下丘脑在生殖功能的衰退中起着关键性的作用，下丘脑星形胶质细胞是参与雌激素正反馈、促进GnRH神经元活化的关键细胞。我们前期研究发现：RP3V星形胶质细胞较早出现特异的增龄性衰老，卵巢摘除可明显减轻该部位星胶细胞的老化。本研究以靶向敲除下丘脑星形胶质细胞ERα的GFAP-Cre：Esr1 lox/lox 小鼠，探讨下丘脑星形胶质细胞在雌激素正反馈中的作用；通过去势后雌激素补充替代，观察雌激素对星形胶质细胞衰老的诱导作用及天然抗氧化剂虾青素延缓该过程的可能分子机制。本课题的研究将揭示：雌激素作用于下丘脑表达ERα星形胶质细胞，合成分泌神经孕酮参与雌激素正反馈，在此过程中雌激素的代谢导致星形胶质细胞发生DNA损伤和氧化应激诱导早期星形胶质细胞衰老，最终引起生殖功能的下降，研究结论有望为将来寻找延缓生殖老化的药物提供相应的作用靶点。

Hypothalamus plays an important role in the decline of the reproductive function in the human and the nonhuman primates and rodents. Especially the hypothalamic astrocyte plays a key role in estrogen positive feedback and activation of GnRH neuron. In our preliminary experiment, astrocyte within RP3V had a characteristic of cellular senescence with increasing age, which can be rescued by ovariectomy. In present study, the GFAP-Cre：Esr1 lox/lox mice line will be used to investigate the astrocyte affecting on estrogen positive feedback. To investigate the role of estrogen contributing astrocyte senescence, ovariectomized mice primed with or without estrogen is used. Moreover, the role and mechanism of natural antioxidant astaxanthin on reproductive dysfunction will be further explored. These studies will reveal that estradiol stimulating progesterone synthesis in astrocytes is a necessary for estrogen positive feedback, meanwhile the metabolism of estrogen induces astrocyte senescence mediated by DNA damage and oxidative stress, which, in turn, contributing the reproductive decline. This study will help to illustrate the mechanism of reproductive senescence and provide new targets for drug development to slowing reproductive decline.