Hippocampal neurons represent events as transferable units of experience

Abstract

The brain codes continuous spatial, temporal and sensory changes in daily experience. Recent studies suggest that the brain also tracks experience as segmented subdivisions (events), but the neural basis for encoding events remains unclear. Here, we designed a maze for mice, composed of four materially indistinguishable lap events, and identify hippocampal CA1 neurons whose activity are modulated not only by spatial location but also lap number. These ‘event-specific rate remapping’ (ESR) cells remain lap-specific even when the maze length is unpredictably altered within trials, which suggests that ESR cells treat lap events as fundamental units. The activity pattern of ESR cells is reused to represent lap events when the maze geometry is altered from square to circle, which suggests that it helps transfer knowledge between experiences. ESR activity is separately manipulable from spatial activity, and may therefore constitute an independent hippocampal code: an ‘event code’ dedicated to organizing experience by events as discrete and transferable units.

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Fig. 1: Experimental design to study the segmentation of experience into units.
Fig. 2: Lap 1, 2, 3 and 4 ESR cells are reliably preserved across days.
Fig. 3: ESR treats events as fundamental units of experience.
Fig. 4: ESR tracks lap events despite changes in maze geometry.
Fig. 5: ESR tracks the relationships between events.
Fig. 6: ESR activity and spatial activity are separately manipulable.
Fig. 7: Discrete ESR activity occurs together with continuous non-spatial activity.

Data availability

The data, reagents and materials that support the findings of this study are available from the corresponding authors upon request.

Code availability

The code that supports the findings of this study is available from the corresponding authors upon request.

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Acknowledgements

We thank M. Wilson, T. Kitamura, J. Z. Young, D. Roy, G. Buzsaki, G. Dragoi, E. Brown, M. Sur, M. Harnett, M. Hasselmo, C. MacDonald, K. Allen, J. Correa, A. Aqrabawi, S. Muralidhar, Q. Ferry, K. Flick, Z. Yang, N. Chen and J. Tao for comments; F. Bushard, C. Twiss, A. Hamalian, C. Ragion, C. Lovett, D. King and Ella Maru Studio for technical assistance; L. Brenner for paper preparation; and the members of Tonegawa Lab for their support. We wish to thank Inscopix, Inc. for scientific collaboration and providing access to the nVoke integrated imaging and optogenetics system. This work was supported by the RIKEN Center for Brain Science, the Howard Hughes Medical Institute, and the JPB Foundation (to S.T.).

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Contributions

C.S. and S.T. designed the study. C.S., W.Y. and S.T. interpreted the data. C.S. and J.M. conducted the surgeries, behavior experiments and computational analyses. C.S., W.Y. and S.T. wrote the paper. All authors discussed and commented on the manuscript.

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Correspondence to Chen Sun or Susumu Tonegawa.

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Extended data

Extended Data Fig. 1 Spatial and Reward properties of CA1 cells on the maze.

a, Left: Summary of mice running in a single session of the standard 4-lap-per-trial task. Mice did not miss a visit into the reward box on any run. Right: Mean run time among trials (n = 14 animals). b, CA1 calcium activity sorted by spatial position and lap number (3506 cells, n = 14 animals). Red label indicates reward box spatial bin, and green label indicates the 100 cm long maze track. Reward box activity during lap 1 (reward eating period) was excluded. c, Characterization of mean spatial properties of CA1 cells active in the lap maze: Left: sparsity, and Right: spatial field size; n = 14 mice. In total, 72% (2509/3506) of CA1 cells from 14 animals were significant place cells. Box and whisker plots display median, 25th and 75th percentiles (box), and maximum and minimum values (whiskers). df, Spatially binned calcium activity along the track (d) 2 example cells that responded to the reward, and (e) One example lap 1, 2, 3, and 4 cell each, and (f) 2 example place cells that did not have lap modulated activity. Top panel: trial-by-trial activity Bottom panel: trial-averaged activity with mean ± SEM. The number of trials for each cell is indicated in each figure panel (df). Standard error was cut off at 0 because negative activity does not exist.

Extended Data Fig. 2 Model correction for Speed and Head direction modulations of CA1 cell activity.

a, The half decay time (the time required for a calcium transient to decay to ½ its maximum height) of 137045 calcium transients across n = 14 animals as they underwent the standard 4-lap task. b, – c, Two example cells with calcium activity level plotted against mean animal running speed (top subpanels), and head direction tuning (bottom subpanels). r denotes Pearson’s correlation. (b) contains 161 nonzero measurements, and (c) contains 54 nonzero measurements of mean calcium activity during the epochs of the experimental session defined in the Methods (subsection “Calcium event filtering”). d, Shuffling procedure preserved the mean calcium activity level as prescribed by the linear model (See Methods) (r denotes Pearson’s correlation. Mean calcium activity measurements taken from 1716479 epochs from all cells recorded during experimental sessions of 14 animals). Epochs are defined in Methods, subsection “Calcium event filtering”.

