Ethanol-responsive brain region expression networks: Implications for behavioral responses to acute ethanol in DBA/2J versus C57BL/6J mice
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.
- SourceAvailable from: Allan V. Kalueff
Behavioural brain research 02/2014; 276. DOI:10.1016/j.bbr.2014.01.038 · 3.39 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 . "
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- "Mice are a powerful model system useful for dissecting the genetic and neurobiological mechanisms which underlie complex behaviors. The C57BL/6J (B6) and DBA/2J (D2) mouse strains are frequently compared                because they are genetically divergent  and because they are the progenitor strains of the BXD recombinant inbred lines . Specifically, the existence of a phenotypic difference between the progenitor strains indicates that a systems genetics approach  using the BXD lines could be utilized to determine the genes and gene mechanisms underlying that phenotype. "
ABSTRACT: Attentional set-shifting deficits are a feature of multiple psychiatric disorders. However, the neurogenetic mechanisms underlying these deficits are largely unknown. In the present study we assessed performance of C57BL/6J and DBA/2J mice on a touchscreen-based attentional set-shifting task similar to those used with humans and non-human primates. In experiment 1, mice discriminated simple white lines followed by compound stimuli composed of white lines superimposed on grey shapes. Although performance of the two strains was largely equivalent during early stages of the task, DBA/2J mice committed significantly more errors compared to C57BL/6J mice on the extra-dimensional shift. Additionally, performance of mice as a group declined across the three compound discrimination reversals. In experiment 2 we assessed salience of the shapes and lines dimensions and determined if dimensional salience, a variable previously shown to affect set-shifting abilities in humans and non-human primates, could be systematically manipulated. Findings from experiment 2 suggested that strain differences during the extra-dimensional shift in experiment 1 were most parsimoniously explained by a consistently impaired ability in DBA/2J mice to discriminate a subset of the compound stimuli. Additionally, unlike maze-based tasks, the relative salience of the two dimensions could be manipulated by systematically altering the width of lines exemplars while retaining other potentially-relevant attributes of the compound stimuli. These findings reveal unique and in some cases strain-dependent phenomena related to discriminations of simple and multidimensional visual stimuli which may facilitate future efforts to identify and fully characterize visual discrimination, reversal learning, and attentional set-shifting deficits in mice.Behavioural brain research 12/2013; 261. DOI:10.1016/j.bbr.2013.12.015 · 3.39 Impact Factor
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- "For qRT-PCR experiments, single nucleus accumbens (NAc) samples from 9-week old, untreated C57BL/6J, DBA/2J, α7 KO and WT mice were microdissected on ice and immediately flash-frozen in liquid nitrogen using a protocol described previously (Kerns et al. 2005). Samples were homogenized with a Polytron ® (Kinematica AG, Bohemia, NY, USA) and extracted using a guanidine/phenol/chloroform method (STAT-60, Tel-Test, Inc., Friendswood, TX, USA). "
ABSTRACT: Mortality from tobacco smoking remains the leading cause of preventable death in the world, yet current cessation therapies are only modestly successful, suggesting new molecular targets are needed. Genetic analysis of gene expression and behavior identified Chrna7 as potentially modulating nicotine place conditioning in the BXD panel of inbred mice. We used gene targeting and pharmacological tools to confirm the role of Chrna7 in nicotine CPP. To identify molecular events downstream of Chrna7 that may modulate nicotine preference, we performed microarray analysis of α7 KO and WT nucleus accumbens tissue, followed by confirmation with quantitative PCR and immunoblotting. In the BXD panel, we found a putative cis eQTL for Chrna7 in nucleus accumbens that correlated inversely to nicotine CPP. We observed that gain-of-function α7 mice did not display nicotine preference at any dose tested, while conversely, α7 KO mice showed nicotine place preference at a dose below that routinely required to produce preference. In B6 mice, the α7 nAChR-selective agonist, PHA-543613, dose-dependently blocked nicotine CPP, which was restored using the α7 nAChR-selective antagonist, MLA. Our genomic studies implicated an mRNA co-expression network regulated by Chrna7 in nucleus accumbens. Mice lacking Chrna7 demonstrate increased insulin signaling in the nucleus accumbens, which may modulate nicotine place preference. Our studies provide novel targets for future work on development of more effective therapeutic approaches to counteract the rewarding properties of nicotine for smoking cessation.Genes Brain and Behavior 11/2013; DOI:10.1111/gbb.12113 · 3.51 Impact Factor