Leptin的抗抑郁作用及受雌激素调控机制的研究

Recently, many studies have shown that leptin, an important feeding-related hormone，play a major role in antidepressant effect. Level of leptin was much higher in female that that in male. In the body leptin level is positively correlated with the level of estrogen. Furthermore, women are almost twice as likely as men to experience depression due to physiological character and social division of labor. However，it is unknown whether leptin-induced antidepressant–like effect was mediated by estrogen. Therefore, based on depression model of female mice with ovariectomy(menopause depression model)、chronic unpredicable stress and chronic ACTH application, using behavioral pharmacology, immunofluorescence double staining and biochemistry, the present study will be aim to explore estrogen-mediated antidepressant-like effect of leptin and its mechanism related to HPA axis hypothesis, monoamine hypothesis, neurotrophic hypothesis and neurogenesis hypothesis. These studies may provide more useful information to elucidate the mechanism of antidepressant-like effect of leptin.

研究表明：Leptin作为重要的摄食调控因子，对抑郁症可能具有改善作用。Leptin在女性体内表达水平相对较高，并与雌激素的表达呈正相关性。女性受生理特点和社会地位的影响，其患抑郁症的机率要远高于男性。然而，Leptin的抗抑郁作用是否受雌激素的调控，目前尚不清楚。因此，在本项目中以卵巢摘除的围绝经期抑郁模型、慢性不可预见性应激诱发的抑郁模型和ACTH诱发的抑郁模型的雌性小鼠为研究对象，基于抑郁症的HPA轴异常调节假说、单胺类假说、神经营养假说和神经元新生假说，通过行为药理学、免疫荧光双重染色及生化学方法，从整体到细胞、分子水平来考察Leptin对雌性小鼠抑郁样行为的影响及受雌激素调控的可能机制，为阐明Leptin的抗抑郁作用机制提供新的理论依据。

临床数据显示：女性体内leptin的表达水平要高于男性2-4倍，并与雌激素的表达呈正相关性。雌激素可能介导了leptin的抗抑郁样作用。然而，leptin是否具有抗抑郁作用，该作用是否介导雌激素的调控尚未见报道。本实验以卵巢摘除诱导围绝经期抑郁的小鼠为模型，基于抑郁症的神经营养假说及神经环路假说，从行为药理学，免疫印迹及免疫荧光染色等实验方法，考察leptin的抗抑郁作用及受雌激素调控的可能机制。卵巢摘除模型小鼠的CREB、pCREB、BDNF表达水平及pCREB/CREB比率显著下降，提示CREB-BDNF信号通路与卵巢摘除小鼠抑郁发病机制有关。Leptin通过上调CREB-BDNF信号通路蛋白表达水平及上调海马区c-Fos神经元表达水平，改善卵巢摘除模型小鼠的抑郁样行为。雌激素的受体拮抗剂tamoxifen对leptin的抗抑郁作用具有一定的拮抗作用。本研究为女性抑郁症的治疗提供新的理论依据。