Extended Data Fig. 3 Robustness of ESR phenomenon to different parameter choices.

a, Analysis procedure with a random quarter of all trials (i.e. 4 to 5 trials) during the standard 4-lap experiment removed, for each mouse. Left: Percentage of previously statistically significant ESR cells that retained their statistical significance (70% = 726/1055 ESR cells, n = 14 mice) compared to previously non-ESR cells that became significant (5% = 131/2451 cells, same animals). Middle and Right: Pearson correlation of ESR activity and spatial activity across days in the standard 4-lap experiment. See Fig. 2(e) for description and methods. (500 cells total). b, ESR correlations between even numbered trials vs odd numbered trials of individual cells, as an indicator for the robustness of ESR patterns between trials. See Fig. 2(e) for description and methods. (611 cells total). c, Standard analysis procedure conducted on the standard 4-lap experiment (see Methods)—albeit with a smaller spatial bin size (6.25 cm x 5 cm). Left: Summary statistics: Percentage of ESR cells in the whole CA1 pyramidal population that were tuned to lap 1, 2, 3, or 4, on a single day in the standard 4-lap experiment (n = 14 animals, 3506 cells). Center and Right: Pearson correlation of ESR activity and spatial activity across days in the standard 4-lap experiment (n = 8 animals, 566 cells). d, The distribution of ESR correlations when cell identities were shuffled across day 1 vs 2 on the standard 4-lap task (n = 8 mice). e, Lap 1, 2, 3, and 4 ESR cells were significantly preserved over days during the standard 4-lap task, even with different thresholds for highly preserved ESR cells. χ2 and p values are shown in the Figure (622 cells total). f, Pearson correlation of ESR activity across days during the standard 4-lap task, calculated using the subpopulation of ESR cells that were active in the main spatial bin during at least 1/2 of all the trials (327 cells total).

Extended Data Fig. 4 ESR is learning dependent and indicates recognition of lap number.

a, Pseudorandom experiment schedule: 20 trials in total where 4 pseudorandomly chosen trials had an extra (5th) lap before reward delivery. b, Mean speed during active periods (defined > 4 cm/s) plotted separately for different lap numbers (left) during standard 4-lap trials (lap 4 vs lap 1: Paired T-test: tstat = 5.48, df = 3, p = 1.2*10-2), and (right) during the unexpected 5-lap trials for the same n = 4 mice (mean ± SD). (One-way ANOVA: F(2,9) = 22.48, p = 0.0003. Tukey-Kramer post-hoc analysis for lap 4 vs lap 1: p = 2.3*10-4, lap 4 vs lap 5: p = 2.9*10-2, lap 1 vs lap 5: p = 1.5*10-2). Blue lines indicate speed of individual mice. c, Experimental schedule for un-trained vs well-trained animals on the standard 4-lap-per-trial task. d, The percentage of significant ESR cells was significantly less during un-trained session (176/1008 cells) comparing with well-trained session in the same mice (335/1168) (χ2 =37.9, p = 7.4*10-10; Blue lines: 5 mice). e, Mean active speed (active periods defined > 4 cm/s) plotted separately for different lap numbers (left) in un-trained animals (lap 4 vs lap 1: Paired T-test: tstat = 2.29, df = 4, p = 0.084), vs (right) the same well-trained animals (n = 5 mice, mean ± SD) (lap 4 vs lap 1: Paired T-test: tstat = 6.42, df = 4, p = 3.0*10-3). Blue lines indicate speed of individual mice. * denotes p < 0.05, ** denotes p < 0.01, *** denotes p < 0.001, N.S. not significant.

Extended Data Fig. 5 Method for image registration across days.

a, Field of view of raw endoscopic image (Top) during day 1 (Left) and day 2 (right) in one example animal. Corresponding locations of cells (Bottom) during the same two sessions, as seen in max projection images after motion correction. Representative of images from n = 4 mice. b, Expanded view of aligned cell locations on day 1 and day 2 from (a). c, Purple: Distances between active cells on Day 1 and their putatively matched cells on Day 2 (650 cells, n = 4 animals). Yellow: Distances between the same cells and their nearest neighbor within Day 1. Plot is cut off at 30µm.

Extended Data Fig. 6 ESR correlation across sessions as calculated using raw ΔF/F activity without model correction.

a, Left: The same single example lap 1, 2, 3, and 4 neurons matched across 2 consecutive test days as Fig. 2a–c, measured by raw ΔF/F calcium activity (i.e. without model correction). Right: ESR correlation across days, calculated using raw ΔF/F activity. The cells here were the same animals and experimental sessions as Fig. 2 above, plotted separately for lap 1, 2, 3 and 4 cell populations (621 cells total). b, – f, ESR correlation of individual cells across sessions, calculated using raw ΔF/F activity, for the (b) fixed maze elongation experiment from Extended Data Fig. 8 (446 cells), (c) random maze elongation experiment from Fig. 3a–f (306 cells), (d) circular maze experiment from Fig. 4 (461 cells), (e) spatial alternation experiment from Extended Data Fig. 10 (371 cells), (f) lap addition experiment from Fig. 5 (378 cells in the first left panel, 58 cells in the second left panel, 41 cells in the two right panels). The cells here were from the same animals and experimental sessions as the corresponding plots in the main Figures, plotted separately for lap 1, 2, 3 and 4 cell populations. (f) right two panels: Box and whisker plots display median, 25th and 75th percentiles (box), and maximum and minimum values (whiskers).

