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Hippocampus and amygdala fear memory engrams re-emerge after contextual fear relapse

Abstract

The formation and extinction of fear memories represent two forms of learning that each engage the hippocampus and amygdala. How cell populations in these areas contribute to fear relapse, however, remains unclear. Here, we demonstrate that, in male mice, cells active during fear conditioning in the dentate gyrus of hippocampus exhibit decreased activity during extinction and are re-engaged after contextual fear relapse. In vivo calcium imaging reveals that relapse drives population dynamics in the basolateral amygdala to revert to a network state similar to the state present during fear conditioning. Finally, we find that optogenetic inactivation of neuronal ensembles active during fear conditioning in either the hippocampus or amygdala is sufficient to disrupt fear expression after relapse, while optogenetic stimulation of these same ensembles after extinction is insufficient to artificially mimic fear relapse. These results suggest that fear relapse triggers a partial re-emergence of the original fear memory representation, providing new insight into the neural substrates of fear relapse.

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Fig. 1: Fear reinstatement re-engages the DG fear ensemble.
Fig. 2: BLA activity patterns change over extinction but resemble the fear conditioning state after fear relapse.
Fig. 3: Optical inhibition of the BLA, DG, or CA1 fear ensemble disrupts reinstated fear.
Fig. 4: BLA, DG, or CA1 fear ensemble stimulation is not sufficient to drive fear reinstatement.

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Acknowledgements

We thank Dr. Joshua Sanes and his lab at the Center for Brain Science, Harvard University, for providing laboratory space within which the initial experiments were conducted, the Center for Brain Science Neuroengineering core for providing technical support, and the Society of Fellows at Harvard University for their support. We also thank Dr. Susumu Tonegawa and his lab for providing the activity-dependent virus cocktail, Dr. Chris MacDonald for consultation on behavioral schedules, and Drs. Leon Reijmers and Patrick Davis, for their help with formulating this project and for their feedback throughout. We also thank Vardhan Dani and Inscopix for their technical assistance as well as Helen Fawcett and the NSF Neurophotonics Research Traineeship Program.

Funding

This work was supported by an NIH Early Independence Award (DP5 OD023106-01), an NIH Transformative R01 Award, a Young Investigator Grant from the Brain and Behavior Research Foundation, a Ludwig Family Foundation grant, and the McKnight Foundation Memory and Cognitive Disorders award.

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YZ and SR conceived the study. YZ, WM, and SR designed experiments and YZ, WM, AM, and SR analyzed data. YZ, WM, CC, AM, EO, ED, SLG, EM, and MS conducted experiments. YZ, WM, and SR wrote the manuscript; all authors edited and commented on the manuscript.

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Correspondence to Steve Ramirez.

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Zaki, Y., Mau, W., Cincotta, C. et al. Hippocampus and amygdala fear memory engrams re-emerge after contextual fear relapse. Neuropsychopharmacol. 47, 1992–2001 (2022). https://doi.org/10.1038/s41386-022-01407-0

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