Estrogens dynamically regulate neurogenesis in the dentate gyrus of adult female rats

Abstract: Estrone and estradiol differentially modulate neuroplasticity and cognition but how they influence maturation pathways of new neurons is not known. The present study assessed the effects of estrone and estradiol on various aspects of neurogenesis in the dentate gyrus (DG) of ovariectomized young adult Sprague-Dawley rats using daily subcutaneous injections of 17β-estradiol or estrone. Rats were injected with a DNA synthesis marker, 5-bromo-2-deoxyuridine (BrdU), and were perfused one, two, or three weeks after BrdU injection and treatment. Immunofluorescent labelling for Sox2 and Ki67 were used to examine the density of neural stem cells and proliferating cells, respectively. Double-immunofluorescent labelling of BrdU with doublecortin (DCX) or NeuN was used to examine the attrition and maturation of adult-born neurons over time. Estradiol reduced the density of neural stem cells in the dorsal DG, whereas estrone reduced the density of neural stem cells in the ventral DG. Furthermore, estradiol enhanced, whereas estrone reduced, cell proliferation after one week but not after longer exposure to hormones. Both estrogens increased the density of BrdU/DCX-ir cells after one week of exposure but showed greater attrition of new neurons between one and two weeks after exposure. Lastly, estradiol decreased the percentage of BrdU/NeuN-ir cells in the dorsal DG after three weeks of treatment. These results demonstrate that estrogens have differential effects to modulate several aspects of adult hippocampal neurogenesis in the short term, but fewer effects after long-term exposure and that estradiol and estrone modulate neurogenesis via different pathways.