Extended Data Fig. 7 Robustness of ESR preservation across days.

a, ESR correlation analysis of the standard 2-day experiment from Fig. 2(a) above, in which trials during day 2 were separated into even numbered trials, and odd numbered trials. b, ESR correlations between (left) all trials from day 1 and even numbered trials from day 2, and (right) all trials from day 1 and odd numbered trials from day 2, of the standard 2-day 4-lap experiment. See Fig. 2(e) for description and methods. c, Proportion of ESR cells that were highly preserved across sessions (Orange) (ESR correlation > 0.6) in each experiment, compared to shuffles (Grey). ESR correlations were calculated between all trials from session 1 and even numbered trials from session 2 (left), and all trials from session 1 and odd numbered trials from session 2 (right). Note that in the optogenetic inhibition experiment, session 1 refers to light-Off trials, while session 2 refers to light-On trials. Blue dots: shows the proportion of cells for each individual animal, in each experiment. χ2 and p values are shown in the Figure. (c) (left): from left to right: 579, 422, 457, 367, 366, 168, 121 total cells respectively. (c) (right): from left to right: 588, 413, 459, 367, 363, 172, 122 total cells respectively.

Extended Data Fig. 8 ESR is unaffected by temporal and spatial variations within events.

a, Distribution of running time across trials for animal 197 during 18 trials; b, Coefficient of variation \(\left( {\frac{{\upsigma }}{{\mathrm{\mu }}}} \right)\) for running time among trials in n = 14 animals. c, Fixed maze elongation experiment: 4-lap-per-trial task on: Day 1: the standard maze and Day 2: the elongated maze. de, Example lap 1, 2, 3, and 4 preferring neurons matched across standard and elongated maze sessions. f, ESR correlations across standard and elongated maze sessions (448 cells, n = 6 mice). The proportion of cells with highly preserved ESR patterns across days (Pearson’s r > 0.6, shown in the Blue box) was significantly greater compared to shuffles. g, Spatial correlations and ESR correlations across days, during the fixed maze elongation experiment (448 cells). h, 185 out of 448 ESR cells had main spatial field not on the shared unstretched half of the maze. Within these 185 cells, 91 cells had highly preserved (Pearson’s r > 0.6) ESR patterns across days (Orange bar) significantly greater compared to shuffles (Grey bar). Blue dots: shows the proportion of cells for each individual animal. χ2 and p values are shown in the Figure.

Extended Data Fig. 9 ESR during the treadmill period.

a, Distribution of top: animal running speed, and bottom: animal head direction during the maze running portion (purple) versus the treadmill running portion (yellow) of the task, for animal 496 in 20 trials. b, Summary data: comparison of standard deviation of top: animal running speed (Paired T-test: tstat = 19.65, df = 4, p = 4.0 * 10-5), and bottom: animal head direction (Paired T-test: tstat = 9.32, df = 4, p = 7.4 * 10-4) during the maze running portion (purple) versus the treadmill running portion (yellow) of the task, for 5 animals. c, CA1 calcium activity sorted by spatial position and lap number (1222 cells, n = 5 animals).

Extended Data Fig. 10 ESR tracks lap events despite spatial trajectory alternation.

a, Alternation experiment: Day 1: standard 4-lap experiment and Day 2: alternating trajectory experiment. bc, Example lap 1, 2, 3, and 4 preferring neurons, matched across standard and alternating maze sessions. d, ESR correlations across the standard and alternating maze sessions (371 cells, n = 4 mice). The proportion of cells with highly preserved ESR patterns across days (Pearson’s r > 0.6, shown in the Blue box) was significantly greater compared to shuffles. e, Spatial correlations and ESR correlations across days, during the alternation experiment (371 cells). f, 177 cells out of 371 ESR cells had main spatial field not on the shared unstretched half of the maze. Within these 177 cells, 105 cells had highly preserved (Pearson’s r > 0.6) ESR patterns across days (Orange bar) significantly greater compared to shuffles (Grey bar). Blue dots: shows the proportion of cells for each individual animal. χ2 and p values are shown in the Figure.

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Sun, C., Yang, W., Martin, J. et al. Hippocampal neurons represent events as transferable units of experience. Nat Neurosci 23, 651–663 (2020). https://doi.org/10.1038/s41593-020-0614-x

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