Reactivating hippocampal-mediated memories during reconsolidation to disrupt fear

Stephanie L. Grella, Amanda H. Fortin, Evan Ruesch, John H. Bladon, Leanna F. Reynolds, Abby Gross, Monika Shpokayte, Christine Cincotta, Yosif Zaki and Steve Ramirez ()
Additional contact information
Stephanie L. Grella: Boston University
Amanda H. Fortin: Boston University
Evan Ruesch: Boston University
John H. Bladon: Boston University
Leanna F. Reynolds: Boston University
Abby Gross: Boston University
Monika Shpokayte: Boston University
Christine Cincotta: Boston University
Yosif Zaki: Icahn School of Medicine at Mount Sinai
Steve Ramirez: Boston University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Memories are stored in the brain as cellular ensembles activated during learning and reactivated during retrieval. Using the Tet-tag system in mice, we label dorsal dentate gyrus neurons activated by positive, neutral or negative experiences with channelrhodopsin-2. Following fear-conditioning, these cells are artificially reactivated during fear memory recall. Optical stimulation of a competing positive memory is sufficient to update the memory during reconsolidation, thereby reducing conditioned fear acutely and enduringly. Moreover, mice demonstrate operant responding for reactivation of a positive memory, confirming its rewarding properties. These results show that interference from a rewarding experience can counteract negative affective states. While memory-updating, induced by memory reactivation, involves a relatively small set of neurons, we also find that activating a large population of randomly labeled dorsal dentate gyrus neurons is effective in promoting reconsolidation. Importantly, memory-updating is specific to the fear memory. These findings implicate the dorsal dentate gyrus as a potential therapeutic node for modulating memories to suppress fear.

Date: 2022
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DOI: 10.1038/s41467-022-32246-8

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