妊娠期母体接触糖皮质激素导致子代抑郁样行为的机制研究

Adverse intrauterine factors，such as prenatal glucocorticoid exposure, lead to an increased risk of behavioral disorders in adulthood, which may be associated with programming effects on the brain. Our previous study demonstrated that prenatal glucocorticoid exposure induced depression-like behavior in the adult offspring rats, which accompanied by an increase in expression of corticotropin-releasing hormone (CRH) and CRH receptors in hippocampus. It is known that CRH and CRH receptors are involved in depression. However, the role of CRH system in depression-like behavior induced by prenatal glucocorticoid exposure remains unclear. The objectives of present study are to investigate the mechanisms involved in depression-like behavior induced by prenatal glucocorticoid exposure, and determine the effects of programming of the hippocampal CRH system on depression-like behavior in the adult offspring rats, further explore the potential mechanisms underlying the programming effects.This study may at least partly explain the increased susceptibility of prenatally stressed subjects to mood disorders including depression in later life. It will also help to furtherly regulate the rational use of glucocorticoids during pregnancy and provide new lines and potential targets for prevention and cure of glucocorticoid-programmed depression.

胎儿期宫内不良环境，如糖皮质激素暴露等可通过印迹效应而引发多种成年疾病。我们前期研究发现，妊娠期母体接触过量糖皮质激素导致子代成年后出现抑郁样行为，同时海马脑区促肾上腺皮质激素释放激素(CRH)及其受体表达增加。CRH及其受体已被证实能够调节抑郁情绪，但其在妊娠期母体高糖皮质激素所致子代抑郁样行为中的作用及机制尚不明确。本项目将在前期工作基础上，系统研究妊娠期母体接触过量糖皮质激素导致子代成年后产生抑郁样行为的机制，明确妊娠期母体高糖皮质激素能否通过对子代海马CRH及其受体表达的印迹效应而导致子代抑郁样行为，并进一步探讨这种印迹效应的产生机制和跨代遗传等。这项研究有助于阐明妊娠期母体高糖皮质激素导致子代抑郁的机制，并为临床上妇女健康生殖、优生优育的指导以及抑郁症的防治提供理论依据。

抑郁症是一种具有高发病率、高死亡率和高致残率的慢性神经系统疾病，其病因和发病机制尚未完全阐明。本项目主要研究了（1）胎儿期宫内不良环境，如糖皮质激素暴露等对动物成年后抑郁情绪的影响及其机制；（2）雌激素缺乏对抑郁情绪的影响、内在机制及防治。. 据报道，妊娠期母体高糖皮质激素会导致子代出现抑郁样行为，且这种抑郁样行为可传递到下一代。我们的研究结果表明，妊娠期接触糖皮质激素导致子代成年后出现抑郁样行为，同时海马CRH及CRHR1表达相应增加，子一代的这些变化通过母系途径传递到子二代；阻断CRH/CRHR1通路可缓解妊娠期接触糖皮质激素所致子代抑郁样行为；妊娠期接触糖皮质激素导致子代海马整体甲基化水平和CRHR1基因启动子区两个CpG位点甲基化水平下降，这可能导致了海马CRHR1的高表达；体外海马脑片也证实，糖皮质激素可通过降低甲基化水平来增加海马CRHR1的表达。以上结果提示，妊娠期母体高糖皮质激素通过影响海马甲基化水平，增加CRHR1表达，进而导致了子代出现抑郁样行为。这一结果有助于阐明妊娠期母体高水平糖皮质激素导致子代抑郁的机制，并为临床上妇女健康生殖、优生优育的指导以及抑郁症的防治提供理论依据。. 随着中国人口老龄化的加剧，女性围绝经期抑郁症的发病人数也在逐年上升，但目前临床上对其防治尚缺乏有针对性的、高效安全的治疗手段。究其原因，是由于雌激素缺乏所致抑郁的核心机制尚未完全阐明。我们研究结果表明，雌激素缺乏，ERβ激活减少，启动了以“NLRP3炎症小体激活”为核心的海马炎症反应，进而引起了抑郁样行为；此外，雌激素缺乏还可干扰海马色氨酸代谢，降低BDNF水平；而运动锻炼则能通过改善海马炎症反应，增加BDNF水平缓解此类抑郁样行为。我们的研究结果有助于阐明雌激素缺乏导致抑郁的分子机制，并为临床上女性心理健康的指导以及围绝经期抑郁症的防治和靶向性治疗方案的开发提供理论依据。