Schmidt Mathias V, Sterlemann Vera, Wagner Klaus, Niederleitner Bertram, Ganea Karin, Liebl Claudia, Deussing Jan M, Berger Stefan, Schütz Günther, Holsboer Florian, Müller Marianne B
Max Planck Institute of Psychiatry, Munich, Germany.
Endocrinology. 2009 Jun;150(6):2709-16. doi: 10.1210/en.2008-1211. Epub 2009 Feb 12.
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.
下丘脑 - 垂体 - 肾上腺（HPA）轴活动的严格调控对于成功适应应激刺激至关重要。正常HPA轴发育的破坏是创伤后应激障碍或抑郁症等疾病的主要危险因素，但导致这些长期后果的分子机制却知之甚少。在此，我们检验垂体糖皮质激素受体（GR）参与调节新生和成年动物HPA轴功能的假说。此外，我们研究垂体GR缺乏诱导的产后高皮质醇血症是否是导致早期生活应激持续影响的主要因素。垂体特异性敲除GR（GR（POMCCre））的条件性敲除小鼠在出生后发育期间表现出基础皮质酮水平过高，但成年后则不然。新生GR（POMCCre）小鼠的高皮质醇血症状态伴随着室旁核中CRH和血管加压素的中枢基因表达变化，但这些改变在后期会恢复正常。在成年小鼠中，垂体GR缺乏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，在类似焦虑行为或认知功能方面没有改变。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GR在中枢参与调节新生动物的HPA轴活动，并介导成年动物的负反馈调节。产后糖皮质激素过量导致成年动物应激应对行为改变，对类似焦虑行为或认知无影响。
