Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area

被引：87

作者：

Koo, Jo Wook ^{[1
,2
]}

Mazei-Robison, Michelle S. ^{[1
,2
,3
]}

LaPlant, Quincey ^{[1
,2
]}

Egervari, Gabor ^{[1
,2
,4
,5
]}

Braunscheidel, Kevin M. ^{[6
]}

Adank, Danielle N. ^{[6
]}

Ferguson, Deveroux ^{[1
,2
]}

Feng, Jian ^{[1
,2
]}

Sun, Haosheng ^{[1
,2
]}

Scobie, Kimberly N. ^{[1
,2
]}

Damez-Werno, Diane M. ^{[1
,2
]}

Ribeiro, Efrain ^{[1
,2
]}

Pena, Catherine Jensen ^{[1
,2
]}

Walker, Deena ^{[1
,2
]}

Bagot, Rosemary C. ^{[1
,2
]}

Cahill, Michael E. ^{[1
,2
]}

Anderson, Sarah Ann R. ^{[1
,2
,4
,5
]}

Labonte, Benoit ^{[1
,2
]}

Hodes, Georgia E. ^{[1
,2
]}

Browne, Heidi ^{[1
,2
]}

Chadwick, Benjamin ^{[1
,2
,4
,5
]}

Robison, Alfred J. ^{[1
,2
,3
]}

Vialou, Vincent F. ^{[1
,2
,7
]}

Dias, Caroline ^{[1
,2
]}

Lorsch, Zachary ^{[1
,2
]}

Mouzon, Ezekiel ^{[1
,2
]}

Lobo, Mary Kay ^{[8
]}

Dietz, David M. ^{[7
]}

Russo, Scott J. ^{[1
,2
]}

Neve, Rachael L. ^{[9
]}

Hurd, Yasmin L. ^{[1
,2
,4
,5
]}

Nestler, Eric J. ^{[1
,2
]}

机构：

[1] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA

[3] Michigan State Univ, Dept Physiol, E Lansing, MI 48824 USA

[4] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[5] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA

[6] SUNY Buffalo, Dept Pharmacol & Toxicol, Buffalo, NY 14260 USA

[7] UPMC, CNRS, INSERM, Unite Mixte Rech 7224,U952, Paris, France

[8] Univ Maryland, Sch Med, Dept Neurobiol & Anat, Baltimore, MD 21201 USA

[9] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA

来源：

NATURE NEUROSCIENCE | 2015年 / 18卷 / 03期

关键词：

MESOLIMBIC DOPAMINE SYSTEM; ELEMENT-BINDING PROTEIN; NEUROTROPHIC FACTOR; METHYLTRANSFERASE ACTIVITY; TRANSCRIPTIONAL REPRESSION; HISTONE DEACETYLASES; NURR1; TRANSCRIPTION; NEURONAL-ACTIVITY; COCAINE REWARD; MORPHINE;

D O I：

10.1038/nn.3932

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 VIA 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 VIA, 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.

引用

页码：415 / 422

页数：8

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