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，啮齿动物海马区的神经元在多个时间尺度上表现出顺序活动；这种活动可能代表了要编码并存储在记忆中的事件的神经元基础。当动物处于给定神经元的“位置场”内时，该神经元开始放电，而在位置场外，放电率基本上为零。自从O‘Keefe和Dostrovsky(1)发现它们以来，人们进行了大量的研究，得出了以下观察结果。位置细胞相对于剩余种群的尖峰活动提供了关于动物位置的额外信息通道，特别是与5-12赫兹西塔频率的局部场电位振荡有关的信息。与后一种振荡相关的尖峰阶段开始于theta的峰值，随着动物的前进而减少，最终离开位场。这一“相位进动”显示了海马区细胞间时间协调的显著程度，并可能为每个theta周期内的短暂顺序模式提供基础。当动物休息或睡觉时，这些序列再次被重新激活，无论是以正向顺序还是反向顺序。大量神经元的连续尖峰出现在100-400毫秒的时间窗口内，并伴随着被称为尖波涟漪的网络事件。总而言之，海马区的位场活动导致观察到的时间序列：1)在行为时间尺度上，当动物运行位置场序列时，2)在海马theta振荡的时间尺度上，因为细胞在theta周期中与位置相关的阶段被激发，以及3)在尖锐波涟漪的时间尺度上，当大量神经元以精细的时间结构激发时。这里概述的研究的目标是在一个统一的框架内揭示这些明显不同的序列产生的潜在机制。为此，这项拟议的工作采用了最先进的海马网络计算模型、自由行为和睡眠大鼠CA1和CA3区域的大规模电生理学与CA3在行为和睡眠期间的光遗传沉默的创新组合。

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.