ERα介导的神经细胞凋亡在更年期抑郁和重复药物流产致远期抑郁与认知功能障碍中的作用研究

发布时间：2018-02-02 17:10

本文关键词： 重复药物流产 ERα 认知抑郁低出生体重　出处：《北京协和医学院》2016年博士论文　论文类型：学位论文

【摘要】：人口老龄化是当今社会人口发展的主要趋势之一,也是世界各国面临的重大社会问题。老年人口在各国所占的比例不断增加,老年健康也成为全社会日益关注的问题之一。更年期抑郁、认知功能障碍与卵巢早衰在老年人群中的发生率也不断增加。抑郁症与认知功能障碍的患者女性均多于男性,老年女性中的患病率是男性的2到3倍。雌激素在女性健康中起着重要作用。女性在青春期、月经周期、怀孕、更年期和绝经期体内雌激素均发生规律性和不规律性改变。并且研究报道,ERα在抑郁症和认知功能障碍中起重要的作用。为了研究雌激素受体在老年健康中的作用,我们利用卵巢切除、重复药物流产及低出生体重小鼠三种动物模型,观察其老年情绪、认知及生殖健康的变化,并探讨ERα在其中所起的作用。1 ERα介导的神经细胞凋亡在更年期抑郁中的作用研究更年期过渡时期雌激素水平发生不规律变化,在绝经后雌激素水平降低。我们利用卵巢切除术建立大鼠更年期模型,给予应激刺激后,大鼠垂直和水平运动显著性减少,糖水摄入率明显降低。TUNEL染色结果显示,海马DG区细胞凋亡明显增加。免疫组化染色结果显示,海马CA1区GAL和ERα表达量升高。下丘脑区中galanin R2和galanin R3的mRNA表达量具有极显著性升高。回补E2后,大鼠垂直和水平运动显著性增加,糖水摄入率明显增加。海马CA1区GAL和ERα表达量降低。下丘脑区中galanin R2和galanin R3的mRNA表达量具有极显著性降低。以上结果表明更年期大鼠在应激刺激后可导致更年期抑郁,其机制可能与ERα和GAL及其受体在海马和下丘脑中的表达变化有关。2 ERα介导重复药物流产致远期认知功能障碍中的作用研究流产导致女性体内雌激素发生骤然改变。我们利用BALB/c小鼠腹腔注2mg/kg RU486建立重复药物流产小鼠模型,结果显示育龄期重复药物流产可导致小鼠老年期体重、活动和认知能力下降。ERα表达量在小鼠老年期的大脑海马和下丘脑平均降低60%～80%。经产母鼠给予ERα拮抗剂MPP后,出现体重下降、动情周期紊乱、认知能力低下。MPP所致SY5Y神经细胞的细胞活力下降和凋亡率升高。以上结果表明ERα在重复药物流产小鼠老年期认知能力低下中起到重要作用。3低出生体重诱发成年及老年期生殖内分泌功能紊乱的研究不良的子宫内环境可导致发育不良及低出生体重,进一步影响生长发育及生殖健康。大脑作为神经调节的指挥中枢,其发育可影响整个生殖内分泌轴。我们通过自然筛选出低出生体重小鼠,对其后续生长发育及生殖内分泌功能进行研究。结果显示,低出生体重小鼠生长发育期、成年期、老年期体重均低于正常对照组。与对照组相比,低出生体重小鼠妊娠失败率显著性升高;生殖内分泌轴激素水平发生明显改变,LBW母鼠老年期血清中GnRH、E2水平降低；子宫形态发生改变,子宫显著性萎缩,子宫横截面积显著性降低；下丘脑中ERa和ERβ表达量升高,P66表达量降低、4-HNE表达量升高。以上结果表明低出生体重小鼠老年期体内E2水平及其受体发生改变,从而导致生殖内分泌功能紊乱。综上所述,卵巢去势大鼠模型进行应激刺激后,产生更年期抑郁,ERa在下丘脑和海马中的表达量升高,细胞凋亡增加。育龄期重复流产可致老年期行为学和认知能力降低,ERa在下丘脑和海马中的表达量降低,MPP所致SY5Y神经细胞的细胞活力下降和凋亡率升高。低出生体重组小鼠成年期妊娠失败率升高,老年期出现不规律动情周期时间提前,下丘脑中ERa和ER β表达量升高,氧化应激水平升高。因此,ERa在调节老年情绪、认知及生殖健康变化中起到作用。
[Abstract]:Population aging is one of the main trends of social population development, which is also a great social problem facing the world. The elderly population in many countries occupied the increasing proportion of elderly health has become one of growing concern in the society. Menopause Depression, cognitive dysfunction and premature ovarian failure in the elderly were also constantly increase in female patients with depression and cognitive dysfunction in elderly women are more than men, the prevalence of male is 2 to 3 times. Estrogen plays an important role in the health of women. Women at puberty, menstrual cycle, pregnancy, estrogen menopause and menopause occurred regularity and regularity change. And research reports alpha, ER play an important role in depression and cognitive dysfunction. In order to study the role of estrogen receptor in elderly health, we use ovariectomized, repeated drug Production logistics and low birth weight in three kinds of animal models, to observe the changes of cognition and emotion in old age, reproductive health, and to explore the effects of the menopause transition period of nerve cell apoptosis of ER alpha in which the role of.1 mediated by ER alpha in climacteric depression in the estrogen level changed irregularly, the estrogen level decreases postmenopausal women. We use to establish a rat model of menopausal oophorectomy, give rats after stress, vertical and horizontal movements were significantly decreased, sucrose intake rate decreased significantly..TUNEL staining showed that apoptotic cells in hippocampal DG area increased significantly. Immunohistochemical staining showed that the CA1 region of the hippocampus GAL and ER alpha expression in hypothalamus increased. Galanin R2 and galanin R3 in the expression of mRNA