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Hippocampal CA2 sharp-wave ripples reactivate and promote social memory

Abstract

The consolidation of spatial memory depends on the reactivation (‘replay’) of hippocampal place cells that were active during recent behaviour. Such reactivation is observed during sharp-wave ripples (SWRs)—synchronous oscillatory electrical events that occur during non-rapid-eye-movement (non-REM) sleep1,2,3,4,5,6,7,8 and whose disruption impairs spatial memory3,5,6,8. Although the hippocampus also encodes a wide range of non-spatial forms of declarative memory, it is not yet known whether SWRs are necessary for such memories. Moreover, although SWRs can arise from either the CA3 or the CA2 region of the hippocampus7,9, the relative importance of SWRs from these regions for memory consolidation is unknown. Here we examine the role of SWRs during the consolidation of social memory—the ability of an animal to recognize and remember a member of the same species—focusing on CA2 because of its essential role in social memory10,11,12. We find that ensembles of CA2 pyramidal neurons that are active during social exploration of previously unknown conspecifics are reactivated during SWRs. Notably, disruption or enhancement of CA2 SWRs suppresses or prolongs social memory, respectively. Thus, SWR-mediated reactivation of hippocampal firing related to recent experience appears to be a general mechanism for binding spatial, temporal and sensory information into high-order memory representations, including social memory.

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Fig. 1: Encoding of conspecifics by activity of CA2 pyramidal cells.
Fig. 2: Effect of SWR disruption on social-memory consolidation.
Fig. 3: Reactivation during sleep of cell ensembles that were active during prior social learning.
Fig. 4: Effect of optogenetic generation of ripples on social-memory recall.

Data availability

Data sets and analytical tools included in this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank G. Buzsaki for comments and resource sharing; members of the Siegelbaum laboratory for comments and discussions on the manuscript; and T. Meira for help with designing the behavioural paradigm. This work was supported by the NVIDIA Corporation, an EMBO Postdoctoral Fellowship (ALTF 120-2017) and a K99 grant from the US National Institutes of Health (NIH; K99MH122582) (to A.O.); a Sir Henry Wellcome Postdoctoral Fellowship and K99 grant (K99MH120343) (to A.F.-R.); a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator award from the Brain and Behavior Foundation founded by the Osterhaus family (to F.L.); and grants MH-104602 and MH-106629 from the National Institute of Mental Health (NIMH) and a grant from the Zegar Family Foundation (to S.A.S.).

Author information

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Authors

Contributions

A.O. and S.A.S. conceptualized the research; A.O. carried out experiments and data collection; A.O and A.F.-R. analysed data; F.L. carried out immunohistochemistry; A.O. wrote the original draft of the manuscript; A.O. and S.A.S. reviewed and edited the manuscript; A.O., A.F.-R and F.L. created figures; S.A.S. supervised the research and acquired funding.

Corresponding authors

Correspondence to Azahara Oliva or Steven A. Siegelbaum.

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Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature thanks Shigeyoshi Fujisawa, Torkel Hafting and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 Behavioural features during a social-memory task.

a, Representative animal trajectories during the task show greater time spent around the novel animal (red) in the test (recall) trial. b, Example video frame showing pose estimation calculated with DeepLabCut (colour markers). Interaction zones were defined as 10 cm by 10 cm squares (dotted lines) in the two corners in which the cups were located. c, The average speed of the animals was not different among trials (F(2) = 0.92, P > 0.05; one-way ANOVA). d, The average speed inside interaction zones around S1 (left plot), S2 or a novel mouse (middle plot) did not differ among trials (F(2) = 3.14, P > 0.05; one-way ANOVA). The average speed did not differ outside interaction zones (F(2) = 1.58, P > 0.05; one-way ANOVA). e, The left plot shows the total time spent inside the interaction zone around S1, S2 or a novel mouse. The total time spent interacting with a novel mouse during the recall trial was greater than with either familiar mouse in any other trial (P < 0.01 for novel versus S1 interaction during third trial and P < 0.05 for novel versus S1 interaction during all of the other trials; two-way ANOVA mouse × trial followed by Tukey’s post hoc test for multiple comparisons). The right plot shows that the total time spent outside interaction zones was not different between trials (F(2) = 0.58, P > 0.05; one-way ANOVA). **P < 0.01, *P < 0.05, rank-sum test; n.s., not significant.

