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Covert capture and attenuation of a hippocampus-dependent fear memory

Abstract

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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Fig. 1: Conditioned freezing to a BW CS is mediated by a contextual fear memory and engages the dHPC.
Fig. 2: A BW CS results in reactivation of a contextual fear engram.
Fig. 3: Chemogenetic activation of a covertly captured HPC neural ensemble drives freezing behavior.
Fig. 4: Covert retrieval of a contextual fear memory results in a labile memory trace that is vulnerable to disruption by protein synthesis inhibition.

Data availability

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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Acknowledgements

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.).

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Contributions

R.L.R., T.D.G. and S.M. designed the experiments, analyzed data and wrote the manuscript. R.L.R. and T.D.G. collected data for all experiments. S.K. assisted with c-Fos data collection and with the behavioral experiments shown in Fig. 1. K.R.R. assisted with the behavioral experiments shown in Fig. 3.

Corresponding author

Correspondence to Stephen Maren.

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The authors declare no competing interests.

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Peer review information Nature Neuroscience thanks Merel Kindt, Amy Milton and Steve Ramirez for their contribution to the peer review of this work.

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Supplementary information

Source data

Source Data Fig. 1

This file contains raw freezing values used to generate plots in Fig. 1.

Source Data Fig. 2

This file contains raw freezing values and cell counts used to generate plots in Fig. 2.

Source Data Fig. 3

This file contains raw freezing values and cell counts used to generate plots in Fig. 3.

Source Data Fig. 4

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

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