Dataset Information

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.

SUBMITTER: Koo JW

PROVIDER: S-EPMC4340719 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Koo Ja Wook JW Mazei-Robison Michelle S MS LaPlant Quincey Q Egervari Gabor G Braunscheidel Kevin M KM Adank Danielle N DN Ferguson Deveroux D Feng Jian J Sun Haosheng H Scobie Kimberly N KN Damez-Werno Diane M DM Ribeiro Efrain E Peña Catherine Jensen CJ Walker Deena D Bagot Rosemary C RC Cahill Michael E ME Anderson Sarah Ann R SA Labonté Benoit B Hodes Georgia E GE Browne Heidi H Chadwick Benjamin B Robison Alfred J AJ Vialou Vincent F VF Dias Caroline C Lorsch Zachary Z Mouzon Ezekiell E Lobo Mary Kay MK Dietz David M DM Russo Scott J SJ Neve Rachael L RL Hurd Yasmin L YL Nestler Eric J EJ

Nature neuroscience 20150202 3

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 rep ...[more]

PMID: 25643298

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Project description:Decades of research have revealed the remarkable complexity of the midbrain dopamine (DA) system, which comprises cells principally located in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Neither homogenous nor serving a singular function, the midbrain DA system is instead composed of distinct cell populations that (1) receive different sets of inputs, (2) project to separate forebrain sites, and (3) are characterized by unique transcriptional and physiological signatures. To appreciate how these differences relate to circuit function, we first need to understand the anatomical connectivity of unique DA pathways and how this connectivity relates to DA-dependent motivated behavior. We and others have provided detailed maps of the input-output relationships of several subpopulations of midbrain DA cells and explored the roles of these different cell populations in directing behavioral output. In this study, we analyze VTA inputs and outputs as a high dimensional dataset (10 outputs, 22 inputs), deploying computational techniques well-suited to finding interpretable patterns in such data. In addition to reinforcing our previous conclusion that the connectivity in the VTA is dependent on spatial organization, our analysis also uncovered a set of inputs elevated onto each projection-defined VTADA cell type. For example, VTADA→NAcLat cells receive preferential innervation from inputs in the basal ganglia, while VTADA→Amygdala cells preferentially receive inputs from populations sending a distributed input across the VTA, which happen to be regions associated with the brain's stress circuitry. In addition, VTADA→NAcMed cells receive ventromedially biased inputs including from the preoptic area, ventral pallidum, and laterodorsal tegmentum, while VTADA→mPFC cells are defined by dominant inputs from the habenula and dorsal raphe. We also go on to show that the biased input logic to the VTADA cells can be recapitulated using projection architecture in the ventral midbrain, reinforcing our finding that most input differences identified using rabies-based (RABV) circuit mapping reflect projection archetypes within the VTA.

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Dataset Information

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

Publications

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

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