Extended Data Fig. 2 Multiregion electrophysiological recordings.

a, Representative histology showing electrode tracks spanning the CA1, CA2 and CA3 areas, with optical fibre over the CA2 pyramidal layer. Blue, DAPI staining. b, ChR2–GFP expression in CA2. Blue, DAPI; green, GFP; pink, PCP4. c, Silicon probe with 100-μm optic fibre glued to one electrode shank, mounted in a movable microdrive to allow for precise localization of the target area. d, Representative sample recordings of LFPs (one trace per electrode) and single units (coloured lines show spikes) in several regions of the hippocampus. Each column represents one electrode shank. The approximate location of pyramidal and granular layers is depicted in the superimposed outline of the hippocampus. e, Average firing responses of single cells from different regions aligned to SWRs detected in CA1 (‘CA1 SPW-Rs’). Note that CA2 cells fired before CA1 and CA3, and that a subpopulation of CA2 units (‘CA2 ramping’) became silent upon SWR onset. f, As in e, but with firing responses aligned to ripples detected in CA2. Note that CA2 cells are strongly activated during CA2 ripples. These results replicate a previous study of rats9.

Extended Data Fig. 3 Classification of single-cell responses during a social-memory task.

a, Examples of simultaneously recorded place cells from CA1 and CA2 regions in one mouse. Each row shows the firing map of one cell; firing maps for trial 1, trial 2 and the memory test (recall) session are shown in each column. Coloured circles represent different stimulus mice. b, Another example of simultaneously recorded place cells, from CA2 and CA3 in a second mouse.

Extended Data Fig. 4 Classification of single-cell responses during a social-memory task.

a, Top, the unrotated correlation was computed as the averaged pixel-wise correlation of the firing maps from trials 1 and 2. Bottom, the rotated correlation was calculated after rotating the map for trial 2 by 180°. b, K-means clustering of unrotated and rotated spatial correlation values for all cells resulted in five clusters (different colours). One cluster (blue) had high unrotated and negative rotated correlations, and are termed social-invariant cells. Another cluster (red) had high rotated and negative unrotated correlation, and are termed social-remapping cells. The other clusters (light grey, dark grey and black) had more similar values for the two correlations. Squares denote CA1, circles CA2 and triangles CA3 pyramidal cells. c, Proportion of CA1, CA2 and CA3 cells from each of the five clusters, colour-coded as in b. d, Distribution of unrotated (empty) and rotated (filled) correlation values between trial 1 and trial 2 for cells in all five clusters. ***P < 0.001, rank-sum test. e, Distribution of unrotated (empty) and rotated (filled) correlation values between the learning trial and recall trial for cells in all five clusters. *P < 0.05, ***P < 0.001; rank-sum test. Correlation performed between the recall trial and that learning trial in which the position of the familiar mouse was in the opposite location. f, Distance from the centre of mass of the place field to the nearest cup for cells in all clusters (F(4,677) = 27.34, P < 4.6 × 10−21; one-way ANOVA). Social-remapping cells had place fields closer to the cups (P < 0.002; Tukey’s post hoc test). g, Place field sizes for cells in all clusters were similar (F(4,677) = 0.39, P > 0.05; one-way ANOVA). h, The number of place fields per cell was similar for all clusters (F(4,677) = 0.68, P > 0.05; one-way ANOVA). i, The fraction of social-remapping cells with place fields next to mouse S1, mouse S2 and other locations.

