Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, 97239-3098, USA.
Biol Psychiatry. 2012 Jul 1;72(1):25-33. doi: 10.1016/j.biopsych.2011.12.012. Epub 2012 Jan 29.
A key finding from recent studies of epigenetic mechanisms of memory is that increasing histone acetylation after a learning experience enhances memory consolidation. This has been demonstrated in several preparations, but little is known about whether excitatory and inhibitory memories are equally sensitive to drugs that promote histone acetylation and how transcriptional changes in the hippocampal-medial prefrontal cortex network contribute to these drug effects.
We compare the long-term behavioral consequences of systemic, intrahippocampal and intra-medial prefrontal cortex administration of the histone deacetylase inhibitor sodium butyrate (NaB) after contextual fear conditioning and extinction 1 and/or 14 days later in male c57BL/6J mice (n = 302). Levels of histone acetylation and expression of the product of the immediate-early gene c-Fos were assessed by immunohistochemistry following infusion of NaB into the hippocampus (n = 26).
Across a variety of conditions, the effects of NaB on extinction were larger and more persistent compared to the effects on initial memory formation. NaB administered following weak extinction induced behavioral extinction, infralimbic histone acetylation and c-Fos expression consistent with strong extinction. No similar effect was seen in the prelimbic cortex. The involvement of the infralimbic cortex was confirmed as infusions of NaB into the infralimbic, but not prelimbic cortex, induced extinction enhancements.
These studies show that the memory modulating ability of drugs that enhance acetylation is sensitive to a variety of behavioral and molecular conditions. We further identify transcriptional changes in the hippocampal-infralimbic circuit associated with extinction enhancements induced by the histone deacetylase inhibitor NaB.
最近关于记忆的表观遗传机制的研究有一个重要发现，即在学习经历后增加组蛋白乙酰化可增强记忆巩固。这在几种制剂中得到了证明，但对于兴奋性和抑制性记忆是否同样对促进组蛋白乙酰化的药物敏感，以及海马-内侧前额叶皮层网络中的转录变化如何促成这些药物作用知之甚少。
我们比较了系统给予、海马内给予和内侧前额叶皮层内给予组蛋白去乙酰化酶抑制剂丁酸钠（NaB）后，在雄性 C57BL/6J 小鼠（n = 302）进行情境恐惧条件反射和 1 天和/或 14 天后的长期行为后果。在将 NaB 注入海马后，通过免疫组织化学评估组蛋白乙酰化水平和即刻早期基因 c-Fos 的产物表达（n = 26）。
在各种条件下，与初始记忆形成相比，NaB 对消退的影响更大且更持久。在弱消退后给予 NaB 会诱导行为消退、扣带回下皮质的组蛋白乙酰化和 c-Fos 表达，与强消退一致。在额前皮质中没有观察到类似的效应。额前皮质的参与得到了证实，因为 NaB 注入额前皮质但不注入额前皮质会引起消退增强。
这些研究表明，增强乙酰化的药物的记忆调节能力对多种行为和分子条件敏感。我们进一步确定了与组蛋白去乙酰化酶抑制剂 NaB 诱导的消退增强相关的海马-扣带回下回路中的转录变化。
