Extinction of Aversive Memories Associated with Morphine Withdrawal Requires ERK-Mediated Epigenetic Regulation of Brain-Derived Neurotrophic Factor Transcription in the Rat Ventromedial Prefrontal Cortex
Extinction of Aversive Memories Associated with Morphine Withdrawal Requires ERK-Mediated Epigenetic Regulation of Brain-Derived Neurotrophic Factor Transcription in the Rat Ventromedial Prefrontal Cortex
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DOI：
10.1523/jneurosci.1991-12.2012
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发表时间：
2012-10
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通讯作者：
Weisheng Wang;Shuo Kang;Wen-tao Liu;Mu Li;Yao Liu;Chuan Yu;Jie Chen;Z. Chi;Ling He
中科院分区：
文献类型：
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作者：
Weisheng Wang;Shuo Kang;Wen-tao Liu;Mu Li;Yao Liu;Chuan Yu;Jie Chen;Z. Chi;Ling He
最近的证据表明，组蛋白去乙酰化酶（HDAC）抑制剂促进药物服用的奖励记忆的消退。然而，关于染色质修饰在药物戒断的厌恶性记忆消退中的作用知之甚少。在这项研究中，我们使用条件性位置厌恶（CPA），一个高度敏感的模型，用于测量药物戒断的厌恶记忆，探讨脑源性神经营养因子（BDNF）基因表达的表观遗传调控在厌恶记忆消退中的作用。我们发现，CPA消退训练诱导急性吗啡依赖大鼠脑源性神经营养因子外显子I转录启动子区的cAMP反应元件结合蛋白（CREB）的募集和组蛋白H3的乙酰化增加，并增加脑源性神经营养因子mRNA和蛋白质在腹内侧前额叶皮层（vmPFC）的表达，这种对脑源性神经营养因子基因转录的表观遗传调控可以通过胞内干预来促进或减弱。在消退训练之前，给予VMPFC输注HDAC抑制剂阿司他丁A或细胞外信号调节激酶（ERK）抑制剂U 0126（1，4-二氨基-2，3-二氰基-1，4-双（甲硫基）丁二烯）。相应地，用U 0126破坏BDNF基因转录的表观遗传调控或用Trk受体拮抗剂K252 a或BDNF清除剂酪氨酸激酶受体B（Trk B）-Fc抑制BDNF信号传导阻断CPA行为的消退。我们还发现，消退训练诱导的ERK和CREB的激活和CPA行为的消退可以通过在vmPFC内输注d-环丝氨酸（一种NMDA受体部分激动剂）或氨基膦戊酸（一种NMDA受体拮抗剂）来增强或抑制。我们的结论是，消除吗啡戒断的厌恶性记忆需要通过激活的ERK-CREB信号通路，也许在NMDA受体依赖的方式在vmPFC的BDNF基因转录的表观遗传调控。
Recent evidence suggests that histone deacetylase (HDAC) inhibitors facilitate extinction of rewarding memory of drug taking. However, little is known about the role of chromatin modification in the extinction of aversive memory of drug withdrawal. In this study, we used conditioned place aversion (CPA), a highly sensitive model for measuring aversive memory of drug withdrawal, to investigate the role of epigenetic regulation of brain-derived neurotrophic factor (BDNF) gene expression in extinction of aversive memory. We found that CPA extinction training induced an increase in recruiting cAMP response element-binding protein (CREB) to and acetylation of histone H3 at the promoters of BDNF exon I transcript and increased BDNF mRNA and protein expression in the ventromedial prefrontal cortex (vmPFC) of acute morphine-dependent rats and that such epigenetic regulation of BDNF gene transcription could be facilitated or diminished by intra-vmPFC infusion of HDAC inhibitor trichostatin A or extracellular signal-regulated kinase (ERK) inhibitor U0126 (1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene) before extinction training. Correspondingly, disruption of the epigenetic regulation of BDNF gene transcription with U0126 or suppression of BDNF signaling with Trk receptor antagonist K252a or BDNF scavenger tyrosine kinase receptor B (TrkB)-Fc blocked extinction of CPA behavior. We also found that extinction training-induced activation of ERK and CREB and extinction of CPA behavior could be potentiated or suppressed by intra-vmPFC infusion of d-cycloserine, a NMDA receptor partial agonist or aminophosphonopentanoic acid, a NMDA receptor antagonist. We conclude that extinction of aversive memory of morphine withdrawal requires epigenetic regulation of BDNF gene transcription in the vmPFC through activation of the ERK-CREB signaling pathway perhaps in a NMDA receptor-dependent manner.