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首页> 外文期刊>Endocrinology >Postnatal glucocorticoid excess due to pituitary glucocorticoid receptor deficiency: differential short- and long-term consequences.
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Postnatal glucocorticoid excess due to pituitary glucocorticoid receptor deficiency: differential short- and long-term consequences.

机译：垂体糖皮质激素受体缺乏导致的产后糖皮质激素过多：短期和长期后果不同。

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A tight regulation of hypothalamic-pituitary-adrenal (HPA) axis activity is essential for successful adaptation to stressful stimuli. Disruption of normal HPA axis development is a main risk factor for diseases such as posttraumatic stress disorder or depression, but the molecular mechanisms that lead to these long-term consequences are poorly understood. Here, we test the hypothesis that the pituitary glucocorticoid receptor (GR) is involved in regulating HPA axis function in neonatal and adult animals. Furthermore, we investigate whether postnatal hypercortisolism induced by pituitary GR deficiency is a main factor contributing to the persistent effects of early-life stress. Conditional knockout mice with a deletion of the GR at the pituitary (GR(POMCCre)) show excessive basal corticosterone levels during postnatal development, but not in adulthood. The hypercortisolemic state of neonatal GR(POMCCre) mice is accompanied by central gene expression changes of CRH and vasopressin in the paraventricular nucleus, but these alterations normalize at later ages. In adult mice, pituitary GR deficiency results in impaired glucocorticoid negative feedback. Furthermore, adult GR(POMCCre) mice display a more active coping strategy in the forced swim test, with no alterations in anxiety like behavior or cognitive functions. Postnatal GR antagonist treatment is able to prevent the long-term behavioral effects in GR(POMCCre) mice. In conclusion, we show that pituitary GRs are centrally involved in regulating HPA axis activity in neonates and mediate negative feedback regulation in adult animals. Postnatal glucocorticoid excess results in an altered stress-coping behavior in adult animals, with no effects on anxiety like behavior or cognition.
机译：下丘脑-垂体-肾上腺（HPA）轴活动的严格调节对于成功适应压力刺激至关重要。正常HPA轴发育的破坏是诸如创伤后应激障碍或抑郁症等疾病的主要危险因素，但是导致这些长期后果的分子机制却鲜为人知。在这里，我们测试了垂体糖皮质激素受体（GR）参与调节新生和成年动物HPA轴功能的假设。此外，我们调查是否由垂体GR不足引起的产后皮质醇增生是促成早期生活压力持续影响的主要因素。垂体GR（GR（POMCCre））缺失的条件性基因敲除小鼠在产后发育过程中显示出过量的基础皮质酮水平，但在成年期则没有。新生GR（POMCCre）小鼠的高皮质激素状态伴随着心室旁核中CRH和血管加压素的中心基因表达变化，但这些变化在以后的年龄才能够正常化。在成年小鼠中，垂体GR缺乏会导致糖皮质激素负反馈受损。此外，成年GR（POMCCre）小鼠在强迫游泳试验中表现出更积极的应对策略，并且没有行为或认知功能等焦虑症状的改变。产后GR拮抗剂治疗能够预防GR（POMCCre）小鼠的长期行为影响。总之，我们表明垂体GRs在新生儿中主要参与调节HPA轴的活动，并在成年动物中介导负反馈调节。产后糖皮质激素过量会导致成年动物的应激应对行为发生变化，而不会对行为或认知等焦虑产生影响。

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