Nonspecific ensemble reactivation in mouse dentate gyrus disrupts spatial working memory

Spatial working memory enables behavioral flexibility and depends upon the hippocampus. The hippocampal dentate gyrus (DG) is hypothesized to act as a pattern separator to disambiguate similar memories. We used activity-dependent labeling strategies in DG to tag multiple memory-associated neuronal ensembles recruited during the course of learning a spatial working memory task. We termed the tagged ensembles "nonspecific" because they arose from experiences across days, maze arenas, and the home cage. Optogenetic stimulation of nonspecific ensembles during the encoding phase within random trials of the task acutely impaired performance during light-on trials only. The degree of reactivation in the dentate hilus, but not the blade, inversely correlated with task accuracy. While our results do not rule out the possibility that the stimulation of random, sparse DG ensembles could lead to similar impairment, they are consistent with the proposed role of DG in pattern separation, completion, and spatial working memory.