The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids
The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids
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DOI：
10.1038/nn1441
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发表时间：
2005-05-01
影响因子：
25
通讯作者：
Piazza, PV
中科院分区：
文献类型：
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作者：
Revest, JM;Di Blasi, F;Piazza, PV
压力的许多行为后果是由压力诱导的高水平糖皮质激素激活糖皮质激素受体介导的。为了探索这些效应的分子机制，我们结合了体内和体外方法。我们分析了糖皮质激素受体基因（GR，也称为 Nr3c1）中携带脑特异性突变（GR（NesCre））的小鼠以及表达内源性糖皮质激素受体或携带可瞬时诱导的组成型活性形式受体（Delta GR）的细胞系。在应激后突变小鼠的海马以及细胞系中，糖皮质激素受体的激活大大增加了 MAPK 信号通路中蛋白质的表达和酶活性，并导致 Egr-1 mRNA 和蛋白质水平增加。与此同时，海马内 MAPK 通路的抑制消除了糖皮质激素引起的情境恐惧调节的增加。目前的结果为糖皮质激素对恐惧记忆的压力相关影响提供了分子机制。
Many of the behavioral consequences of stress are mediated by the activation of the glucocorticoid receptor by stress-induced high levels of glucocorticoid hormones. To explore the molecular mechanisms of these effects, we combined in vivo and in vitro approaches. We analyzed mice carrying a brain-specific mutation (GR(NesCre)) in the glucocorticoid receptor gene (GR, also called Nr3c1) and cell lines that either express endogenous glucocorticoid receptor or carry a constitutively active form of the receptor (Delta GR) that can be transiently induced. In the hippocampus of the mutant mice after stress, as well as in the cell lines, activation of glucocorticoid receptors greatly increased the expression and enzymatic activity of proteins in the MAPK signaling pathway and led to an increase in the levels of both Egr-1 mRNA and protein. In parallel, inhibition of the MAPK pathway within the hippocampus abolished the increase in contextual fear conditioning induced by glucocorticoids. The present results provide a molecular mechanism for the stress-related effects of glucocorticoids on fear memories.