Simple SummaryThis study was aimed to explore the role of brain-derived estrogen (BDE2) in hippocampal neurogenesis with aging in female rats. Our results revealed that cell differentiation was significantly declined over the middle age (14-Mon), while the differentiation of astrocytes and microglia markedly elevated and exhibited excessive activation. The newborn immature neurons clustered in hippocampal subgranular zone (SGZ) area in 1-Mon juvenile, then sharply dropped thereafter and the number of neural stem cells declined over 14-Mon age. Female forebrain neuronal aromatase knockout (FBN-ARO-KO) rats showed declined neurogenesis in dentate gyrus (DG) region at 1, 6 and 18-Mon ages, compared to WT controls. In addition, letrozole suppressed neurogenesis at 1-Mon age. On the contrary, astrogenesis was elevated over middle age and FBN-ARO-KO promoted the differentiation and activation of astrocytes and microglia in the DG region. FBN-ARO-KO rats also displayed decreased levels of CREB-BDNF signal and cognitive-related proteins, as well as impaired spatial learning and memory in juvenile (1 Mon) and adulthood (6 Mon). Our results suggest that long-term shortage of aromatase-BDE2 signaling may accelerate brain inflammation by increase local gliogenesis and activation, and that BDE2 plays a key role for the maintaining of hippocampal neurogenesis and cognitive function.AbstractAlthough 17β-estradiol (E2) can be locally synthesized in the brain, whether and how brain-derived E2 (BDE2) impacts neurogenesis with aging is largely unclear. In this study, we examined the hippocampal neural stem cells, neurogenesis, and gliogenesis of 1, 3, 6, 14, and 18-month (Mon) female rats. Female forebrain neuronalaromataseknockout (FBN-ARO-KO) rats and letrozole-treated rats were also employed. We demonstraed that (1) the number of neural stem cells declined over 14-Mon age, and the differentiation of astrocytes and microglia markedly elevated and exhibited excessive activation. KO rats showed declines in astrocyte A2 subtype and elevation in A1 subtype at 18 Mon; (2) neurogenesis sharply dropped from 1-Mon age; (3) KO suppressed dentate gyrus (DG) neurogenesis at 1, 6 and 18 Mon. Additionally, KO and letrozole treatment led to declined neurogenesis at 1-Mon age, compared to age-matched WT controls; (4) FBN-ARO-KO inhibited CREB-BDNF activation, and decreased protein levels of neurofilament, spinophilin and PSD95. Notably, hippocampal-dependent spatial learning and memory was impaired in juvenile (1 Mon) and adulthood (6 Mon) KO rats. Taken together, we demonstrated that BDE2 plays a pivotal role for hippocampal neurogenesis, as well as learning and memory during female aging, especially in juvenile and middle age.