Bidirectional switch of the valence associated with a hippocampal contextual memory engram

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The valence of memories is malleable because of their intrinsic reconstructive property1. This property of memory has been used clinically to treat maladaptive behaviours2. However, the neuronal mechanisms and brain circuits that enable the switching of the valence of memories remain largely unknown. Here we investigated these mechanisms by applying the recently developed memory engram cell- manipulation technique3,4. We labelled with channelrhodopsin-2 (ChR2) a population of cells in either the dorsal dentate gyrus (DG) of the hippocampus or the basolateral complex of the amygdala (BLA) that were specifically activated during contextual fear or reward conditioning. Both groups of fear-conditioned mice displayed aversive light-dependent responses in an optogenetic place avoidance test, whereas both DG- and BLA-labelled mice that underwent reward conditioning exhibited an appetitive response in an optogenetic place preference test. Next, in an attempt to reverse the valence of memory within a subject, mice whose DG or BLA engram had initially been labelled by contextual fear or reward conditioning were subjected to a second conditioning of the opposite valence while their original DG or BLA engram was reactivated by blue light. Subsequent optogenetic place avoidance and preference tests revealed that although the DG-engram group displayed a response indicating a switch of the memory valence, the BLA-engram group did not. This switch was also evident at the cellular level by a change in functional connectivity between DG engram-bearing cells and BLA engram-bearing cells. Thus, we found that in the DG, the neurons carrying the memory engram of a given neutral context have plasticity such that the valence of a conditioned response evoked by their reactivation can be reversed by re-associating this contextual memory engram with a new unconditioned stimulus of an opposite valence. Our present work provides new insight into the functional neural circuits underlying the malleability of emotional memory.

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We thank X. Zhou, C. Potter, D. Plana, J. Martin, M. Tsitsiklis, H. Sullivan, W. Yu and A. Moffa for help with the experiments; K. L. Mulroy, T. Ryan and D. Roy for comments and discussions on the manuscript, and all the members of the Tonegawa laboratory for their support. This work was supported by the funds from the RIKEN Brain Science Institute, the Howard Hughes Medical Institute and The JPB Foundation to S.T., and the National Institutes of Health Pre-doctoral Training Grant T32GM007287 to J.K.

Author information

Author notes

    • Roger L. Redondo
    •  & Joshua Kim

    These authors contributed equally to this work.


  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

    • Roger L. Redondo
    • , Joshua Kim
    • , Autumn L. Arons
    • , Steve Ramirez
    • , Xu Liu
    •  & Susumu Tonegawa
  2. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Roger L. Redondo
    • , Autumn L. Arons
    • , Xu Liu
    •  & Susumu Tonegawa


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R.L.R., J.K. and S.T. contributed to the study design. R.L.R., J.K. and S.R. contributed to the data collection. X.L. cloned all constructs. R.L.R., J.K. and A.L.A. conducted the surgeries. R.L.R. and J.K. conducted the behavioural experiments. R.L.R. conducted the functional connectivity experiments. J.K. conducted the reversal experiments. R.L.R. contributed to the setup of the behavioural and optogenetic apparatus and programmed the behavioural software to run the experiments. R.L.R., J.K. 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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