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.
A list of the 307 genes found to be upregulated or downregulated by ethanol in PFC, VTA or NA of B6 or D2 mice. ID number represents cluster membership from Figure 4.
Authors:
Kerns RT, Ravindranathan A, Hassan S, Cage MP, York T, Sikela JM, Williams RW, Miles MF
Whole Brain Gene Expression Correlates for ST_BACKGROUND measured in BXD RI Males obtained using INIA Brain mRNA M430 (Jun06) RMA. The ST_BACKGROUND measures Background startle response under the domain Basal Behavior. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Whole Brain Gene Expression Correlates for MDMA_ACT_MDA_1 measured in BXD RI Males obtained using INIA Brain mRNA M430 (Jun06) RMA. The MDMA_ACT_MDA_1 measures Locomotor response of 10 mg/kg MDMA injected on Day 2 under the domain MDMA. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Neocortex Gene Expression Correlates for POSTURE measured in BXD RI Females & Males obtained using GeneNetwork Neocortex ILM6v1.1 (Feb08) RankInv. The POSTURE measures Morphine - Postural Effects under the domain Morphine. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Neocortex Gene Expression Correlates for POSTURE measured in BXD RI Females obtained using GeneNetwork Neocortex ILM6v1.1 (Feb08) RankInv. The POSTURE measures Morphine - Postural Effects under the domain Morphine. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Whole Brain Gene Expression Correlates for VOCA_THRESHOLD measured in BXD RI Females obtained using INIA Brain mRNA M430 (Jun06) RMA. The VOCA_THRESHOLD measures Vocalization Threshold - shock intensity (mA) under the domain Stress Vocalization. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Genes containing SNPs associated with Alcohol Dependence in Netherlands Study of Depression and Anxiety Sample. The analysis is a case-control study of 178 female and 140 male alcohol dependent cases and 929 female and 313 male controls. Alcohol dependence is defined as ever reporting a CAGE score > 2. Controls never reported a CAGE score > 2.
Authors:
Lind PA, Macgregor S, Vink JM, Pergadia ML, Hansell NK, de Moor MH, Smit AB, Hottenga JJ, Richter MM, Heath AC, Martin NG, Willemsen G, de Geus EJ, Vogelzangs N, Penninx BW, Whitfield JB, Montgomery GW, Boomsma DI, Madden PA
cocaine related behavior 2 (Cocrb2) spans 144.050573 - 194.050573 Mbp (NCBI Build 37) on Chr 1. Obtained from MGI (http://www.informatics.jax.org) by searching for QTLs containing the keyword .
QTL for ethanol conditioned taste aversion on Chr1 at NA (167.59 Mbp , Build 37)
Description:
ethanol conditioned taste aversion spans 142.59 - 192.59 Mbp (NCBI Build 37) on Chr1. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
QTL for cocaine related behavior on Chr1 at D1Ncvs12 (169.05 Mbp , Build 37)
Description:
cocaine related behavior spans 144.05 - 194.05 Mbp (NCBI Build 37) on Chr1. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
QTL for METH responses for climbing on Chr1 at D1Ncvs12 (169.05 Mbp , Build 37)
Description:
METH responses for climbing spans 144.05 - 194.05 Mbp (NCBI Build 37) on Chr1. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
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