The transcriptional response to chronic stress and glucocorticoid receptor blockade in the hippocampal dentate gyrus
The transcriptional response to chronic stress and glucocorticoid receptor blockade in the hippocampal dentate gyrus
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DOI：
10.1002/hipo.20905
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发表时间：
2012-02-01
期刊：
影响因子：
3.5
通讯作者：
Lucassen, Paul J.
中科院分区：
文献类型：
--
作者：
Datson, Nicole A.;Speksnijder, Niels;Lucassen, Paul J.
海马的齿状回（DG）在学习和记忆中起着至关重要的作用。这个亚区是独特的，它能够在整个生命中产生新的神经元，并将这些新的神经元整合到海马电路中。神经发生进一步与海马可塑性和抑郁症有关。暴露于慢性应激会影响DG的功能和形态，并抑制神经发生和长时程增强（LTP）与认知的后果。以往的研究表明，糖皮质激素受体（GR）阻断剂米非司酮（RU 486）的短暂治疗迅速逆转应激和糖皮质激素对神经发生的影响。然而，压力诱导的影响和RU 486对DG的影响的分子途径在很大程度上是未知的。因此，本研究的目的是（1）通过微阵列分析研究DG中哪些基因和途径对慢性应激敏感，以及（2）研究GR的阻断在多大程度上可以使这些应激诱导的DG基因表达效应正常化。慢性应激暴露影响DG中90个基因的表达（P < 0.01），其中与脑发育、形态发生和突触传递相关的基因表达量较高。RU 486处理应激动物影响了107个基因的表达;然而，大多数基因与应激反应不同。有趣的是，我们发现CREBBP通过RU 486治疗正常化至对照动物中观察到的水平，这表明CREB信号传导可能在介导慢性应激对神经发生、LTP和钙电流的影响中起核心作用。已确定的遗传途径提供了对海马DG的应激诱导的适应性可塑性的深入了解，海马DG在学习和记忆中是如此重要，并将指导未来对这些应激效应的功能结果和调制的研究。(C)2010 Wiley Periodicals，Inc.
The dentate gyrus (DG) of the hippocampus plays a crucial role in learning and memory. This subregion is unique in its ability to generate new neurons throughout life and integrate these new neurons into the hippocampal circuitry. Neurogenesis has further been implicated in hippocampal plasticity and depression. Exposure to chronic stress affects DG function and morphology and suppresses neurogenesis and long-term potentiation (LTP) with consequences for cognition. Previous studies demonstrated that glucocorticoid receptor (GR) blockade by a brief treatment with the GR antagonist mifepristone (RU486) rapidly reverses the stress and glucocorticoid effects on neurogenesis. The molecular pathways underlying both the stress-induced effects and the RU486 effects on the DG are, however, largely unknown. The aim of this study was therefore (1) to investigate by microarray analysis which genes and pathways in the DG are sensitive to chronic stress and (2) to investigate to what extent blockade of GR can normalize these stress-induced effects on DG gene expression. Chronic stress exposure affected the expression of 90 genes in the DG (P < 0.01), with an overrepresentation of genes involved in brain development and morphogenesis and synaptic transmission. RU486 treatment of stressed animals affected expression of 107 genes; however, mostly different genes than those responding to stress. Interestingly, we found CREBBP to be normalized by RU486 treatment to levels observed in control animals, suggesting that CREB-signaling may play a central role in mediating the chronic stress effects on neurogenesis, LTP and calcium currents. The identified genetic pathways provide insight into the stress-induced adaptive plasticity of the hippocampal DG that is so central in learning and memory and will direct future studies on the functional outcome and modulation of these stress effects. (C) 2010 Wiley Periodicals, Inc.