Ontogeny of hypothalamic glucocorticoid receptor-mediated inhibition of the hypothalamic-pituitary-adrenal axis in mice.
Ontogeny of hypothalamic glucocorticoid receptor-mediated inhibition of the hypothalamic-pituitary-adrenal axis in mice.
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DOI：
10.3109/10253890.2015.1046832
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Muglia LJ
中科院分区：
文献类型：
--
作者：
Laryea G;Arnett M;Muglia LJ
下丘脑室旁核（PVN）的糖皮质激素受体（GR）是下丘脑-垂体-肾上腺（HPA）轴负反馈调节的重要调节因子。先前对成年小鼠内源性PVN GR功能的评价表明，PVN中GR外显子3缺失的小鼠（Sim1Cre-GRe3 Δ）具有高度活跃的HPA轴、生长障碍和代谢紊乱。在这里，我们假设，缺乏通过PVN GR的HPA轴的负反馈抑制，如通过在生命早期PVN GR的损失所证明的，将具有发育阶段特异性的后果。免疫荧光显示，与对照小鼠相比，Sim 1Cre-GRe 3 Δ小鼠早在出生后第2天就表现出PVN GR丧失。原位杂交结果显示，与对照组相比，Sim1Cre-GRe3 Δ小鼠出生后第10天PVN中促肾上腺皮质激素释放激素（CRH）mRNA水平也有所增加。皮质酮放射免疫分析显示，PVN GR和CRH表达的破坏导致雄性Sim1Cre-GRe3 Δ小鼠在青春期早期的基础皮质酮分泌升高，并在青春期后期至成年期增加应激诱导（抑制）的皮质酮分泌。相比之下，雌性Sim1Cre-GRe3 Δ小鼠直到成年才表现出皮质酮破坏。皮质酮分泌的昼夜节律性在所有年龄组的雄性和雌性小鼠中均正常，无论基因型如何，只有一个例外。在青春期后期，雌性Sim1Cre-GRe3 Δ小鼠由于在最低点显著升高的循环水平而破坏了昼夜皮质酮分泌。我们的结论是PVN GR功能成熟在一个较早的发展时间点在男性比女性小鼠，从而导致性别之间的差异应力反应。
Glucocorticoid receptors (GR) in the paraventricular nucleus of the hypothalamus (PVN) are important regulators of negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Previous evaluation of endogenous PVN GR function in adult mice demonstrated that mice with loss of GR exon 3 in the PVN (Sim1Cre-GRe3Δ) have a hyperactive HPA axis, growth impairment, and metabolic disruptions. Here, we hypothesized that lack of negative feedback inhibition of the HPA axis through PVN GR, as demonstrated through loss of PVN GR early in life, will have developmental-stage-specific consequences. Immunofluorescence revealed that Sim1Cre-GRe3Δ mice display PVN GR loss as early as postnatal day 2 compared to control mice. Sim1Cre-GRe3Δ mice compared to controls also displayed increased corticotropin-releasing hormone (CRH) mRNA in the PVN at postnatal day 10, as shown by in situ hybridization. Corticosterone radioimmunoassay revealed that the disruptions in PVN GR and CRH expression led to elevated basal corticosterone secretion in male Sim1Cre-GRe3Δ mice by early adolescence and increased stress-induced (restraint) corticosterone secretion in late adolescence into adulthood. In comparison, female Sim1Cre-GRe3Δ mice did not display corticosterone disruption until adulthood. Circadian rhythmicity of corticosterone secretion was normal for male and female mice at all age groups regardless of genotype with one exception. In late adolescence, female Sim1Cre-GRe3Δ mice had disrupted circadian corticosterone secretion due to significantly elevated circulating levels at nadir. We conclude that PVN GR function matures at an earlier developmental time point in male than in female mice and thus leads to later differential stress responsiveness between sexes.
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影响因子：
10.6
作者：
Carpenter, Linda L.;Carvalho, John P.;Price, Lawrence H.
通讯作者：
Price, Lawrence H.
影响因子：
5.3
作者：
Russell, Georgina M.;Henley, David E.;Lightman, Stafford L.
通讯作者：
Lightman, Stafford L.
DOI：
10.1097/00004583-200109000-00009
发表时间：
2001-09-01
影响因子：
13.3
作者：
Durston, S;Pol, HEH;van Engeland, H
通讯作者：
van Engeland, H
影响因子：
7.4
作者：
Handa RJ;Weiser MJ
通讯作者：
Weiser MJ
DOI：
10.1196/annals.1308.017
发表时间：
2004-01-01
期刊：
ADOLESCENT BRAIN DEVELOPMENT: VULNERABILITIES AND OPPORTUNITIES
影响因子：
--
作者：
Arnsten, AFT;Shansky, RM
通讯作者：
Shansky, RM