雌激素在围绝经期抑郁大鼠发病机制中的cAMP-PKA信号通路研究

The prevalence of depression in perimenopausal women is the highest than any other age groups of woman. Our preliminary research about the prevalence of depression in perimenopausal women was 25.06%. Data shows that depression has become the world's fourth largest disease and will be the first female deaths and disability diseases. Depression has become a serious mental health concern in the modern society. The specific mechanism for perimenopausal depression highest prevalence is still not fully understood.The most evident for women entering menopause is the physiological changes of ovarian function and estrogen level in the body. May highest prevalence of perimenopausal depression cause by reproductive endocrine change? Cyclic adenosine monophosphate (cAMP) signal transduction pathway plays an important role in the regulation of emotion, is the hotspot in research on emotional disorders. This subject of study is to establish the perimenopausal depression rat models from chronic unpredictable mild stress for the study of case-control and interference with exogenous estrogen. From the pros and cons to study the rat's brain tissue E2, 5-HT, NA and its receptors changes relation with the cAMP-PKA signal transduction pathway and the target protein CREB and BDNF mRNA and protein expression level, in order to reveal the neurobiological mechanisms of depression during menopause from molecular biology. The study may provide the theoretical and rationale basis for the development of more effective treatment for perimenopausal depression.

围绝经期是妇女患抑郁症最高的时期，我们前期调研显示围绝经期妇女抑郁症的发生率为25.06%。数据显示抑郁症已成为世界第四大疾患，将成为女性死亡和残疾的首位疾病，严重困扰着现代社会，围绝经期抑郁高发的具体机理尚未有详尽研究。女性进入围绝经期最为明显的生理改变是卵巢功能衰退，体内雌激素水平发生显著变化，那么围绝经期抑郁的高发是否与妇女的生殖内分泌改变有关呢？环磷酸腺苷（cAMP）信号转导通路在情绪调节中发挥着重要作用，是目前情绪障碍研究的热点。本课题拟通过慢性未预知应激首次建立围绝经期抑郁大鼠模型，采用病例对照研究及外源性雌激素干预方法，从正反两方面探索大鼠脑组织E2、5-HT 、NA及其相应受体的变化对cAMP-PKA信号转导通路及下游CREB和BDNF mRNA、蛋白表达量的影响，以期从分子生物水平揭示围绝经期抑郁发生的神经生物学机理，为开发最为有效的治疗方法提供理论依据和新思路。

抑郁症已成为世界第四大疾患，将成为女性死亡和残疾的首位疾病，严重困扰着现代社会。围绝经期是妇女患抑郁症最高的时期，研究显示围绝经期妇女抑郁症的发生率为25.06%，但围绝经期抑郁高发的具体机理尚未有详尽研究。女性进入围绝经期最为明显的生理改变是卵巢功能衰退，体内雌激素水平发生显著变化。本课题通过慢性未预知应激首次建立围绝经期抑郁大鼠模型。研究发现围绝经期血清雌激素水平的降低与围绝经期抑郁的发生有关，进一步研究发现围绝经期抑郁大鼠海马CREB mRNA表达显著下调，蛋白CREB、TrKB和ERβ表达显著下降，cAMP-PKA信号通路中的cAMP和 PKA水平下降，这些变化可能与围绝经期大鼠抑郁的发生有关。对围绝经期大鼠采用外源性雌激素灌胃后再进行慢性未预知应激刺激，中高等剂量的外源性雌激素补充可改善抑郁刺激大鼠的行为变化，海马中蛋白CREB和TrkB表达升高，高剂量雌激素治疗组表达升高最显著。雌激素补充治疗后接受慢性未预知应激抑郁刺激大鼠海马的cAMP和PKA表达升高，高剂量雌激素治疗组表达升高最显著。本研究提示围绝经期雌激素水平的降低在抑郁症的发病中发挥了一定作用，围绝经期外源性补充雌激素对抑郁的发生有一定的缓解或预防作用。本研究在一定程度上阐述了围绝经期抑郁的发病机理，提示围绝经期抑郁模型大鼠海马cAMP-PKA信号通路下调，而雌激素可以通过上调海马cAMP-PKA 信号通路而发挥抗抑郁作用。本研究为开发围绝经期抑郁最为有效的治疗方法提供了理论依据和思路。