Disruption of theta-timescale spiking impairs learning but spares hippocampal replay

The ability to rapidly learn and retrieve salient information about new environments is critical for survival. In mammals, the hippocampus plays a crucial role in that learning. Specialized features of hippocampal population coding, including network-level theta oscillatory activity, location-specific firing of principal cells, and reactivation of experience during immobility (replay), have been implicated in rapid storage and retrieval of spatial information. Disruptions of theta and replay jointly, or replay alone, are sufficient to impair learning; however, the specific contribution of theta-associated temporal structure during locomotion remains unknown. In this study, we manipulated hippocampal spiking activity in rats specifically during locomotion by optogenetically activating septal parvalbumin-expressing GABAergic neurons. We developed a closed-loop, theta phase-specific stimulation protocol that reliably reduced theta power shortly after stimulation onset. This manipulation preserved the place codes of individual cells but disrupted the fine temporal structure of endogenous spatio-temporal representations (for example, theta sequences) at the pairwise and population level. Theta disruption during locomotion was also sufficient to cause pronounced deficits in learning the more cognitively challenging component of a spatial alternation task, even though disruption was applied on only [~]66% of trials. Notably, network effects accompanying theta disruption were restricted to locomotor periods; we did not observe changes in replay rate, length, or content during immobility. Together, these results demonstrate the importance of the precise temporal microstructure of locomotion-associated spatial representations in the hippocampus for learning.