Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Leiden, The Netherlands.
Hippocampus. 2012 Feb;22(2):359-71. doi: 10.1002/hipo.20905. Epub 2010 Dec 23.
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.
海马齿状回（DG）在学习和记忆中起着至关重要的作用。这个亚区的独特之处在于它能够在整个生命过程中产生新的神经元，并将这些新的神经元整合到海马回路中。神经发生进一步涉及海马体的可塑性和抑郁。慢性应激暴露会影响 DG 的功能和形态，并抑制神经发生和长时程增强（LTP），从而影响认知。先前的研究表明，用糖皮质激素受体（GR）拮抗剂米非司酮（RU486）进行短暂治疗可以迅速逆转应激和糖皮质激素对神经发生的影响。然而，应激诱导效应和 RU486 对 DG 的影响的分子途径在很大程度上尚不清楚。因此，本研究的目的是（1）通过微阵列分析来研究 DG 中哪些基因和途径对慢性应激敏感，（2）研究 GR 阻断在多大程度上可以使这些应激对 DG 基因表达的影响正常化。慢性应激暴露影响 DG 中 90 个基因的表达（P < 0.01），其中涉及大脑发育和形态发生以及突触传递的基因表达上调。RU486 处理应激动物影响 107 个基因的表达；然而，与应激反应的基因大多不同。有趣的是，我们发现 CREBBP 被 RU486 处理正常化到对照动物的水平，这表明 CREB 信号通路可能在介导慢性应激对神经发生、LTP 和钙电流的影响中发挥核心作用。所鉴定的遗传途径提供了对海马体 DG 的应激诱导适应性可塑性的深入了解，这在学习和记忆中至关重要，并将指导未来对这些应激效应的功能结果和调节的研究。
