17[beta]-Estradiol, but not estrone, increases the survival and activation of new neurons in the hippocampus in response to spatial memory in adult female rats

Estrogens fluctuate across the lifespan in women, with circulating 17[beta]-estradiol levels higher pre-menopause than estrone and circulating estrone levels higher postmenopause than 17[beta]-estradiol. Estrone is a common component of hormone replacement therapies, but research shows that 17[beta]-estradiol may have a greater positive impact on cognition. Previous studies show that acute estrone and 17[beta]-estradiol impact hippocampus-dependent learning and cell proliferation in the dentate gyrus in a dose-dependent manner in adult female rats. The current study explores how chronic treatment with estrone and 17[beta]-estradiol differentially influences spatial learning, hippocampal neurogenesis and activation of new neurons in response to spatial memory. Adult female rats received daily injections of vehicle (sesame oil), or a 10μg dose of either 17[beta]-estradiol or estrone for 20days. One day following the first hormone injection all rats were injected with the DNA synthesis marker, bromodeoxyuridine. On days 11-15 after BrdU injection rats were trained on a spatial reference version of the Morris water maze, and five days later (day 20 of estrogens treatment) were given a probe trial to assess memory retention. Cell proliferation was assessed by the endogenous cell cycle marker, Ki67, cell survival was assessed by counting the number and density of BrdU-ir cells in the dentate gyrus and cell activation was assessed by the percentage of BrdU-ir cells that were co-labeled with the immediate early gene product zif268. There were no significant differences between groups in acquisition or retention of Morris water maze. However, the 17[beta]-estradiol group had significantly higher, while the estrone group had significantly lower, levels of cell survival (BrdU-ir cells) in the dentate gyrus compared to controls. Furthermore, rats injected with 17[beta]-estradiol showed significantly higher levels of activation of new neurons in response to spatial memory compared to controls. These results provide insight into how estrogens differentially influence the brain and behavior, and may provide insight into the development of hormone replacement therapies for women. Highlights: Chronic estrone and 17[beta]-estradiol did not affect acquisition of the Morris water maze. 17[beta]-estradiol increased, while estrone decreased, hippocampal neurogenesis. 17[beta]-estradiol increased activation of new hippocampal neurons in response to spatial memory. This research