本文關(guān)鍵詞： 著床前束縛應(yīng)激 糖皮質(zhì)激素 后代焦慮 卵母細(xì)胞發(fā)育能力 胚胎培養(yǎng) 凋亡 Fas/FasL 小鼠　出處：《山東農(nóng)業(yè)大學(xué)》2016年博士論文　論文類型：學(xué)位論文

【摘要】：PART I:研究表明應(yīng)激可以導(dǎo)致糖皮質(zhì)激素過(guò)量分泌并損傷卵母細(xì)胞發(fā)育能力。我們實(shí)驗(yàn)室前期工作發(fā)現(xiàn)注射糖皮質(zhì)激素(皮質(zhì)醇)同樣導(dǎo)致小鼠卵母細(xì)胞發(fā)育能力下降,但體外成熟過(guò)程中添加應(yīng)激生理濃度的糖皮質(zhì)激素并不影響卵母細(xì)胞的成熟和胚胎的發(fā)育。本實(shí)驗(yàn)主要通過(guò)檢測(cè)注射皮質(zhì)醇后小鼠卵母細(xì)胞的發(fā)育能力,卵巢細(xì)胞凋亡情況,Fas/Fas L信號(hào)通路的激活來(lái)探索糖皮質(zhì)激素?fù)p傷卵母細(xì)胞發(fā)育能力的具體機(jī)制。結(jié)果顯示注射糖皮質(zhì)激素(皮質(zhì)醇)顯著降低雌性小鼠(a)卵母細(xì)胞發(fā)育能力,(b)血清和卵巢中E2/P4的比例,(c)壁顆粒細(xì)胞中胰島素樣生長(zhǎng)因子1(IGF1)、腦源性營(yíng)養(yǎng)因子(BDNF)及糖皮質(zhì)激素受體(GR)的表達(dá)。同時(shí)顯著升高(a)血清和卵巢中皮質(zhì)醇的含量,(b)壁顆粒細(xì)胞和卵丘細(xì)胞的凋亡比例,(c)體外成熟培養(yǎng)過(guò)程中卵丘細(xì)胞分泌的Fas L,(d)壁顆粒細(xì)胞、卵丘細(xì)胞和卵母細(xì)胞中Fas的表達(dá)。當(dāng)給Fas L基因突變小鼠(gld小鼠)注射皮質(zhì)醇后,發(fā)現(xiàn)其卵母細(xì)胞發(fā)育能力的削弱程度、壁顆粒細(xì)胞和卵丘細(xì)胞的凋亡比例與野生型相比都有很大幅度的緩解。由此可以得出以下結(jié)論:糖皮質(zhì)激素是通過(guò)激活Fas系統(tǒng)導(dǎo)致卵巢細(xì)胞凋亡進(jìn)而損傷卵母細(xì)胞發(fā)育潛能。到目前為止,本實(shí)驗(yàn)是首次揭示糖皮質(zhì)激素降低卵母細(xì)胞發(fā)育能力的機(jī)制,這將有助于進(jìn)一步理解糖皮質(zhì)激素在應(yīng)激相關(guān)疾病中作用。PART II:人類流行病學(xué)研究表明產(chǎn)前應(yīng)激可能會(huì)損傷情感發(fā)育,增加后代患抑郁癥、焦慮癥、精神分裂癥、自閉癥的機(jī)率。但是產(chǎn)前應(yīng)激影響后代行為和神經(jīng)內(nèi)分泌系統(tǒng)的機(jī)制尚不十分清楚。另外,大多數(shù)這方面的研究都集中于妊娠晚期。關(guān)于著床前應(yīng)激對(duì)后代影響的研究很少,而有關(guān)這方面的體外試驗(yàn)更是缺乏。本實(shí)驗(yàn)主要研究著床前心理應(yīng)激是否影響后代焦慮行為,并且運(yùn)用體內(nèi)和體外外兩種模型研究后代行為的改變是否是通過(guò)應(yīng)激增加糖皮質(zhì)激素的分泌引起的。結(jié)果表明著床前應(yīng)激和體外培養(yǎng)胚胎過(guò)程中添加糖皮質(zhì)激素(皮質(zhì)酮)都可以增加后代焦慮行為,導(dǎo)致后代海馬區(qū)糖皮質(zhì)激素受體(GR)和腦源性營(yíng)養(yǎng)因子(BDNF)的下調(diào),并促進(jìn)糖皮質(zhì)激素的分泌。而且體外培養(yǎng)過(guò)程中添加皮質(zhì)酮會(huì)下調(diào)胚胎內(nèi)糖皮質(zhì)激素受體的表達(dá)。由此可以得出以下結(jié)論:著床前心理應(yīng)激是通過(guò)促進(jìn)妊娠母鼠糖皮質(zhì)激素的分泌,進(jìn)而引起胚胎內(nèi)糖皮質(zhì)激素受體表達(dá)下降,最終導(dǎo)致后代焦慮水平上升。本研究是首次報(bào)道著床前應(yīng)激和體外培養(yǎng)胚胎時(shí)添加糖皮質(zhì)激素會(huì)增加后代的焦慮行為,這些實(shí)驗(yàn)結(jié)果可以幫助我們進(jìn)一步理解產(chǎn)前應(yīng)激影響后代行為的具體機(jī)制。
[Abstract]:PART I: studies have shown that stress can cause hypersecretion of glucocorticoids and damage oocyte development. Our laboratory work found that injecting glucocorticoid (cortisol). The development ability of mouse oocytes was also decreased. However, glucocorticoids added to stress physiological concentration during in vitro maturation did not affect the maturation of oocytes and the development of embryos. Apoptosis of ovarian cells. Activation of Fas/Fas L signaling pathway to explore the specific mechanism of glucocorticoid injury on oocyte development. Oocyte development. The ratio of E _ 2 / P _ 4 in serum and ovary was found in parietal granulosa cells, and insulin-like growth factor-1 (IGF1) was found in parietal granulosa cells. The expression of brain-derived nutrition factor (BDNF) and glucocorticoid