biostudies-literatureSosa MSimons FoundationU.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)Howard Hughes Medical InstituteNIDA NIH HHSNIMH NIH HHSHelen Hay Whitney Foundation (HHWF)U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)U.S. Department of Health & Human Services | NIH | National Institute on Drug AbuseJames S. McDonnell FoundationU.S. Department of Health & Human Services | NIH | National Institute of Mental HealthHoward Hughes Medical Institute (HHMI)James S. McDonnell Foundation (McDonnell Foundation)Vallee Foundation (Bert L. & N. Kuggie Vallee Foundation)U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and StrokeVallee FoundationNINDS NIH HHSHelen Hay Whitney Foundation1497-1509https://www.ebi.ac.uk/biostudies/studies/S-EPMC12229899biostudies-literatureUnknown28(7)To reinforce rewarding behaviors, events leading up to and following rewards must be remembered. Hippocampal place cell activity spans spatial and non-spatial episodes, but whether hippocampal activity encodes entire sequences of events relative to reward is unknown. Here, to test this possibility, we performed two-photon imaging of hippocampal CA1 as mice navigated virtual environments with changing hidden reward locations. We found that when the reward moved, a subpopulation of neurons updated their firing fields to the same relative position with respect to reward, constructing behavioral timescale sequences spanning the entire task. Over learning, this reward-relative representation became more robust as additional neurons were recruited, and changes in reward-relative firing often preNature neuroscienceA flexible hippocampal population code for experience relative to reward.PMC12229899K99MH135993NA542987SPIP50 DA0420121R01MH126904-01A1R01 MH126904R01 MH130452), BRAIN Initiative U19NS118284U19 NS118284R01MH130452K99 MH135993Sosa MPlitt MHGiocomo LMfalseA flexible hippocampal population code for experience relative to reward.To reinforce rewarding behaviors, events leading up to and following rewards must be remembered. Hippocampal place cell activity spans spatial and non-spatial episodes, but whether hippocampal activity encodes entire sequences of events relative to reward is unknown. Here, to test this possibility, we performed two-photon imaging of hippocampal CA1 as mice navigated virtual environments with changing hidden reward locations. We found that when the reward moved, a subpopulation of neurons updated their firing fields to the same relative position with respect to reward, constructing behavioral timescale sequences spanning the entire task. Over learning, this reward-relative representation became more robust as additional neurons were recruited, and changes in reward-relative firing often pre2025-01-01T00:00:00Z2025 Jul2026-03-16T00:44:49.453Z2025-08-15T03:06:39.371ZS-EPMC122298994050031410.1038/s41593-025-01985-4