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

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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.