Reactivating Hippocampal-Mediated Memories to Disrupt the Reconsolidation of Fear

Grella, S. L.; Fortin, A. H.; Bladon, J. H.; Reynolds, L. F.; Ruesch, E.; Gross, A.; Shpokayte, M.; Cincotta, C.; Zaki, Y.; Ramirez, S.

doi:10.1101/2021.09.16.460695

bioRxiv · 10.1101/2021.09.16.460695

Reactivating Hippocampal-Mediated Memories to Disrupt the Reconsolidation of Fear

Grella, S. L.·Fortin, A. H.·Bladon, J. H.·Reynolds, L. F.·Ruesch, E.·Gross, A.·Shpokayte, M.·Cincotta, C.·Zaki, Y.·Ramirez, S.

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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.

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Grella, S. L., Fortin, A. H., Bladon, J. H., Reynolds, L. F., Ruesch, E., Gross, A., Shpokayte, M., Cincotta, C., Zaki, Y., Ramirez, S.. 2021-09-20. Reactivating Hippocampal-Mediated Memories to Disrupt the Reconsolidation of Fear. https://doi.org/10.1101/2021.09.16.460695

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