is significantly higher. Covering E2, rat vertical and horizontal movements increased significantly, sugar intake rate increased significantly. The hippocampus To reduce the amount of GAL and ER expression of CA1 galanin in hypothalamus area. R2 and galanin R3 mRNA expression significantly decreased. These results showed that menopause rats can lead to depression in menopause after stress, and its mechanism may be ER alpha and GAL and its receptor in the hippocampus and hypothalamus in the expression of.2 ER alpha mediated repeated drug abortion period Zhiyuan cognitive deficits in the role of abortion in female estrogen has a sudden change. We use BALB/c 2mg/kg RU486 mice by intraperitoneal injection to establish a mouse model of repeated drug abortion, repeated drug abortion showed that childbearing age can lead to senile mice weight, activity and cognitive decline in.ER alpha expression in senile mice the brain hippocampus and hypothalamus decreased from 60% to 80%. were given multiparous ER alpha antagonist MPP, weight loss, estrous cycle disorder, cognitive ability Decreased cell viability and apoptosis induced by low.MPP SY5Y nerve cell rate increased. The above results suggest that ER alpha in repeated drug abortion mice senile cognitive ability plays an important role in the research of low.3 low birth weight and adult reproductive endocrine function disorder induced by the elderly poor uterineenvironment can lead to stunted growth and low birth weight. The effects of growth and reproductive health. The central command brain as neural regulation, its development can affect the whole reproductive endocrine axis. We screened by natural low birth weight of mice, the subsequent growth and reproductive endocrine function were studied. The results showed that low birth weight in the growth period, adulthood, old age weight were lower than the control group. Compared with the control group, low birth weight in pregnancy failure rate increased significantly; reproductive endocrine hormone levels Obvious changes in LBW mice aged GnRH in serum, decreased E2 level; uterine morphological changes, significant atrophy of uterus, uterine cross-sectional area decreased significantly; the amount of ERa increased and the expression of ER in hypothalamus, P66 expression decreased, 4-HNE expression increased. The above results show that the low birth level of E2 and its receptor in vivo senile mice body weight change, resulting in reproductive endocrine disorders. In conclusion, ovariectomized rats model after stress, produce menopausal depression, the expression of ERa in hypothalamus and hippocampus in increased, cell apoptosis increased. Reducing repeated abortion can cause senile reproductive behavior and cognitive ability, the expression of ERa in hypothalamus and in the hippocampus decreased, decreased cell viability and apoptosis of MPP induced by SY5Y nerve cell rate increased. The low birth weight group in adult mice during pregnancy failure rate increased, the elderly It is not regular that the estrous cycle is ahead of time, the expression of ERa and ER beta in hypothalamus is increased, and the level of oxidative stress is increased. Therefore, ERa plays a role in regulating the changes of the elderly's mood, cognition and reproductive health.

【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R749;R169.42

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