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

Ja Wook Koo, Michelle S. Mazei-Robison, Quincey Laplant, Gabor Egervari, Kevin M. Braunscheidel, Danielle N. Adank, Deveroux Ferguson, Jian Feng, Haosheng Sun, Kimberly N. Scobie, Diane M. Damez-Werno, Efrain Ribeiro, Catherine Jensen Peña, Deena Walker, Rosemary C. Bagot, Michael E. Cahill, Sarah Ann R. Anderson, Benoit Labonté, Georgia E. Hodes, Heidi BrowneBenjamin Chadwick, Alfred J. Robison, Vincent F. Vialou, Caroline Dias, Zachary Lorsch, Ezekiell Mouzon, Mary Kay Lobo, David M. Dietz, Scott J. Russo, Rachael L. Neve, Yasmin L. Hurd, Eric J. Nestler

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)415-425
Number of pages11
JournalNature neuroscience
Volume18
Issue number3
DOIs
StatePublished - Mar 27 2015

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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    Koo, J. W., Mazei-Robison, M. S., Laplant, Q., Egervari, G., Braunscheidel, K. M., Adank, D. N., Ferguson, D., Feng, J., Sun, H., Scobie, K. N., Damez-Werno, D. M., Ribeiro, E., Peña, C. J., Walker, D., Bagot, R. C., Cahill, M. E., Anderson, S. A. R., Labonté, B., Hodes, G. E., ... Nestler, E. J. (2015). Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area. Nature neuroscience, 18(3), 415-425. https://doi.org/10.1038/nn.3932