Extended Data Fig. 5 Place-cell properties of social-invariant and social-remapping cells across regions during the social-discrimination task.

ae, Place-cell properties for CA1, CA2 and CA3 social-invariant and social-remapping cells. a, Peak firing rate; b, place field size; c, spatial information in bits per spike; d, spatial selectivity index; e, number of place fields per cell. f, Whole-session average firing rate for social-remapping and social-invariant cells from the different subregions. g, Fraction of cells with 1, 2 or more place fields in the different regions. h, Theta firing phase distribution (firing probability per bin of phases) for social-remapping, social-invariant and other cells from different regions. Rayleigh’s test was used against the null hypothesis (see Methods). i, Mean vector length of a cell’s firing (‘modulation strength’) during theta oscillations for CA1, CA2 and CA3 pyramidal cells. j, Average firing rate for CA1, CA2 and CA3 cells during immobility and running (at a velocity greater than 5 cm s−1) periods during the task. *P < 0.05, **P < 0.01; rank-sum test. k, Representative examples of CA1, CA2 and CA3 cell firing rate (shown as distance from origin) as a function of head direction. l, Distributions of P-values show a similar lack of head direction tuning for social-remapping, social-invariant and other cells in CA1, CA2 and CA3 regions. Dashed line, P = 0.05. m, Proportions of social-invariant, social-remapping and other cells that were significantly modulated by head direction (P < 0.05) per region.

Extended Data Fig. 6 Object-recognition task: single-cell responses, optogenetic manipulations and reactivation properties per region.

a, Schema of the task. The behavioural paradigm used to assess social memory was also used to assess object-recognition memory. Two previously unseen objects (O1 and O2) were presented for 5 min in the first trial; the position of the objects was then swapped in a second trial of another 5 min. After a home-cage period of 1 h, a memory-recall test trial was performed with one of the previous objects and one novel object (N). b, Performance of the discrimination index for animals in the test trial, for wild-type (WT) mice (where the discrimination index was significantly greater than 0; P < 0.001, t-test; n = 10 sessions with 4 animals), mice with CA2 silenced in trials 1 and 2 during the interaction with the specific object presented again in the recall trial (discrimination index significantly greater than 0; P < 0.05, t-test; n = 10 sessions in 10 animals), and mice with CA1 silenced in trials 1 and 2 during interaction with the specific object presented again in the recall trial (discrimination index not significantly different from 0; P > 0.05, t-test; n = 10 sessions in 10 animals). c, Examples of firing maps for two CA2 cells (green and blue) in the object memory task. The first cell had a stable place field in the two learning and test trials, while the second remapped to follow the position of one object. d, K-means clustering of unrotated and rotated spatial correlation values for all cells. The red cluster corresponds to a subset of cells (‘object-remapping cells’) with high rotated and negative unrotated correlation, analogous to social-remapping cells. Squares denote CA1, circles CA2 and triangles CA3 pyramidal cells. e, Distribution of unrotated (empty) and rotated (filled) correlation values for the two clusters of cells in d. ***P < 0.001; rank-sum test. f, Proportion of CA1, CA2 and CA3 cells from each of the two clusters in d. g, Proportion of object-remapping and social-remapping cells in CA1, CA2 and CA3. **P < 0.01; Fisher’s exact test.

Extended Data Fig. 7 Effect of optogenetic disruption of SWRs on firing rates and field potentials, and reactivation of hippocampal cells during SWRs.

