Early life stress triggers sustained changes in histone deacetylase expression and histone H4 modifications that alter responsiveness to adolescent antidepressant treatment.
Early life stress triggers sustained changes in histone deacetylase expression and histone H4 modifications that alter responsiveness to adolescent antidepressant treatment.
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DOI：
10.1016/j.nbd.2011.09.005
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发表时间：
2012-01
影响因子：
6.1
通讯作者：
Schmauss, Claudia
中科院分区：
文献类型：
--
作者：
Levine, Amir;Worrell, Trent R.;Zimnisky, Ross;Schmauss, Claudia
关键词：
早期生活压力可以引起基因表达和行为的长期变化。最近对啮齿动物的研究表明，这些持久的影响取决于遗传背景。表观遗传因素是否也起作用还有待研究。在这里，我们暴露的压力敏感的小鼠品系Balb/c和更有弹性的应变C57 B1/6到一个强大的早期生活压力的范例，婴儿母亲分离。在Balb/c小鼠中，婴儿母亲分离导致成年前脑新皮层中编码组蛋白去乙酰化酶（HDAC）1，3，7，8和10的mRNA表达减少，这种影响伴随着乙酰化组蛋白H4蛋白，特别是乙酰化H4 K12蛋白的表达增加。HDAC表达和组蛋白修饰的这些变化在暴露于早期生活应激的C57 Bl/6小鼠中未检测到。此外，在与母亲分开的Balb/c小鼠中检测到的H4 K12超乙酰化的逆转（用仅激活HDAC的低剂量茶碱进行慢性青春期治疗来实现）恶化了由这种早期生活压力暴露引起的异常情绪表型。相比之下，氟西汀，一种在母亲分开的Balb/c小鼠中具有强效抗抑郁功效的药物，增强了由早期生活压力引发的所有组蛋白修饰。此外，在非应激的Balb/c小鼠中，HDAC抑制剂和氟西汀联合给药（而不是单独给药氟西汀）可引起抗抑郁作用，并引发组蛋白H4表达的变化，这与氟西汀治疗暴露于早期生活应激的小鼠所引起的变化相似。这些结果表明，Balb/c小鼠开发表观遗传修饰后，早期生活应激暴露，在情绪表型方面，是适应性的，并提高抗抑郁药物的疗效。
Early life stress can elicit long-lasting changes in gene expression and behavior. Recent studies on rodents suggest that these lasting effects depend on the genetic background. Whether epigenetic factors also play a role remains to be investigated. Here we exposed the stress-susceptible mouse strain Balb/c and the more resilient strain C57Bl/6 to a powerful early life stress paradigm, infant maternal separation. In Balb/c mice, infant maternal separation led to decreased expression of mRNA encoding the histone deacetylases (HDACs) 1, 3, 7, 8, and 10 in the forebrain neocortex in adulthood, an effect accompanied by increased expression of acetylated histone H4 proteins, especially acetylated H4K12 protein. These changes in HDAC expression and histone modifications were not detected in C57Bl/6 mice exposed to early life stress. Moreover, a reversal of the H4K12 hyperacetylation detected in infant maternally separated Balb/c mice (achieved with chronic adolescent treatment with a low dose of theophylline that only activates HDACs) worsened the abnormal emotional phenotype resulting from this early life stress exposure. In contrast, fluoxetine, a drug with potent antidepressant efficacy in infant maternally separated Balb/c mice, potentiated all histone modifications triggered by early life stress. Moreover, in non-stressed Balb/c mice, co-administration of an HDAC inhibitor and fluoxetine, but not fluoxetine alone, elicited antidepressant effects and also triggered changes in histone H4 expression that were similar to those provoked by fluoxetine treatment of mice exposed to early life stress. These results suggest that Balb/c mice develop epigenetic modifications after early life stress exposure that, in terms of the emotive phenotype, are of adaptive nature, and that enhance the efficacy of antidepressant drugs.
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影响因子：
--
作者：
Green, Jennifer Greif;McLaughlin, Katie A.;Berglund, Patricia A.;Gruber, Michael J.;Sampson, Nancy A.;Zaslavsky, Alan M.;Kessler, Ronald C.
通讯作者：
Kessler, Ronald C.
DOI：
10.1038/nrg2485
发表时间：
2009-01
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.3
作者：
Bhansali, Punita;Dunning, Jane;Schmauss, Claudia
通讯作者：
Schmauss, Claudia
影响因子：
8.2
作者：
Holmes, A;le Guisquet, AM;Belzung, C
通讯作者：
Belzung, C
影响因子：
56.9
作者：
Peleg, Shahaf;Sananbenesi, Farahnaz;Fischer, Andre
通讯作者：
Fischer, Andre