Repression of contexual fear memory induced by isoflurane is accompanied by reduction in histone acetylation and rescued by sodium butyrate.
Repression of contexual fear memory induced by isoflurane is accompanied by reduction in histone acetylation and rescued by sodium butyrate.
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DOI：
10.1093/bja/aeu184
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发表时间：
2014-10
影响因子：
9.8
通讯作者：
T. Zhong;Q. Qing;Y. Yang;W. Zou;Z. Ye;J. Yan;Q. Guo
中科院分区：
文献类型：
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作者：
T. Zhong;Q. Qing;Y. Yang;W. Zou;Z. Ye;J. Yan;Q. Guo
背景：在情境恐惧条件反射(CFC)试验中，异氟醚会导致小鼠的健忘症。组蛋白乙酰化是染色质修饰的一种形式，参与记忆形成的转录调控。我们研究了异氟醚诱导的情景恐惧记忆抑制是否与海马组蛋白乙酰化改变有关，以及组蛋白去乙酰酶抑制剂丁酸钠(SB)是否可以挽救这种抑制。方法成年C57BL/6小鼠慢性腹腔注射SB或赋形剂28d。在进行氯氟化碳训练之前，将小鼠暴露在异氟醚或空气中30min，第二天进行氯氟化碳测试。CFs训练后1h检测海马组蛋白乙酰化程度。同时还对参与学习记忆形成的即刻早期基因(IEG)c-Fos进行了研究。结果在氯氟化碳试验中，异氟醚暴露的小鼠冰冻时间明显缩短。这些小鼠在CFC训练后1h还表现出海马区H3K14、H4K5和H4K12乙酰化水平的降低，以及c-Fos表达的降低。所有这些变化在接受SB长期治疗的异氟醚暴露的小鼠中都得到了缓解。结论异氟醚可抑制CFC训练后大鼠海马组蛋白乙酰化，下调c-Fos基因表达。这些变化与异氟醚诱导的健忘症有关。HDAC抑制剂SB可能通过促进组蛋白乙酰化和组蛋白乙酰化介导的基因表达来防止被抑制的情景恐惧记忆，以回应氟氯化碳训练。
BACKGROUND Isoflurane produces amnesia in mice during contextual fear conditioning (CFC) trials. Histone acetylation is a form of chromatin modification involved in the transcriptional regulation underlying memory formation. We investigated whether isoflurane-induced repression of contextual fear memory is related to altered histone acetylation in the hippocampus, and whether it can be rescued by the histone deacetylases inhibitor sodium butyrate (SB). METHODS Adult C57BL/6 mice were chronically given intraperitoneal injections of SB or vehicle for 28 days. Immediately before CFC training, the mice were exposed to isoflurane or air for 30 min and CFC testing was performed the next day. Hippocampal histone acetylation was analysed 1 h after CFC training. c-Fos, an immediate early gene (IEG) suggested to participate in learning and memory formation, was also investigated at the same timepoint. RESULTS Mice exposed to isoflurane showed a reduction in freezing time during the CFC test. These mice also exhibited reduced hippocampal H3K14, H4K5, and H4K12 acetylation 1 h after CFC training, and also decreased c-Fos expression. All of these changes were attenuated in isoflurane-exposed mice that were chronically treated with SB. CONCLUSIONS Isoflurane suppresses histone acetylation and down-regulates c-Fos gene expression in CA1 of the hippocampus after CFC training. These changes are associated with isoflurane-induced amnesia. The HDAC inhibitor SB prevented repressed contextual fear memory, presumably by promoting histone acetylation and histone acetylation-mediated gene expression in response to CFC training.