Reactivating Hippocampal-Mediated Memories to Disrupt the Reconsolidation of Fear

Memories are stored in the brain as cellular ensembles activated during learning and reactivated during retrieval. Using the Tet-tag system, we labeled dorsal dentate gyrus (dDG) neurons activated by positive, neutral or negative experiences with channelrhodopsin-2. Following fear-conditioning, these cells were artificially reactivated during fear memory recall. Optical stimulation of a competing positive memory was sufficient to disrupt reconsolidation, thereby reducing conditioned fear acutely and enduringly. Moreover, mice demonstrated 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 interference induced by memory reactivation involved a relatively small set of neurons, we also found that activating a large population of randomly labeled dDG neurons was effective at disrupting reconsolidation. Importantly, reconsolidation-interference was specific to the fear memory. These findings implicate the dDG as a potential therapeutic node for modulating memories to suppress fear. ### Competing Interest Statement The authors have declared no competing interest.