a, The closed-loop SWR truncation system: two signals (for real positive events—‘ripple band’—and noise) are extracted from the recording board and filtered in the ripple band (100–300 Hz); a waveform rectifier and a low-pass filter are applied (using a CED 1401 device); upon detection of a positive event (real positive event = 1 and noise = 0), two current sources are triggered and light is delivered bilaterally through the optic fibres connected to the animal. b, Estimation of detection performance. Left graph, a subsample of events detected by our on-line system in three sessions (n = 1,000) was validated by ground truth (offline detected events); the plot shows percentage of true positives (SWR) versus false positives (no-SWR). Right graph, a subsample of true events (detected offline) in three sessions (n = 1,000) were cross-validated with our online detector to quantify the percentage of events detected (SWRs disrupted) and missed. c, CA1, CA2 and CA3 LFP patterns during CA2 SWR disruption. d, CA1, CA2 and CA3 average firing responses to normal and truncated SWRs show strong suppression of firing after stimulation with light (blue bar) (n = 53, 148, 87 CA1, CA2, CA3 cells; P < 10−6, 9.7 × 10−7, 1.14 × 10−8, respectively; rank-sign test). e, The firing of CA2 pyramidal cells was suppressed by brief yellow-light pulses (yellow rectangle) in Amigo2–Cre animals expressing AAV2/5 EF1a.DIO.eArch3.0–eYFP in CA2. Curves show mean and s.e.m. (n = 58, P < 0.03; rank-sign test). f, Example session in which 30-s pulses of yellow light (yellow bars) were delivered once every two minutes to the CA2 region of Amigo2–Cre mice expressing eArch3.0. The black trace shows ripple-band (100–300 Hz) power in the CA1 pyramidal layer, and magenta traces shows detected SWRs. Note the suppression of CA1 SWRs during illumination. g, Example session showing the decreased rate of CA2 SWRs owing to photoactivation of eArch3.0 (P < 0.0246; Wilcoxon’s rank-sum test). The yellow dashed line shows the period of light stimulation, and the black and blue traces show SWR rate before and during the period of photostimulation, respectively. h, Social-memory recall was suppressed following CA2 silencing by yellow-light pulses (30 s, once every 2 min) during the post-sleep period in Amigo2–Cre mice injected with AAV–DIO–eArch3.0 (n = 9; discrimination index not significantly different from 0; P > 0.05, t-test), whereas social memory was present in Cre littermate controls injected with the same virus and receiving the same light pulses (n = 8; discrimination index differed significantly from 0; P < 0.01).

Extended Data Fig. 8 Reactivation of hippocampal cells during SWRs following social learning.

a, Firing-rate correlation matrices for an example session (all cell pairs) during pre-sleep, learning trials and post-sleep sessions. The colour bar shows colour-coded r values. Note the increase in post-sleep coactivation in some cell pairs that were coactive during the task (red arrow). b, (EV – REV) measure of post-sleep reactivation of correlated firing during learning trials in control sessions (‘no manipulation’), sessions with optogenetic SWR disruption, and sessions with random optogenetic stimulation. Significant reactivation was observed in CA1 and CA2 control sessions (P = 0.03 and 0.0028, respectively; Wilcoxon’s rank-sum test) or following random stimulation (P = 0.008 and 0.04 for CA1 and CA2, respectively, Wilcoxon’s rank-sum test). There was no significant reactivation in CA1 or CA2 with SWR disruption. CA3 failed to show significant reactivation in any session (P > 0.05). c, d, Significant reactivation (EV – REV) was observed in CA1 (P < 0.05, t-test) and CA2 (P < 0.01) during the entire slow-wave sleep period (c) but not the REM sleep period (P > 0.05, t-test) (d). e, EV and REV for a subsample of approximately the same number of cells for different regions (CA1, n = 73; CA2, n = 69; CA3, n = 67). f, Cells from CA1 and CA2 that contributed the most to the total explained variance (first quartile) had a significantly higher rotated spatial correlation (social-remapping) than the rest of the cells (P = 0.0354 and P = 0.0223 for CA1 and CA2 respectively; P > 0.05 for CA3; Wilcoxon’s rank-signed test). gi, Average peri-SWR firing-rate responses for social-remapping and social-invariant cells from CA1 (g), CA2 (h) and CA3 (i) region in pre- and post-sleep. Note that social-remapping cells show higher SWR firing rates in post-sleep but not pre-sleep sessions (CA1, n = 151, P = 0.0055; CA2, n = 306, P = 0.016; CA3, n = 79, P > 0.05).

Extended Data Fig. 9 Strength of assembly activity during the social-memory discrimination task.

a, Distribution of assembly social-gain values from different regions. Assembly social gain is defined as the mean assembly strength during exploration within the interaction zone, divided by the mean assembly strength during exploration outside the interaction zone. Social gain was significantly greater than 1 for CA1 (P < 10−6; rank-sign and CA2 (P < 10−19) but not CA3 (P > 0.05). b, The left pair of bars shows socially related assembly strength ((assembly strength inside social interaction zone minus strength outside social interaction zone)/(sum of strengths)) for social-discriminant and non-discriminant assemblies (P < 10−3; rank-sum test). The right pair of bars shows that the normalized social-discrimination assembly strength (the difference between assembly strength during interaction with the preferred mouse minus the strength during the interaction with the other mouse, divided by the sum of these two strengths) was greater for discriminant compared with non-discriminant assemblies (P < 10−8). c, Discriminant assemblies were reactivated during the recall trial significantly more strongly than non-discriminant assemblies (P = 0.0421). df, Average peri-SWR activation of discriminant and non-discriminant assemblies in different hippocampal regions is shown for: d, CA1, n = 116, P = 0.0252; e, CA2, n = 213, P = 0.0144; and f, CA3, n = 59, P > 0.05.

