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Engrams or memory traces are the neuronal ensembles that collectively store individual experiences. Genetic strategies based on immediate early genes (IEGs), such as Arc/Arg3.1 , allow us to tag the ensembles active during memory encoding and compare them to those active during retrieval. However, these strategies only allow for the tagging of one neural ensemble. Here, we developed a multiple Arc (mArc) system that allows for the tagging of two Arc + ensembles. We validated this system by investigating how context, time, and valence influence neuronal ensemble reactivation in the dentate gyrus (DG). We show that similar contextual and valenced experiences are encoded in overlapping DG ensembles. We also find that ensembles are modulated by time, where experiences closer in time are encoded in more similar ensembles. These results highlight the dynamic nature of DG ensembles and show that the mArc system provides a powerful approach for investigating multiple memories in the brain., Highlights: The mArc system allows for the tagging of two Arc + ensembles in the same mouse DG ensembles labeled by the mArc system receive increased excitatory inputContext, valence, and time influence DG ensemble reactivationDG neural ensembles are reactivated less with increasing time.

Brain development is highly dynamic and asynchronous, marked by the sequential maturation of functional circuits across the brain. The timing and mechanisms driving circuit maturation remain elusive due to an inability to identify and map maturing neuronal populations. Here we create DevATLAS (Developmental Activation Timing-based Longitudinal Acquisition System) to overcome this obstacle. We develop whole-brain mapping methods to construct the first longitudinal, spatiotemporal map of circuit maturation in early postnatal mouse brains. Moreover, we uncover dramatic impairments within the deep cortical layers in a neurodevelopmental disorders (NDDs) model, demonstrating the utility of this resource to pinpoint when and where circuit maturation is disrupted. Using DevATLAS, we reveal that early experiences accelerate the development of hippocampus-dependent learning by increasing the synaptically mature granule cell population in the dentate gyrus. Finally, DevATLAS enables the discovery of molecular mechanisms driving activity-dependent circuit maturation., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.