腹侧被盖区中阿片类物质抑制脑源性神经营养因子（Bdnf）基因表达的表观遗传基础。
Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area.
作者信息
Koo Ja Wook, Mazei-Robison Michelle S, LaPlant Quincey, Egervari Gabor, Braunscheidel Kevin M, Adank Danielle N, Ferguson Deveroux, Feng Jian, Sun Haosheng, Scobie Kimberly N, Damez-Werno Diane M, Ribeiro Efrain, Peña Catherine Jensen, Walker Deena, Bagot Rosemary C, Cahill Michael E, Anderson Sarah Ann R, Labonté Benoit, Hodes Georgia E, Browne Heidi, Chadwick Benjamin, Robison Alfred J, Vialou Vincent F, Dias Caroline, Lorsch Zachary, Mouzon Ezekiell, Lobo Mary Kay, Dietz David M, Russo Scott J, Neve Rachael L, Hurd Yasmin L, Nestler Eric J
机构信息
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Physiology, Michigan State University, East Lansing, Michigan, USA.
出版信息
Nat Neurosci. 2015 Mar;18(3):415-22. doi: 10.1038/nn.3932. Epub 2015 Feb 2.
Brain-derived neurotrophic factor (BDNF) has a crucial role in modulating neural and behavioral plasticity to drugs of abuse. We found a persistent downregulation of exon-specific Bdnf expression in the ventral tegmental area (VTA) in response to chronic opiate exposure, which was mediated by specific epigenetic modifications at the corresponding Bdnf gene promoters. Exposure to chronic morphine increased stalling of RNA polymerase II at these Bdnf promoters in VTA and altered permissive and repressive histone modifications and occupancy of their regulatory proteins at the specific promoters. Furthermore, we found that morphine suppressed binding of phospho-CREB (cAMP response element binding protein) to Bdnf promoters in VTA, which resulted from enrichment of trimethylated H3K27 at the promoters, and that decreased NURR1 (nuclear receptor related-1) expression also contributed to Bdnf repression and associated behavioral plasticity to morphine. Our findings suggest previously unknown epigenetic mechanisms of morphine-induced molecular and behavioral neuroadaptations.
脑源性神经营养因子（BDNF）在调节对滥用药物的神经和行为可塑性方面起着关键作用。我们发现，长期暴露于阿片类药物会导致腹侧被盖区（VTA）中外显子特异性Bdnf表达持续下调，这是由相应Bdnf基因启动子处的特定表观遗传修饰介导的。长期暴露于吗啡会增加VTA中这些Bdnf启动子处RNA聚合酶II的停滞，并改变允许性和抑制性组蛋白修饰以及其调节蛋白在特定启动子处的占据情况。此外，我们发现吗啡抑制了磷酸化CREB（cAMP反应元件结合蛋白）与VTA中Bdnf启动子的结合，这是由于启动子处三甲基化H3K27的富集所致，并且NURR1（核受体相关蛋白1）表达的降低也导致了Bdnf的抑制以及与吗啡相关的行为可塑性。我们的研究结果揭示了吗啡诱导分子和行为神经适应的先前未知的表观遗传机制。
Zotero 插件