Extended Data Fig. 10 Generation of CA2 ripple oscillations enhances social-memory recall.

a, LFPs showing ripple activity in CA1 (red), CA2 (green) and CA3 (blue) in response to optogenetic triggering of ripple in CA2. b, Rate of ripples in sessions with optogenetic triggering of SWRs (‘artificial CA2’) was significantly higher than in control sessions (‘spontaneous’) (P < 0.05, rank-sum test). c, Firing rates of all pyramidal cells during spontaneous versus optogenetically triggered CA2 ripples were highly correlated (CA1, n = 67, r = 0.63, P < 10−13; Pearson’s correlation; CA2, n = 147, r = 0.75, P < 3 × 10−22; CA3, n = 40, r = 0.48, P = 0.01). d, Firing-rate gain (increase in firing rate during ripples, divided by average firing rate) of pyramidal cells during spontaneous versus triggered ripples for CA1 (n = 67, r = 0.57, P < 10−6), CA2 (n = 147, r = 0.74, P < 3 × 10−35) and CA3 (n = 40, r = 0.25, P > 0.05). e, Social-discrimination indices for Amigo2–Cre littermate controls injected with Cre-dependent ChR2 AAV with (n = 6, P > 0.05) and without (n = 10, P > 0.05) light stimulation did not differ. f, Effect of social gain on a neuron’s ripple participation gain (post-sleep participation minus pre-sleep participation, divided by their sum). CA1 and CA2 cells showed greater ripple participation gain for cells with positive versus negative social gain for both spontaneous SWRs (CA1 and CA2, n = 67 and n = 147; P < 0.05 and P < 3.4 × 10−3, respectively) and triggered SWRs (CA1 and CA2, P < 0.05 and P < 2.8 × 10−3, respectively). CA3 ripple participation gain showed no effect of social gain for either type of SWR (n = 40, P > 0.05). g, Histology of CA3-implanted Grik-4 animals, previously injected with Cre-dependent AAV expressing ChR2–eYFP (green). h, Close-up view of the CA3 area. i, Examples of spontaneous and optogenetically triggered ripples in CA3. White lines are LFPs from CA2; colour maps show wavelet spectrograms; dashed lines demarcate the period of illumination. j, LFPs showing ripple activity in CA1 and CA3 but not CA2 after optogenetic triggering of ripples in CA3. k, The rate of events in sessions with CA3-triggered ripples was significantly higher than in non-stimulated sessions (P < 0.003), with no significant difference compared with the rate of ripples in response to CA2-triggered ripples (P > 0.05). l, The participation probability (the fraction of ripples in which a neuron fires at least one spike) of all pyramidal cells during spontaneous versus triggered CA2 ripples was highly correlated (CA1, n = 96, r = 0.66, P < 7 × 10−10, Pearson’s correlation; CA2, n = 67, r = 0.34, P < 3 × 10−22; CA3, n = 112, r = 0.67, P = 3 × 10−15). m, A similar result was obtained by comparing firing rates (CA1, r = 0.59, P < 2 × 10−7; CA2, r = 0.49, P < 1.7 × 10−5; CA3, r = 0.66, P < 8 × 10−10). n, The firing-rate gain (in-ripple firing rate divided by baseline firing rate) showed similar tendencies (CA1, r = 0.63, P < 1.6 × 10−12; CA2, r = 0.47, P < 2.1 × 10−3; CA3, r = 0.71, P < 1.7 × 10−18).

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Oliva, A., Fernández-Ruiz, A., Leroy, F. et al. Hippocampal CA2 sharp-wave ripples reactivate and promote social memory. Nature 587, 264–269 (2020). https://doi.org/10.1038/s41586-020-2758-y

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