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
Hippocampus Gene Expression Correlates for ZM_EOPEN measured in BXD RI Females obtained using GeneNetwork Hippocampus Consortium M430v2 (Jun06) RMA. The ZM_EOPEN measures Zero Maze - total entries in open quadrants 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
Striatum Gene Expression Correlates for COCA_TIME_COND_CHG measured in BXD RI Females & Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The COCA_TIME_COND_CHG measures Cocaine CPP - difference in time spent relative to baseline drug exposure under the domain Cocaine. 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
Striatum Gene Expression Correlates for COCA_TIME_PCT_CHANGE measured in BXD RI Females & Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The COCA_TIME_PCT_CHANGE measures Cocaine CPP - difference in percent test time spent relative to preconditioning under the domain Cocaine. 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
Hippocampus Gene Expression Correlates for VOCA_THRESHOLD measured in BXD RI Females obtained using GeneNetwork Hippocampus Consortium M430v2 (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
Hippocampus Gene Expression Correlates for ZM_PCT_OPEN measured in BXD RI Females obtained using GeneNetwork Hippocampus Consortium M430v2 (Jun06) RMA. The ZM_PCT_OPEN measures Zero Maze - Percentage open time 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
Hippocampus Gene Expression Correlates for ZM_TCLOSED measured in BXD RI Females obtained using GeneNetwork Hippocampus Consortium M430v2 (Jun06) RMA. The ZM_TCLOSED measures Zero Maze - Time in Closed Arms 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
Hippocampus Gene Expression Correlates for ZM_TOPEN measured in BXD RI Females obtained using GeneNetwork Hippocampus Consortium M430v2 (Jun06) RMA. The ZM_TOPEN measures Zero Maze - total time in open quadrants 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
QTL for nicotine sensitivity on Chr13 at D13Mit59 (37.58 Mbp , Build 37)
Description:
nicotine sensitivity spans 12.58 - 62.58 Mbp (NCBI Build 37) on Chr13. 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 ethanol withdrawal on Chr13 at D13Ncvs35 (71.29 Mbp , Build 37)
Description:
ethanol withdrawal spans 46.29 - 96.29 Mbp (NCBI Build 37) on Chr13. 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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