receptor (GRG) increased significantly (P < 0.05). Meanwhile, the content of cortisol in serum and ovary was significantly higher than that in parietal granulosa cells and cumulus cells. (C) parietal granulosa cells secreted by cumulus cells during maturation in vitro. The expression of Fas in cumulus cells and oocytes. After injecting cortisol into Fas L mutant mice (GLD mice), it was found that the oocyte development ability was weakened. The percentage of apoptosis in parietal granulosa cells and cumulus cells was significantly alleviated compared with wild-type cells. Glucocorticoid induces ovarian cell apoptosis by activating the Fas system and thus impairs oocyte developmental potential. This experiment is the first to reveal the mechanism of glucocorticoid decreasing oocyte development ability. This will help to further understand the role of glucocorticoids in stress-related diseases .PART II: human epidemiological studies have shown that prenatal stress may damage emotional development and increase depression in offspring. The risk of anxiety, schizophrenia, and autism. But the mechanisms by which prenatal stress affects offspring's behavior and neuroendocrine system are not well understood. Most of these studies have focused on late pregnancy, and little research has been done on the effects of pre-implantation stress on offspring. However, there is a lack of in vitro experiments in this field. This study mainly studied whether pre-implantation psychological stress affects the anxiety behavior of offspring. Two models in vivo and in vitro were used to study whether the behavior change of offspring was caused by stress increasing the secretion of glucocorticoid. The results showed that preimplantation stress and in vitro embryo culture were supplemented with glucocorticoid. (. Corticosterone) can increase anxiety behavior in offspring. This results in down-regulation of glucocorticoid receptor (GRG) and brain-derived nutrition factor (BDNF) in hippocampal area of offspring. And to promote the secretion of glucocorticoids. Moreover, adding corticosterone in vitro can down-regulate the expression of glucocorticoid receptors in embryos. Preimplantation psychological stress promotes the secretion of glucocorticoid in pregnant rats. In turn, the expression of glucocorticoid receptor in embryos decreased. This is the first study to report that pre-implantation stress and glucocorticoid supplementation in vitro embryo culture can increase anxiety behavior in offspring. These results can help us to further understand the specific mechanism of prenatal stress affecting offspring behavior.
【學(xué)位授予單位】：山東農(nóng)業(yè)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：Q492

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本文編號(hào)：1461677