PDF(Pubmed)
Abstract：
Although 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 neuronal aromatase knockout (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.
摘要：
虽然17β-雌二醇（E2）可以在大脑中局部合成，脑源性E2(BDE2)是否以及如何影响衰老的神经发生尚不清楚.在这项研究中,我们检查了海马神经干细胞，神经发生，1、3、6、14和18个月（Mon）雌性大鼠的神经胶质生成。还使用雌性前脑神经元芳香化酶敲除(FBN-ARO-KO)大鼠和来曲唑处理的大鼠。我们证明（1）神经干细胞的数量在14岁以上下降，星形胶质细胞和小胶质细胞的分化明显升高，并表现出过度激活。KO大鼠在18Mon时显示星形胶质细胞A2亚型下降和A1亚型升高；（2）神经发生从1月开始急剧下降；（3）KO在1、6和18月抑制齿状回（DG）神经发生。此外,KO和来曲唑治疗导致一岁时神经发生下降，与年龄匹配的WT对照相比；（4）FBN-ARO-KO抑制CREB-BDNF激活，神经丝的蛋白质水平下降，spinophilin和PSD95。值得注意的是,幼年（1月）和成年（6月）KO大鼠海马依赖性空间学习和记忆受损。一起来看,我们证明BDE2在海马神经发生中起关键作用，以及女性衰老期间的学习和记忆，尤其是在青少年和中年。
