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 Browne; Benjamin 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

doi:10.1038/nn.3932

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 journal › Article › peer-review

89 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 language	English (US)
Pages (from-to)	415-425
Number of pages	11
Journal	Nature Neuroscience
Volume	18
Issue number	3
DOIs	https://doi.org/10.1038/nn.3932
State	Published - Mar 27 2015
Externally published	Yes

ASJC Scopus subject areas

General Neuroscience

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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

Koo, JW, Mazei-Robison, MS, Laplant, Q, Egervari, G, Braunscheidel, KM, Adank, DN, Ferguson, D, Feng, J, Sun, H, Scobie, KN, Damez-Werno, DM, Ribeiro, E, Peña, CJ, Walker, D, Bagot, RC, Cahill, ME, Anderson, SAR, Labonté, B, Hodes, GE, Browne, H, Chadwick, B, Robison, AJ, Vialou, VF, Dias, C, Lorsch, Z, Mouzon, E, Lobo, MK, Dietz, DM, Russo, SJ, Neve, RL, Hurd, YL & Nestler, EJ 2015, 'Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area', Nature Neuroscience, vol. 18, no. 3, pp. 415-425. https://doi.org/10.1038/nn.3932

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title = "Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area",

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.",

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

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AU - Koo, Ja Wook

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AU - Laplant, Quincey

AU - Egervari, Gabor

AU - Braunscheidel, Kevin M.

AU - Adank, Danielle N.

AU - Ferguson, Deveroux

AU - Feng, Jian

AU - Sun, Haosheng

AU - Scobie, Kimberly N.

AU - Damez-Werno, Diane M.

AU - Ribeiro, Efrain

AU - Peña, Catherine Jensen

AU - Walker, Deena

AU - Bagot, Rosemary C.

AU - Cahill, Michael E.

AU - Anderson, Sarah Ann R.

AU - Labonté, Benoit

AU - Hodes, Georgia E.

AU - Browne, Heidi

AU - Chadwick, Benjamin

AU - Robison, Alfred J.

AU - Vialou, Vincent F.

AU - Dias, Caroline

AU - Lorsch, Zachary

AU - Mouzon, Ezekiell

AU - Lobo, Mary Kay

AU - Dietz, David M.

AU - Russo, Scott J.

AU - Neve, Rachael L.

AU - Hurd, Yasmin L.

AU - Nestler, Eric J.

PY - 2015/3/27

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N2 - 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.

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

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