Down-regulation of hypothalamic corticotropin-releasing hormone messenger ribonucleic acid (mRNA) precedes early-life experience-induced changes in hippocampal glucocorticoid receptor mRNA
Down-regulation of hypothalamic corticotropin-releasing hormone messenger ribonucleic acid (mRNA) precedes early-life experience-induced changes in hippocampal glucocorticoid receptor mRNA
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DOI：
10.1210/en.142.1.89
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发表时间：
2001-01-01
期刊：
影响因子：
4.8
通讯作者：
Baram, TZ
中科院分区：
文献类型：
--
作者：
Avishai-Eliner, S;Eghbal-Ahmadi, M;Baram, TZ
早期生活经历，包括母亲的互动，深刻地影响着成年后的荷尔蒙应激反应。在大鼠中，在关键的新生儿时期的日常处理导致控制荷尔蒙分泌的关键分子的显著和永久的调节，以应对压力。因此，在生命早期处理的成年大鼠，海马糖皮质激素受体(GR)表达增加，而下丘脑CRH信使RNA(MRNA)水平和应激诱导的糖皮质激素释放减少。最近的研究强调了增加母体感官输入给被处理的大鼠作为这些变化的关键决定因素的作用。然而，从增强感觉体验到长期调节GR和CRH基因表达的关键早期事件的分子机制仍然很大程度上仍未解决。为了阐明控制这一分子级联反应的关键主要基因，我们确定了三个发育年龄的GR-mRNA水平以及下丘脑和杏仁核GRH-mRNA表达的变化顺序，以及这些变化与激素应激反应降低的出现之间的时间关系。每天处理的大鼠下丘脑GRH-mRNA水平的下调在出生后第9天就已经明显，并持续到出生后第23天和45天，即青春期以后。相反，与处理相关的海马GR-mRNA表达上调出现在出生后第23天，即远远晚于下丘脑CRH表达的变化。从出生后第23天开始，处理过的大鼠的激素应激反应就开始减少。这些发现表明，早期、快速和持续的下丘脑CRH基因表达变化可能在早期生活经历长期影响激素应激反应的机制中发挥关键作用(S)。
Early-life experiences, including maternal interaction, profoundly influence hormonal stress responses during adulthood. In rats, daily handling during a critical neonatal period leads to a significant and permanent modulation of key molecules that govern hormonal secretion in response to stress. Thus, hippocampal glucocorticoid receptor (GR) expression is increased, whereas hypothalamic CRH-messenger RNA (mRNA) levels and stress-induced glucocorticoid release are reduced in adult rats handled early in life. Recent studies have highlighted the role of augmented maternal sensory input to handled rats as a key determinant of these changes. However, the molecular mechanisms, and particularly the critical, early events leading from enhanced sensory experience to long-lasting modulation of GR and CRH gene expression, remain largely unresolved.To elucidate the critical, primary genes governing this molecular cascade, we determined the sequence of changes in GR-mRNA levels and in hypothalamic and amygdala GRH-mRNA expression at three developmental ages, and the temporal relationship between each of these changes and the emergence of reduced hormonal stress-responses.Down-regulation of hypothalamic GRH-mRNA levels in daily-handled rats was evident already by postnatal day 9, and was sustained through postnatal days 23 and 45, i.e. beyond puberty. In contrast, handling-related up-regulation of hippocampal GR-mRNA expression emerged subsequent to the 23rd postnatal day, i.e. much later than changes in hypothalamic CRH expression. The hormonal stress response of handled rats was reduced starting before postnatal day 23. These findings indicate that early, rapid, and persistent changes of hypothalamic CRH gene expression may play a critical role in the mechanism(s) by which early-life experience influences the hormonal stress-response long-term.