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Covert capture and attenuation of a hippocampus-dependent fear memory

Nature Neuroscience volume 24, pages 677–684 (2021)Cite this article

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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.

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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.

References

  1. Craske, M. G., Treanor, M., Conway, C. C., Zbozinek, T. & Vervliet, B. Maximizing exposure therapy: an inhibitory learning approach. Behav. Res. Ther. 58, 10–23 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  2. McNally, R. J. Mechanisms of exposure therapy: how neuroscience can improve psychological treatments for anxiety disorders. Clin. Psychol. Rev. 27, 750–759 (2007).

    Article  PubMed  Google Scholar 

  3. Vervliet, B., Craske, M. G. & Hermans, D. Fear extinction and relapse: state of the art. Annu. Rev. Clin. Psychol. 9, 215–248 (2013).

    Article  PubMed  Google Scholar 

  4. Nader, K., Schafe, G. E. & Le Doux, J. E. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406, 722–726 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Przybyslawski, J. & Sara, S. J. Reconsolidation of memory after its reactivation. Behav. Brain Res. 84, 241–246 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Duvarci, S. & Nader, K. Characterization of fear memory reconsolidation. J. Neurosci. 24, 9269–9275 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kindt, M., Soeter, M. & Vervliet, B. Beyond extinction: erasing human fear responses and preventing the return of fear. Nat. Neurosci. 12, 256–258 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Phelps, E. A. & Hofmann, S. G. Memory editing from science fiction to clinical practice. Nature 572, 43–50 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Blundell, J., Kouser, M. & Powell, C. M. Systemic inhibition of mammalian target of rapamycin inhibits fear memory reconsolidation. Neurobiol. Learn. Mem. 90, 28–35 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Debiec, J., LeDoux, J. E. & Nader, K. Cellular and systems reconsolidation in the hippocampus. Neuron 36, 527–538 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Eshuis, L. V. et al. Efficacy of immersive PTSD treatments: a systematic review of virtual and augmented reality exposure therapy and a meta-analysis of virtual reality exposure therapy. J. Psychiatr. Res. https://doi.org/10.1016/j.jpsychires.2020.11.030 (2020).

  12. Soeter, M. & Kindt, M. Retrieval cues that trigger reconsolidation of associative fear memory are not necessarily an exact replica of the original learning experience. Front. Behav. Neurosci. 9, 122 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Runyan, J. D. & Dash, P. K. Inhibition of hippocampal protein synthesis following recall disrupts expression of episodic-like memory in trace conditioning. Hippocampus 15, 333–339 (2005).

    Article  PubMed  Google Scholar 

  14. Goode, T. D., Ressler, R. L., Acca, G. M., Miles, O. W. & Maren, S. Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals. eLife 8, e46525 (2019).

  15. Ressler, R. L., Goode, T. D., Evemy, C. & Maren, S. NMDA receptors in the CeA and BNST differentially regulate fear conditioning to predictable and unpredictable threats. Neurobiol. Learn. Mem. 174, 107281 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chang, R. C., Blaisdell, A. P. & Miller, R. R. Backward conditioning: mediation by the context. J. Exp. Psychol. Anim. Behav. Process. 29, 171–183 (2003).

    Article  PubMed  Google Scholar 

  17. Maren, S., Phan, K. L. & Liberzon, I. The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat. Rev. Neurosci. 14, 417–428 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu, X. et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484, 381–385 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tanaka, K. Z. et al. Cortical representations are reinstated by the hippocampus during memory retrieval. Neuron 84, 347–354 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. Denny, C. A. et al. Hippocampal memory traces are differentially modulated by experience, time, and adult neurogenesis. Neuron 83, 189–201 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen, B. K. et al. Artificially enhancing and suppressing hippocampus-mediated memories. Curr. Biol. 29, 1885–1894 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Josselyn, S. A. & Tonegawa, S. Memory engrams: recalling the past and imagining the future. Science 367, eaaw4325 (2020).

  23. Goode, T. D., Tanaka, K. Z., Sahay, A. & McHugh, T. J. An integrated index: engrams, place cells, and hippocampal memory. Neuron 107, 805–820 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tonegawa, S., Morrissey, M. D. & Kitamura, T. The role of engram cells in the systems consolidation of memory. Nat. Rev. Neurosci. 19, 485–498 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Davis, P. & Reijmers, L. G. The dynamic nature of fear engrams in the basolateral amygdala. Brain Res. Bull. 141, 44–49 (2018).

    Article  PubMed  Google Scholar 

  26. Alfei, J. M. et al. Generalization and recovery of post-retrieval amnesia. J. Exp. Psychol. Gen. 149, 2063–2083 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Debiec, J., Doyère, V., Nader, K. & Ledoux, J. E. Directly reactivated, but not indirectly reactivated, memories undergo reconsolidation in the amygdala. Proc. Natl Acad. Sci. USA 103, 3428–3433 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lattal, K. M. & Abel, T. Behavioral impairments caused by injections of the protein synthesis inhibitor anisomycin after contextual retrieval reverse with time. Proc. Natl Acad. Sci. USA 101, 4667–4672 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ryan, T. J., Roy, D. S., Pignatelli, M., Arons, A. & Tonegawa, S. Memory. Engram cells retain memory under retrograde amnesia. Science 348, 1007–1013 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Roy, D. S., Muralidhar, S., Smith, L. M. & Tonegawa, S. Silent memory engrams as the basis for retrograde amnesia. Proc. Natl Acad. Sci. USA 114, E9972–E9979 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Trent, S., Barnes, P., Hall, J. & Thomas, K. L. Rescue of long-term memory after reconsolidation blockade. Nat. Commun. 6, 7897 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Gisquet-Verrier, P. et al. Integration of new information with active memory accounts for retrograde amnesia: a challenge to the consolidation/reconsolidation hypothesis? J. Neurosci. 35, 11623–11633 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schroyens, N., Sigwald, E. L., Van Den Noortgate, W., Beckers, T. & Luyten, L. Reactivation-dependent amnesia for contextual fear memories: evidence for publication bias. eNeuro 8, ENEURO.0108-20.2020 (2020).

  34. Luyten, L., Schnell, A. E., Schroyens, N. & Beckers, T. Lack of drug-induced post-retrieval amnesia for auditory fear memories in rats. BMC Biol. 19, 17 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Swanson, L. W. Brain maps 4.0-structure of the rat brain: an open access atlas with global nervous system nomenclature ontology and flatmaps. J. Comp. Neurol. 526, 935–943 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gafford, G. M., Parsons, R. G. & Helmstetter, F. J. Consolidation and reconsolidation of contextual fear memory requires mammalian target of rapamycin-dependent translation in the dorsal hippocampus. Neuroscience 182, 98–104 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Maren, S. Overtraining does not mitigate contextual fear conditioning deficits produced by neurotoxic lesions of the basolateral amygdala. J. Neurosci. 18, 3088–3097 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671–675 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Marek, R. et al. Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear. Nat. Neurosci. 21, 384–392 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shrestha, P. et al. Cell-type-specific drug-inducible protein synthesis inhibition demonstrates that memory consolidation requires rapid neuronal translation. Nat. Neurosci. 23, 281–292 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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  1. These authors contributed equally: Reed L. Ressler, Travis D. Goode.

Authors and Affiliations

  1. Department of Psychological and Brain Sciences and Institute for Neuroscience, Texas A&M University, College Station, TX, USA

    Reed L. Ressler, Travis D. Goode, Sohmee Kim, Karthik R. Ramanathan & Stephen Maren

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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.

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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 24, 677–684 (2021). https://doi.org/10.1038/s41593-021-00825-5

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