theta oscillations, as cells fire with location-dependent phases in a theta cycle, and 3) at the timescale of sharp-wave ripples, when large populations of neurons fire with fine temporal structure. The goal of the research outlined here is to uncover the mechanisms underlying the generation of these apparently different sequences within a unified framework. To this end the proposed work employs an innovative combination of state-of-the-art computational modeling of the hippocampal network, large-scale electrophysiology in the CA 1 and CA3 regions of freely-behaving and sleeping rats, with optogenetic silencing of CA3 during behavior and sleep.