Parallel processing of past and future memories through reactivation and synaptic plasticity mechanisms during sleep.

Every day, we experience new episodes and store new memories. Although memories are stored in corresponding engram cells, how different sets of engram cells are selected for current and next episodes, and how they create their memories, remains unclear. Here we show that in male mice, hippocampal CA1 neurons show an organized synchronous activity in prelearning home cage sleep that correlates with the learning ensembles only in engram cells, termed preconfigured ensembles. Moreover, after learning, a subset of nonengram cells develops population activity, which is constructed during postlearning offline periods, and then emerges to represent engram cells for new learning. Our model suggests a potential role of synaptic depression and scaling in the reorganization of the activity of nonengram cells. Together, our findings indicate that during offline periods there are two parallel processes occurring: conserving of past memories through reactivation, and preparation for upcoming ones through offline synaptic plasticity mechanisms.