The continuous addition of new dentate granule cells (DGCs), which is regulated exquisitely by brain activity, renders the hippocampus plastic. However, how neural circuits encode experiences to affect the addition of adult-born neurons remains unknown. Here, we used endoscopic Ca 2ϩ imaging to track the real-time activity of individual DGCs in freely behaving mice. For the first time, we found that active DGCs responded to a novel experience by increasing their Ca 2ϩ event frequency preferentially. This elevated activity, which we found to be associated with object exploration, returned to baseline by 1 h in the same environment, but could be dishabituated via introduction to a novel environment. To transition seamlessly between environments, we next established a freely controllable virtual reality system for unrestrained mice. We again observed increased firing of active neurons in a virtual enriched environment. Interestingly, multiple novel virtual experiences increased the number of newborn neurons accumulatively compared with a single experience. Finally, optogenetic silencing of existing DGCs during novel environmental exploration perturbed experience-induced neuronal addition. Our study shows that the adult brain conveys novel, enriched experiences to increase the addition of adult-born hippocampal neurons by increasing the firing of active DGCs.

Highlights d Hippocampus-engaged exploration induces functional hyperemia in the dentate gyrus d Functional hyperemia is critical to exploration-induced hippocampal neurogenesis d Parvalbumin-expressing neurons increase blood flow via nitric-oxide signaling d Functional hyperemia elevates IGF-1 pathway activity in the dentate gyrus

The process of circuit integration of newly-generated dentate granule cells of the hippocampus has been presumed to be a dynamic process. In fact, little is known regarding the initial development of newly generated neurons prior to circuit integration and the significance of this stage for circuit integration. Here, using advanced live imaging methods, we systematically analyze the dynamic dispersion of newly generated neurons in the neurogenic zone and observe that cells that are physically adjacent coordinate their lateral dispersion. Whole-cell recordings of adjacent newly generated neurons reveal that they are coupled via gap junctions. The dispersion of newly generated cells in the neurogenic zone is restricted when this coupling is disrupted, which severely impairs their subsequent integration into the hippocampal circuit. The results of this study reveal that the dynamic dispersion of newly generated dentate granule cells in the neurogenic zone is a required developmental stage for circuit integration.

Auditory-cued goal-oriented behaviors requires the participation of cortical and subcortical brain areas, but how neural circuits associate sensory-based decisions with goal locations through learning remains poorly understood. The hippocampus is critical for spatial coding, suggesting its possible involvement in transforming sensory inputs to the goal-oriented decisions. Here, we developed an auditory discrimination task in which rats learned to navigate to goal locations based on the frequencies of auditory stimuli. Using in vivo calcium imaging in freely behaving rats over the course of learning, we found that dentate granule cells became more active, spatially tuned, and responsive to task-related variables as learning progressed. Furthermore, only after task learning, the activity of dentate granule cell ensembles represented the navigation path and predicts auditory decisions as early as when rats began to approach the goals. Finally, chemogenetic silencing of dentate gyrus suppressed task learning. Our results demonstrate that dentate granule cells gain task-relevant firing pattern through reinforcement learning and could be a potential link of sensory decisions to spatial navigation.

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