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Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks

BACKGROUND: A systems biology approach based on the assembly and interrogation of gene regulatory networks, or interactomes, was used to study neuroadaptation processes associated with the transition to alcohol dependence at the molecular level. RESULTS: Using a rat model of dependent and non-depend...

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Autores principales: Repunte-Canonigo, Vez, Shin, William, Vendruscolo, Leandro F, Lefebvre, Celine, van der Stap, Lena, Kawamura, Tomoya, Schlosburg, Joel E, Alvarez, Mariano, Koob, George F, Califano, Andrea, Sanna, Pietro Paolo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410476/
https://www.ncbi.nlm.nih.gov/pubmed/25886852
http://dx.doi.org/10.1186/s13059-015-0593-5
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author Repunte-Canonigo, Vez
Shin, William
Vendruscolo, Leandro F
Lefebvre, Celine
van der Stap, Lena
Kawamura, Tomoya
Schlosburg, Joel E
Alvarez, Mariano
Koob, George F
Califano, Andrea
Sanna, Pietro Paolo
author_facet Repunte-Canonigo, Vez
Shin, William
Vendruscolo, Leandro F
Lefebvre, Celine
van der Stap, Lena
Kawamura, Tomoya
Schlosburg, Joel E
Alvarez, Mariano
Koob, George F
Califano, Andrea
Sanna, Pietro Paolo
author_sort Repunte-Canonigo, Vez
collection PubMed
description BACKGROUND: A systems biology approach based on the assembly and interrogation of gene regulatory networks, or interactomes, was used to study neuroadaptation processes associated with the transition to alcohol dependence at the molecular level. RESULTS: Using a rat model of dependent and non-dependent alcohol self-administration, we reverse engineered a global transcriptional regulatory network during protracted abstinence, a period when relapse rates are highest. We then interrogated the network to identify master regulator genes that mechanistically regulate brain region-specific signatures associated with dependent and non-dependent alcohol self-administration. Among these, the gene coding for the glucocorticoid receptor was independently identified as a master regulator in multiple brain regions, including the medial prefrontal cortex, nucleus accumbens, central nucleus of the amygdala, and ventral tegmental area, consistent with the view that brain reward and stress systems are dysregulated during protracted abstinence. Administration of the glucocorticoid antagonist mifepristone in either the nucleus accumbens or ventral tegmental area selectively decreased dependent, excessive, alcohol self-administration in rats but had no effect on non-dependent, moderate, alcohol self-administration. CONCLUSIONS: Our study suggests that assembly and analysis of regulatory networks is an effective strategy for the identification of key regulators of long-term neuroplastic changes within specific brain regions that play a functional role in alcohol dependence. More specifically, our results support a key role for regulatory networks downstream of the glucocorticoid receptor in excessive alcohol drinking during protracted alcohol abstinence. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-015-0593-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-44104762015-04-28 Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks Repunte-Canonigo, Vez Shin, William Vendruscolo, Leandro F Lefebvre, Celine van der Stap, Lena Kawamura, Tomoya Schlosburg, Joel E Alvarez, Mariano Koob, George F Califano, Andrea Sanna, Pietro Paolo Genome Biol Research BACKGROUND: A systems biology approach based on the assembly and interrogation of gene regulatory networks, or interactomes, was used to study neuroadaptation processes associated with the transition to alcohol dependence at the molecular level. RESULTS: Using a rat model of dependent and non-dependent alcohol self-administration, we reverse engineered a global transcriptional regulatory network during protracted abstinence, a period when relapse rates are highest. We then interrogated the network to identify master regulator genes that mechanistically regulate brain region-specific signatures associated with dependent and non-dependent alcohol self-administration. Among these, the gene coding for the glucocorticoid receptor was independently identified as a master regulator in multiple brain regions, including the medial prefrontal cortex, nucleus accumbens, central nucleus of the amygdala, and ventral tegmental area, consistent with the view that brain reward and stress systems are dysregulated during protracted abstinence. Administration of the glucocorticoid antagonist mifepristone in either the nucleus accumbens or ventral tegmental area selectively decreased dependent, excessive, alcohol self-administration in rats but had no effect on non-dependent, moderate, alcohol self-administration. CONCLUSIONS: Our study suggests that assembly and analysis of regulatory networks is an effective strategy for the identification of key regulators of long-term neuroplastic changes within specific brain regions that play a functional role in alcohol dependence. More specifically, our results support a key role for regulatory networks downstream of the glucocorticoid receptor in excessive alcohol drinking during protracted alcohol abstinence. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-015-0593-5) contains supplementary material, which is available to authorized users. BioMed Central 2015-02-02 2015 /pmc/articles/PMC4410476/ /pubmed/25886852 http://dx.doi.org/10.1186/s13059-015-0593-5 Text en © Repunte-Canonigo et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Repunte-Canonigo, Vez
Shin, William
Vendruscolo, Leandro F
Lefebvre, Celine
van der Stap, Lena
Kawamura, Tomoya
Schlosburg, Joel E
Alvarez, Mariano
Koob, George F
Califano, Andrea
Sanna, Pietro Paolo
Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks
title Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks
title_full Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks
title_fullStr Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks
title_full_unstemmed Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks
title_short Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks
title_sort identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410476/
https://www.ncbi.nlm.nih.gov/pubmed/25886852
http://dx.doi.org/10.1186/s13059-015-0593-5
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