Bredy Timothy W, Barad Mark
Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, California 90095, USA.
Learn Mem. 2008 Jan 3;15(1):39-45. doi: 10.1101/lm.801108. Print 2008 Jan.
Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its function as a histone deacetylase inhibitor (HDAC). Here we report that VPA enhances long-term memory for both acquisition and extinction of cued-fear. Interestingly, VPA enhances extinction, but also enhances renewal of the original conditioned fear when tested in a within-subjects design. This effect appears to be related to a reconsolidation-like process since a single CS reminder in the presence of VPA can enhance long-term memory for the original fear in the context in which fear conditioning takes place. We also show that by modifying the intertrial interval during extinction training, VPA can strengthen reconsolidation of the original fear memory or enhance long-term memory for extinction such that it becomes independent of context. These findings have important implications for the use of HDAC inhibitors as adjuncts to behavior therapy in the treatment of phobia and related anxiety disorders.
组蛋白修饰有助于基因表达的表观遗传调控，这一过程现已被认为对长期记忆的巩固很重要。丙戊酸（VPA）多年来一直用作抗惊厥药和情绪稳定剂，它对学习和记忆有影响，并通过作为组蛋白脱乙酰酶抑制剂（HDAC）发挥作用来增强条件性恐惧的消退。在此我们报告，VPA增强了线索性恐惧习得和消退的长期记忆。有趣的是，VPA增强了消退，但在被试内设计中测试时也增强了原始条件性恐惧的恢复。这种效应似乎与一种类似重新巩固的过程有关，因为在VPA存在的情况下单次条件刺激提示可以增强恐惧条件化发生情境中原始恐惧的长期记忆。我们还表明，通过在消退训练期间改变试验间隔，VPA可以加强原始恐惧记忆的重新巩固或增强消退的长期记忆，使其变得与情境无关。这些发现对于使用HDAC抑制剂作为行为疗法辅助手段治疗恐惧症和相关焦虑症具有重要意义。
