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Optogenetic reactivation of memory ensembles in the retrosplenial cortex induces systems consolidation

Significance This study examines a question in memory research that has been extant since the observation of temporally graded retrograde amnesia in patient HM after temporal lobe resection; namely, how does the circuit structure underlying memory change over prolonged periods after initial learning, such that recent memories require the hippocampus whereas older remote memories do not? We use optogenetic reactivation of the neurons active naturally during initial learning (engram neurons) to show that postlearning neural replay can produce this shift in memory. Interestingly, this was only observed in sleeping, not awake, mice. This is consistent with a model in which natural activity in memory ensemble during offline periods results in the circuit change to remote memory. The neural circuits underlying memory change over prolonged periods after learning, in a process known as systems consolidation. Postlearning spontaneous reactivation of memory-related neural ensembles is thought to mediate this process, although a causal link has not been established. Here we test this hypothesis in mice by using optogenetics to selectively reactivate neural ensembles representing a contextual fear memory (sometimes referred to as engram neurons). High-frequency stimulation of these ensembles in the retrosplenial cortex 1 day after learning produced a recent memory with features normally observed in consolidated remote memories, including higher engagement of neocortical areas during retrieval, contextual generalization, and decreased hippocampal dependence. Moreover, this effect was only present if memory ensembles were reactivated during sleep or light anesthesia. These results provide direct support for postlearning memory ensemble reactivation as a mechanism of systems consolidation, and show that this process can be accelerated by ensemble reactivation in an unconscious state.