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
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.
"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. "
[Show abstract][Hide abstract] 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.
Frontiers in Physiology 09/2014; 5:346. DOI:10.3389/fphys.2014.00346 · 3.53 Impact Factor
"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 . For example, high-throughput genomics provides an extraordinary view into the genetic architecture of animal and human behavior, the interconnectivity of complex traits  , and " network " models of animal phenotypes (as part of phenomics), which are crucial for exploring neuropsychiatric processes    . 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 . "
"Zhao et al. (2012) performed a cross-species meta-analysis by ranking genes differentially expressed in mouse brains in response to ethanol (Kerns et al. 2005; Mulligan et al. 2006) based on orthologs implicated in alcohol-related phenotypes across multiple species, including humans (Reich et al. 1998; Mayfield et al. 2002; Kuo et al. 2006; Prescott et al. 2006; Hodgkinson et al. 2008); C. elegans (Kwon et al. 2004) and D. melanogaster (Morozova et al. 2006, 2007) and identified BDNF, GABRA2, GABRB1, MPDZ, NPY and NPY2R among the top ranked genes. "
[Show abstract][Hide abstract] ABSTRACT: Alcohol abuse and alcoholism incur a heavy socioeconomic cost in many countries. Both genetic and environmental factors contribute to variation in the inebriating effects of alcohol and alcohol addiction among individuals within and across populations. From a genetics perspective, alcohol sensitivity is a quantitative trait determined by the cumulative effects of multiple segregating genes and their interactions with the environment. This review summarizes insights from model organisms as well as human populations that represent our current understanding of the genetic and genomic underpinnings that govern alcohol metabolism and the sedative and addictive effects of alcohol on the nervous system.
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