Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear
Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear
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DOI：
10.1101/lm.500907
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发表时间：
2007-04-01
影响因子：
2
通讯作者：
Barad, Mark
中科院分区：
文献类型：
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作者：
Bredy, Timothy W.;Wu, Hao;Barad, Mark
条件性恐惧的消除是抑制学习和人类焦虑症行为治疗的重要模型。与其他形式的学习一样，消退学习是持久的，并且依赖于受调控的基因表达。表观遗传机制对基因表达的持续变化做出了重要贡献；因此，在这些研究中，我们研究了基因表达的表观遗传调控是否有助于恐惧消退。由于脑源性神经营养因子（BDNF）对于突触可塑性和长期记忆的维持至关重要，因此我们在提示恐惧消失后检查了两个 BDNF 基因启动子周围的组蛋白修饰，将其作为学习诱导的基因表达表观遗传调控的潜在目标。丙戊酸 (VPA) 曾一度用作抗惊厥药和情绪稳定剂，可调节 BDNF 的表达，并且是一种组蛋白脱乙酰酶 (HDAC) 抑制剂。在这里，我们报道，条件性恐惧的消失伴随着 BDNF P4 基因启动子周围组蛋白 H4 乙酰化的显着增加，以及前额皮质中 BDNF 外显子 I 和 IV mRNA 表达的增加，VPA 由于其 HDAC 抑制剂作用而增强了长期记忆，并且 VPA 增强了弱消退训练对 BDNF P1 和 P4 基因启动子周围组蛋白 H4 乙酰化的影响。 BDNF 外显子 IV mRNA 表达。这些结果表明组蛋白 H4 修饰、BDNF 基因表达的表观遗传调控和条件性恐惧消除的长期记忆之间存在关系。此外，他们认为 HDAC 抑制剂可能成为人类焦虑症心理治疗的有用药理学辅助剂。
Extinction of conditioned fear is an important model both of inhibitory learning and of behavior therapy for human anxiety disorders. Like other forms of learning, extinction learning is long-lasting and depends on regulated gene expression. Epigenetic mechanisms make an important contribution to persistent changes in gene expression; therefore, in these studies, we have investigated whether epigenetic regulation of gene expression contributes to fear extinction. Since brain-derived neurotrophic factor ( BDNF) is crucial for synaptic plasticity and for the maintenance of long-term memory, we examined histone modifications around two BDNF gene promoters after extinction of cued fear, as potential targets of learning-induced epigenetic regulation of gene expression. Valproic acid ( VPA), used for some time as an anticonvulsant and a mood stabilizer, modulates the expression of BDNF, and is a histone deacetylase ( HDAC) inhibitor. Here, we report that extinction of conditioned fear is accompanied by a significant increase in histone H4 acetylation around the BDNF P4 gene promoter and increases in BDNF exon I and IV mRNA expression in prefrontal cortex, that VPA enhances long-term memory for extinction because of its HDAC inhibitor effects, and that VPA potentiates the effect of weak extinction training on histone H4 acetylation around both the BDNF P1 and P4 gene promoters and on BDNF exon IV mRNA expression. These results suggest a relationship between histone H4 modification, epigenetic regulation of BDNF gene expression, and long-term memory for extinction of conditioned fear. In addition, they suggest that HDAC inhibitors may become a useful pharmacological adjunct to psychotherapy for human anxiety disorders.