Mouse

Hippocampal CA2 sharp-wave ripples reactivate and promote social memory

AbstractThe 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.

Data availabilityData sets and analytical tools included in this study are available from the corresponding authors upon reasonable request.References1.Wilson, M. A. & McNaughton, B. L. Reactivation of hippocampal ensemble memories during sleep. Science 265, 676–679 (1994).ADS 
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Download referencesAcknowledgementsWe 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 informationAffiliationsDepartment of Neuroscience, The Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USAAzahara Oliva, Felix Leroy & Steven A. SiegelbaumNew York University Neuroscience Institute, New York University, New York, NY, USAAntonio Fernández-RuizDepartment of Pharmacology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USASteven A. SiegelbaumContributionsA.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 authorsCorrespondence to
Azahara Oliva or Steven A. Siegelbaum.Ethics declarations

Competing interests
The authors declare no competing interests.

Additional informationPeer 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 tablesExtended 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 
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