Bredy Timothy W, Wu Hao, Crego Cortney, Zellhoefer Jessica, Sun Yi E, Barad Mark
Department of Psychiatry and Biobehavioral Sciences, Brain Research Institute, Semel Institute for Neuroscience and Human Behavior, Los Angeles, California 90095, USA.
Learn Mem. 2007 Apr 6;14(4):268-76. doi: 10.1101/lm.500907. Print 2007 Apr.
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.
条件性恐惧的消退是抑制性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，消退学习具有持久性，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起着重要作用；因此，在这些研究中，我们调查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）对突触可塑性和长期记忆的维持至关重要，我们在提示性恐惧消退后，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靶点。丙戊酸（VPA）长期以来用作抗惊厥药和情绪稳定剂，可调节BDNF的表达，是一种组蛋白脱乙酰酶（HDAC）抑制剂。在此，我们报告，条件性恐惧的消退伴随着BDNF P4基因启动子周围组蛋白H4乙酰化的显著增加以及前额叶皮质中BDNF外显子I和IV mRNA表达的增加，VPA因其HDAC抑制作用增强了消退的长期记忆，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乙酰化以及BDNF外显子IV mRNA表达的影响。这些结果表明组蛋白H4修饰、BDNF基因表达的表观遗传调控与条件性恐惧消退的长期记忆之间存在关联。此外，它们表明HDAC抑制剂可能成为人类焦虑症心理治疗的一种有用的药理学辅助手段。
