Kerns R, Ravindranathan A, Hassan S, Cage M, York T, Sikela J et al. Ethanol-responsive brain region expression networks: implications for behavioral responses to acute ethanol in DBA/2J versus C57BL/6J mice. J Neurosci 25: 2255-2266

Department of Pharmacology/Toxicology and the Center for Study of Biological Complexity, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 04/2005; 25(9):2255-66. DOI: 10.1523/JNEUROSCI.4372-04.2005
Source: PubMed


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.

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    • "In particular, NNAT and AP1S1 have prior evidence of involvement with AD[81]. NNAT, an imprinted gene expressed early in brain development, was shown to regulate dendritic calcium levels in hippocampal neurons and was differentially expressed in the NAc, PFC, and VTA of an acute ethanol response mouse model[82,83]. AP1S1, a clathrin-related protein involved in membrane trafficking and endocytosis, as well as the causal gene for MENDIK (mental retardation, enteropathy, deafness, neuropathy, ichthyosis and keratoderma) syndrome, was differentially expressed in the PFC of chronic alcoholics[9,84]. Although we did not observe significant enrichment of AD GWAS signals among our significant eQTLs for miRNA hubs, NNAT and PSMB5 from neuronal expression-associated mRNA modules, M yellow and M turquoise , respectively, were both cooperatively targeted by hsa-miR-34 family miRNAs. "
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    ABSTRACT: Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-typespecific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.
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    • "DBA/2J mice show significant ethanol-induced locomotor stimulation and reduced alcohol consumption relative to C57BL/6J. Kerns et al. (2005) took advantage of these behavioral differences, and examined global gene expression using microarrays in these two strains in the nucleus accumbens, prefrontal cortex, and ventral tegmental area 4 h following acute ethanol (2 g/kg) or saline injection. The BK channel encoding gene, KCNMA1, was one of only 307 genes found to be regulated in response to ethanol in either strain in any of the brain regions. "
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    ABSTRACT: Alcohol abuse is a significant public health problem. Understanding the molecular effects of ethanol is important for the identification of at risk individuals, as well as the development of novel pharmacotherapies. The large conductance calcium sensitive potassium (BK) channel has emerged as an important player in the behavioral response to ethanol in genetic studies in several model organisms and in humans. The BK channel, slo-1, was identified in a forward genetics screen as a major ethanol target in C. elegans for the effects of ethanol on locomotion and egg-laying behaviors. Regulation of the expression of the BK channel, slo, in Drosophila underlies the development of rapid tolerance to ethanol and benzyl alcohol sedation. Rodent expression studies of the BK-encoding KCNMA1 gene have identified regulation of mRNA levels in response to ethanol exposure, and knock out studies in mice have demonstrated that the β subunits of the BK channel, β1 and β4, can modulate ethanol sensitivity of the channel in electrophysiological preparations, and can influence drinking behavior. In human genetics studies, both KCNMA1 and the genes encoding β subunits of the BK channel have been associated with alcohol dependence. This review describes the genetic data for a role for BK channels in mediating behavioral responses to ethanol across these species.
    Full-text · Article · Sep 2014 · Frontiers in Physiology
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    • "Therefore, the use of bioinformatics tools becomes vital in order to analyze the enormity of data and identify patterns and phenotypes, as well as to decipher underlying interconnected physiological pathways [18]. For example, high-throughput genomics provides an extraordinary view into the genetic architecture of animal and human behavior, the interconnectivity of complex traits [65] [66], and " network " models of animal phenotypes (as part of phenomics), which are crucial for exploring neuropsychiatric processes [3] [67] [68] [69]. Nevertheless, further integration of heterogeneous data, especially gene and protein expression pathways, is critical because deciphering such networks and their interplay poses one of the greatest challenges in current systems biology [70]. "

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