Letter | Published:

Activating positive memory engrams suppresses depression-like behaviour

Nature volume 522, pages 335339 (18 June 2015) | Download Citation

Abstract

Stress is considered a potent environmental risk factor for many behavioural abnormalities, including anxiety and mood disorders1,2. Animal models can exhibit limited but quantifiable behavioural impairments resulting from chronic stress, including deficits in motivation, abnormal responses to behavioural challenges, and anhedonia3,4,5. The hippocampus is thought to negatively regulate the stress response and to mediate various cognitive and mnemonic aspects of stress-induced impairments2,3,5, although the neuronal underpinnings sufficient to support behavioural improvements are largely unknown. Here we acutely rescue stress-induced depression-related behaviours in mice by optogenetically reactivating dentate gyrus cells that were previously active during a positive experience. A brain-wide histological investigation, coupled with pharmacological and projection-specific optogenetic blockade experiments, identified glutamatergic activity in the hippocampus–amygdala–nucleus-accumbens pathway as a candidate circuit supporting the acute rescue. Finally, chronically reactivating hippocampal cells associated with a positive memory resulted in the rescue of stress-induced behavioural impairments and neurogenesis at time points beyond the light stimulation. Together, our data suggest that activating positive memories artificially is sufficient to suppress depression-like behaviours and point to dentate gyrus engram cells as potential therapeutic nodes for intervening with maladaptive behavioural states.

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Acknowledgements

We thank B. Chen, D. S. Roy, and J. Kim for help with the experiments, T. J. Ryan and T. Kitamura for the TRE–ArchT–eGFP construct, J. Sarinana and E. Hueske for comments and extensive discussions on the manuscript, and all the members of the Tonegawa laboratory for their support. We dedicate this study to the memory of Xu Liu, who made major contributions to memory engram research. This work was supported by RIKEN Brain Science Institute and Howard Hughes Medical Institute.

Author information

Author notes

    • Xu Liu

    Deceased.

Affiliations

  1. RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Steve Ramirez
    • , Christopher J. MacDonald
    • , Anthony Moffa
    • , Joanne Zhou
    • , Roger L. Redondo
    •  & Susumu Tonegawa
  2. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Roger L. Redondo
    •  & Susumu Tonegawa

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Contributions

S.R., X.L., C.M., A.M., J.Z., R.L.R. and S.T. contributed to the study design. S.R., X.L., A.M., J.Z., C.M. and R.L.R. contributed to the data collection and interpretation. X.L. cloned all constructs. S.R., X.L., C.M., J.Z. and A.M. conducted the surgeries, behaviour experiments, and histological analyses. S.R., X.L. and S.T. wrote the paper. All authors discussed and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Susumu Tonegawa.

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DOI

https://doi.org/10.1038/nature14514

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