Reconsolidation may be a viable therapeutic target to inhibit pathological fear memories. In the clinic, incidental or imaginal reminders are used for safe retrieval of traumatic memories of experiences that occurred elsewhere. However, it is unknown whether indirectly retrieved traumatic memories are sensitive to disruption. Here we used a backward (BW) conditioning procedure to indirectly retrieve and manipulate a hippocampus (HPC)-dependent contextual fear engram in male rats. We show that conditioned freezing to a BW conditioned stimulus (CS) is mediated by fear to the conditioning context, activates HPC ensembles that can be covertly captured and chemogenetically activated to drive fear, and is impaired by post-retrieval protein synthesis inhibition. These results reveal that indirectly retrieved contextual fear memories reactivate HPC ensembles and undergo protein synthesis-dependent reconsolidation. Clinical interventions that rely on indirect retrieval of traumatic memories, such as imaginal exposure, may open a window for editing or erasure of neural representations that drive pathological fear.
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The data that support the findings of this study are available from the corresponding author upon request. Source data are provided with this paper.
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We thank S. Tonegawa for kindly providing plasmids (pAAV.TRE.hM3Dq.mCherry and pAAV.cFos.tTA). We also thank J. Liu and A. Martinez for technical assistance, and M. Kindt, A. Milton, and S. Ramirez for their helpful reviews of the manuscript. This work was supported by NIH grant nos. F31MH107113 (T.D.G.), R01MH065961 and R01MH117852 (S.M.), and by a Brain & Behavioral Research Foundation Distinguished Investigator grant (S.M.).
The authors declare no competing interests.
Peer review information Nature Neuroscience thanks Merel Kindt, Amy Milton and Steve Ramirez 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.
This file contains raw freezing values used to generate plots in Fig. 1.
This file contains raw freezing values and cell counts used to generate plots in Fig. 2.
This file contains raw freezing values and cell counts used to generate plots in Fig. 3.
This file contains raw freezing values used to generate plots in Fig. 4.
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Ressler, R.L., Goode, T.D., Kim, S. et al. Covert capture and attenuation of a hippocampus-dependent fear memory. Nat Neurosci (2021). https://doi.org/10.1038/s41593-021-00825-5