Abstract

Recent studies suggest that a shared neural ensemble may link distinct memories encoded close in time1,2,3,4,5,6,7,8,9,10,11,12. According to the memory allocation hypothesis1,2, learning triggers a temporary increase in neuronal excitability13,14,15 that biases the representation of a subsequent memory to the neuronal ensemble encoding the first memory, such that recall of one memory increases the likelihood of recalling the other memory. Here we show in mice that the overlap between the hippocampal CA1 ensembles activated by two distinct contexts acquired within a day is higher than when they are separated by a week. Several findings indicate that this overlap of neuronal ensembles links two contextual memories. First, fear paired with one context is transferred to a neutral context when the two contexts are acquired within a day but not across a week. Second, the first memory strengthens the second memory within a day but not across a week. Older mice, known to have lower CA1 excitability15,16, do not show the overlap between ensembles, the transfer of fear between contexts, or the strengthening of the second memory. Finally, in aged mice, increasing cellular excitability and activating a common ensemble of CA1 neurons during two distinct context exposures rescued the deficit in linking memories. Taken together, these findings demonstrate that contextual memories encoded close in time are linked by directing storage into overlapping ensembles. Alteration of these processes by ageing could affect the temporal structure of memories, thus impairing efficient recall of related information.

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Acknowledgements

We thank B. Khakh for support in the development of the miniaturized microscopes. We thank E. Thai, D. Tarzi, A. Ahuja, K. Lew, E. Lu, E. Stuart, S. Zhang, S. Ghiaee, C. Yang, A. Fariborzi, K. Cheng, N. Rao, A. Chang, C. Grimmick and M. Einstein for help with experiments; N. Rao for assistance with graphical design; and all members of the Silva laboratory for their support. This work was supported by National Institute on Aging R37 AG013622 and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation to A.J.S.; National Institutes of Health RO1 MH101198, 1U54 HD087101 and VA Merit Award BX00152401A1 to P.G.; National Research Service Award F32 MH97413 and Behavioral Neuroscience Training Grant T32 MH15795 to D.J.C.; Neurobehavioral Genetics Training Grant T32 NS048004 and Neural Microcircuits Training Grant T32 NS058280 to D.A.; Cellular Neurobiology Training Grant T32 NS710133 and Epilepsy Foundation Postdoctoral Research Training Fellowship to T.S.; National Institutes of Health U01 NS094286-01 and David Geffen School of Medicine Dean’s Fund for development of open-source miniaturized microscopes to A.J.S. and P.G.

Author information

Author notes

    • Denise J. Cai
    • , Daniel Aharoni
    • , Tristan Shuman
    •  & Justin Shobe

    These authors contributed equally to this work.

Affiliations

  1. Departments of Neurobiology, Psychiatry & Biobehavioral Sciences and Psychology, Integrative Center for Learning and Memory, Brain Research Institute, University of California, Los Angeles, California 90095, USA

    • Denise J. Cai
    • , Daniel Aharoni
    • , Justin Shobe
    • , Weilin Song
    • , Brandon Wei
    • , Michael Veshkini
    • , Mimi La-Vu
    • , Isaac Kim
    • , Yoshitake Sano
    • , Miou Zhou
    • , Ayal Lavi
    •  & Alcino J. Silva
  2. Departments of Neurology and Psychiatry & Biobehavioral Sciences, Integrative Center for Learning and Memory, Brain Research Institute, University of California, Los Angeles, California 90095, USA

    • Daniel Aharoni
    • , Tristan Shuman
    • , Jerry Lou
    • , Sergio E. Flores
    •  & Peyman Golshani
  3. West Los Angeles VA Medical Center, 11301 Wilshire Blvd, Los Angeles, California 90073, USA

    • Daniel Aharoni
    • , Tristan Shuman
    • , Jerry Lou
    • , Sergio E. Flores
    •  & Peyman Golshani
  4. Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA

    • Jeremy Biane
    •  & Mark Tuszynski
  5. Veterans Affairs Medical Center, San Diego, California 92161, USA

    • Jeremy Biane
    •  & Mark Tuszynski
  6. Departments of Cell Biology and Neurosciences, Institute for Childhood and Neglected Diseases, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

    • Karsten Baumgaertel
    •  & Mark Mayford
  7. Division of Hematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA

    • Masakazu Kamata

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Contributions

D.J.C., J.S., T.S., D.A. and A.J.S. contributed to the study design. D.A., T.S., D.J.C., P.G. and A.J.S. developed the miniature microscope system. D.A. engineered hardware and software associated with the miniature microscope and wrote the MATLAB analysis suite. T.S., D.J.C., W.S., J.S., S.E.F., J.L. and I.K. performed surgeries. D.J.C., T.S., M.L., W.S. and B.W. conducted calcium imaging and TetTag experiments. M.M. engineered and provided TetTag mice. D.J.C., J.S., T.S., M.L., W.S., B.W., M.V. and M.Z. conducted behavioural experiments. D.J.C., D.A., T.S. and A.L. analysed the data. J.B., D.J.C. and T.S. conducted in vitro physiology experiments. M.T. supported physiology experiments. Y.S. and M.K. made DREADD virus. D.J.C., I.K., B.W. and K.B. managed the mouse colony. D.J.C., T.S., D.A., J.S. and A.J.S. wrote the paper. All authors discussed and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Peyman Golshani or Alcino J. Silva.

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DOI

https://doi.org/10.1038/nature17955

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