Ethanol-responsive brain region expression networks: Implications for behavioral responses to acute ethanol in DBA/2J versus C57BL/6J mice

Robnet T. Kerns, Ajay Ravindranathan, Sajida Hassan, Mary P. Cage, Tim York, James M. Sikela, Robert W. Williams, Michael F. Miles

Research output: Contribution to journalArticle

167 Citations (Scopus)

Abstract

Activation of the mesolimbic dopamine reward pathway by acute ethanol produces reinforcement and changes in gene expression that appear to be crucial to the molecular basis for adaptive behaviors and addiction. The inbred mouse strains DBA/2J and C57BL/6J exhibit contrasting acute behavioral responses to ethanol. We used oligonucleotide microarrays and bioinformatics methods to characterize patterns of gene expression in three brain regions of the mesolimbic reward pathway of these strains. Expression profiling included examination of both differences in gene expression 4 h after saline injection or acute ethanol (2 g/kg). Using a rigorous stepwise method for microarray analysis, we identified 788 genes differentially expressed in control DBA/2J versus C57BL/6J mice and 307 ethanol-regulated genes in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. There were strikingly divergent patterns of ethanol-responsive gene expression in the two strains. Ethanol-responsive genes also showed clustering at discrete chromosomal regions, suggesting local chromatin effects in regulation. Ethanol-regulated genes were generally related to neuroplasticity, but regulation of discrete functional groups and pathways was brain region specific: glucocorticoid signaling, neurogenesis, and myelination in the prefrontal cortex; neuropeptide signaling and developmental genes, including factor Bdnf, in the nucleus accumbens; and retinoic acid signaling in the ventral tegmental area. Bioinformatics analysis identified several potential candidate genes for quantitative trait loci linked to ethanol behaviors, further supporting a role for expression profiling in identifying genes for complex traits. Brain region-specific changes in signaling and neuronal plasticity may be critical components in development of lasting ethanol behavioral phenotypes such as dependence, sensitization, and craving.

Original languageEnglish (US)
Pages (from-to)2255-2266
Number of pages12
JournalJournal of Neuroscience
Volume25
Issue number9
DOIs
StatePublished - Mar 2 2005

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Inbred C57BL Mouse
Ethanol
Brain
Gene Expression
Ventral Tegmental Area
Neuronal Plasticity
Genes
Nucleus Accumbens
Prefrontal Cortex
Computational Biology
Reward
Developmental Genes
Inbred Strains Mice
Quantitative Trait Loci
Psychological Adaptation
Neurogenesis
Microarray Analysis
Tretinoin
Oligonucleotide Array Sequence Analysis
Neuropeptides

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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Ethanol-responsive brain region expression networks : Implications for behavioral responses to acute ethanol in DBA/2J versus C57BL/6J mice. / Kerns, Robnet T.; Ravindranathan, Ajay; Hassan, Sajida; Cage, Mary P.; York, Tim; Sikela, James M.; Williams, Robert W.; Miles, Michael F.

In: Journal of Neuroscience, Vol. 25, No. 9, 02.03.2005, p. 2255-2266.

Research output: Contribution to journalArticle

Kerns, Robnet T. ; Ravindranathan, Ajay ; Hassan, Sajida ; Cage, Mary P. ; York, Tim ; Sikela, James M. ; Williams, Robert W. ; Miles, Michael F. / Ethanol-responsive brain region expression networks : Implications for behavioral responses to acute ethanol in DBA/2J versus C57BL/6J mice. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 9. pp. 2255-2266.
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