Hippocampal sequences span experience relative to rewards

Abstract

Hippocampal place cells fire in sequences that span spatial environments, and remap, or change their preferred firing locations, across different environments. This sequential firing is common to multiple modalities beyond space, suggesting that hippocampal activity can anchor to the most behaviorally relevant or salient aspects of experience. As reward is a highly salient event, we hypothesized that broad sequences of hippocampal activity can likewise become anchored relative to reward. To test this hypothesis, we performed two-photon imaging of calcium activity in hippocampal area CA1 as mice navigated virtual linear environments with multiple changing hidden reward locations. We found that when the reward moved, a subpopulation of cells remapped to the same relative position with respect to reward, including previously undescribed cells with fields distant from reward. These reward-relative cells constructed sequences that spanned the task structure irrespective of spatial stimuli. The density of the reward-relative sequences increased with task experience as additional neurons were recruited to the reward-relative population. In contrast, a largely separate subpopulation of cells maintained a place code relative to the spatial environment. These findings provide insight into how separate hippocampal ensembles may flexibly encode multiple behaviorally salient reference frames, reflecting the structure of the experience.