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

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: 6.75). 04/2005; 25(9):2255-66. DOI: 10.1523/JNEUROSCI.4372-04.2005
Source: PubMed

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.

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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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    • "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 [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] because they are genetically divergent [34] and because they are the progenitor strains of the BXD recombinant inbred lines [35]. Specifically, the existence of a phenotypic difference between the progenitor strains indicates that a systems genetics approach [36] using the BXD lines could be utilized to determine the genes and gene mechanisms underlying that phenotype. "
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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). "
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