Article | Published:

Neural ensemble dynamics underlying a long-term associative memory

Nature volume 543, pages 670675 (30 March 2017) | Download Citation

Abstract

The brain’s ability to associate different stimuli is vital for long-term memory, but how neural ensembles encode associative memories is unknown. Here we studied how cell ensembles in the basal and lateral amygdala encode associations between conditioned and unconditioned stimuli (CS and US, respectively). Using a miniature fluorescence microscope, we tracked the Ca2+ dynamics of ensembles of amygdalar neurons during fear learning and extinction over 6 days in behaving mice. Fear conditioning induced both up- and down-regulation of individual cells’ CS-evoked responses. This bi-directional plasticity mainly occurred after conditioning, and reshaped the neural ensemble representation of the CS to become more similar to the US representation. During extinction training with repetitive CS presentations, the CS representation became more distinctive without reverting to its original form. Throughout the experiments, the strength of the ensemble-encoded CS–US association predicted the level of behavioural conditioning in each mouse. These findings support a supervised learning model in which activation of the US representation guides the transformation of the CS representation.

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Acknowledgements

G. Venkatraman, B. Ahanonu, J. Li, B. Rossi, C. Herry, S. Ciocchi and J. Bacelo provided technical assistance. We appreciate Swiss National Science Foundation (B.F.G.), Swiss National Science Foundation, Ambizione (J.G.), US National Science Foundation (L.J.K.), Stanford University (L.J.K., J.D.M.), Simons Foundation (L.J.K.), and Helen Hay Whitney Foundation (M.C.L.) fellowships. A.L. received support from the Swiss National Science Foundation, Novartis Research Foundation, and an ERC Advanced grant. M.J.S. received support from HHMI and DARPA.

Author information

Author notes

    • Francois Grenier

    Present address: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.

Affiliations

  1. James H. Clark Center for Biomedical Engineering & Sciences, Stanford University, Stanford, California, USA

    • Benjamin F. Grewe
    • , Lacey J. Kitch
    • , Jerome A. Lecoq
    • , Jesse D. Marshall
    • , Margaret C. Larkin
    • , Pablo E. Jercog
    • , Jin Zhong Li
    •  & Mark J. Schnitzer
  2. Howard Hughes Medical Institute, Stanford University, Stanford, California, USA

    • Benjamin F. Grewe
    • , Lacey J. Kitch
    • , Jerome A. Lecoq
    • , Jesse D. Marshall
    • , Pablo E. Jercog
    •  & Mark J. Schnitzer
  3. CNC Program, Stanford University, Stanford, California, USA

    • Benjamin F. Grewe
    • , Lacey J. Kitch
    • , Jerome A. Lecoq
    • , Jones G. Parker
    • , Jesse D. Marshall
    • , Margaret C. Larkin
    • , Pablo E. Jercog
    • , Jin Zhong Li
    •  & Mark J. Schnitzer
  4. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland

    • Jan Gründemann
    • , Francois Grenier
    •  & Andreas Lüthi
  5. Pfizer Neuroscience Research, Cambridge, Massachusetts, USA

    • Jones G. Parker
  6. University of Basel, Basel, Switzerland

    • Andreas Lüthi

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Contributions

B.F.G. designed experiments. B.F.G., J.G.P. and J.G. established the Ca2+ imaging protocol and performed experiments. B.F.G., P.E.J, A.L. and M.J.S. designed analyses. B.F.G. and J.D.M. analysed data. J.A.L., L.J.K., J.D.M. and M.C.L. provided software code and advised on analyses. J.Z.L. constructed virus. F.G. and A.L. provided electrophysiological data. B.F.G. and M.J.S. wrote the paper. J.G., A.L. and all authors edited the paper. A.L. and M.J.S. supervised the research.

Competing interests

M.J.S. is a scientific co-founder of Inscopix, Inc., which produces the miniature fluorescence microscope used in this study.

Corresponding author

Correspondence to Mark J. Schnitzer.

Reviewer Information Nature thanks V. Bolshakov 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.

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DOI

https://doi.org/10.1038/nature21682

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