Alternating Sequences of Future and Past Behavior Encoded Within Hippocampal Theta Oscillations




Wang, Mengni

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Experience necessarily occurs in a sequence, and adaptive behavior requires the ability to analyze experience, both prospectively and retrospectively. It remains unclear how forward-ordered neural activity can facilitate storage or expression of reverse-ordered sequences, which are observed in ripple-based reverse replay and may underlie human episodic memory retrieval. Specifically, hippocampal function is critical for representation and storage of sequential information during spatial navigation of animals. Pyramidal neurons in the hippocampus have been found to intuitively encode locations in space, and are thus termed "place cells". During active exploration, place cells display "phase precession" relative to the ongoing 4-12 Hz theta rhythm, firing at progressively earlier phases of theta as the rat traverses a cell's place field. Across large populations of place cells, phase precession is hypothesized to produce theta sequences, temporally organized sequences of neural firing which encode short virtual trajectories ahead of the animal. While forward theta sequences during experience help explain prospective memory formation, it is unclear how retrospective evaluation of prior behavior can be consolidated. To understand how reverse-ordered memory arises from forward-ordered behavior, I analyzed an in-vivo electrophysiological dataset in which the simultaneous activity of hundreds of neurons was recorded while rats were engaged in navigational tasks in multiple environments. I observe that during active navigation, hippocampal CA1 place cell ensembles are inherently organized to produce independent forward- and reverse-ordered sequences within each theta oscillation, providing a circuit-level basis for retrospective evaluation and storage during ongoing behavior. The cellular mechanisms underlying the reverse-ordered sweep of the theta sequences is theta phase procession arising in a minority of place cells (bimodal cells) which display two preferred firing phases in theta and preferentially participate in reverse replay during subsequent rest. Independent modulation of the reverse and forward theta sweeps suggests separate upstream circuit inputs, with the reverse theta sequence likely driven by layer III entorhinal cortex. These findings reveal a novel and unexpected aspect of theta-based hippocampal encoding and provide a biological mechanism supporting the expression of reverse-ordered memory.

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