Adult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging

Summary Adult neurogenesis is impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in a progressing decline in hippocampal acetylcholine and the slow emergence of profound working memory deficits. These deficits were accompanied by compensatory rewiring of cholinergic dentate gyrus inputs such that ventrally projecting neurons were recruited by the dorsal projection. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.