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
Neocortex Gene Expression Correlates for HAND_BASELINE measured in BXD RI Females obtained using GeneNetwork Neocortex ILM6v1.1 (Feb08) RankInv. The HAND_BASELINE measures Handling induced convulsion baseline under the domain Ethanol HIC. 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 HIC_SCORE measured in BXD RI Males obtained using GeneNetwork Neocortex ILM6v1.1 (Feb08) RankInv. The HIC_SCORE measures Handling induced convulsion score under the domain Ethanol HIC. 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 POSTURE measured in BXD RI Females & Males obtained using INIA Brain mRNA M430 (Jun06) RMA. 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 POSTURE measured in BXD RI Females obtained using INIA Brain mRNA M430 (Jun06) RMA. 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
Renthal W, Kumar A, Xiao G, Wilkinson M, Covington HE 3rd, Maze I, Sikder D, Robison AJ, LaPlant Q, Dietz DM, Russo SJ, Vialou V, Chakravarty S, Kodadek TJ, Stack A, Kabbaj M, Nestler EJ
from Lewohl et al., 2000; from case group one (identical to case group used in PCR-differential display experiments reported by Fan et al., 1999); includes three uncomplicated alcoholics, one alcoholic with cirrhosis, and one alcoholic with concomitant Wernicke encephalopathy
Authors:
Lewohl JM, Wang L, Miles MF, Zhang L, Dodd PR, Harris RA
QTL for nicotine sensitivity on Chr7 at D7Mit66 (116.91 Mbp , Build 37)
Description:
nicotine sensitivity spans 91.91 - 141.91 Mbp (NCBI Build 37) on Chr7. 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 alcohol preference locus on Chr7 at D7Mit105 (126.73 Mbp , Build 37)
Description:
alcohol preference locus spans 101.73 - 151.73 Mbp (NCBI Build 37) on Chr7. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
alcohol preference locus 14, female specific at D7Mit105 with a LOD score of 1.84 (p < 0.004) spans and preference correlation of 0.591 101.73 - 151.73 Mbp (NCBI Build 37) on Chr7. 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 home cage activity on Chr7 at D7Mit12 (129.57 Mbp , Build 37)
Description:
METH responses for home cage activity spans 104.57 - 154.57 Mbp (NCBI Build 37) on Chr7. 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 body temperature on Chr7 at Xmv76 (137.02 Mbp , Build 37)
Description:
METH responses for body temperature spans 112.02 - 162.02 Mbp (NCBI Build 37) on Chr7. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
Chronic cocaine - Cocaine-paired (conditioned place preference) vs. Control (saline or cocaine-non-paired) DNA microarray All genes on microarray presented After the pre-conditioning phase where animals were allowed access to either compartment for 15 minutes for 4 consecutive days, the conditioning phase for the cocaine-paired groups and cocaine non-paired groups began, consisting of eight subsequent daily sessions. For both groups, cocaine (10 mg / kg) or saline injections were administered on alternate days. For the cocaine-paired groups, rats were immediately placed in one of the two compartments for 30 min with the door in place restricting a z transformation followed by z test and anova followed by Student-Newman-Keuls' post hoc test. Gene expression profile was assessed 24 h after the last conditioning session that corresponded to 48 h after last cocaine exposure, when drug has been eliminated from the body and transient transcriptional changes are likely to be minimal. Therefore, changes in gene expression at this time-point are likely to reflect longer lasting adaptations that may account for maintenance of cocaine-induced memories. The complete lists of normalized gene expression values for the hippocampus of saline-treated, cocaine non-paired and cocaine-paired groups are presented. Analyses revealed that 214 transcripts were differentially regulated in the hippocampus of cocaine-paired rats vs. non-paired and saline-treated controls. Cocaine-induced conditioned place preference caused significant increases in the expression of 151 genes and caused decreases in the expression of 63 genes. (NIF Table ID 130.1 [83])
Authors:
Krasnova IN, Li SM, Wood WH, McCoy MT, Prabhu VV, Becker KG, Katz JL, Cadet JL
Chronic cocaine - Cocaine-paired (conditioned place preference) vs. Control (saline or cocaine-non-paired) DNA microarray All genes on microarray presented After the pre-conditioning phase where animals were allowed access to either compartment for 15 minutes for 4 consecutive days, the conditioning phase for the cocaine-paired groups and cocaine non-paired groups began, consisting of eight subsequent daily sessions. For both groups, cocaine (10 mg / kg) or saline injections were administered on alternate days. For the cocaine-paired groups, rats were immediately placed in one of the two compartments for 30 min with the door in place restricting a z transformation followed by z test and anova followed by Student-Newman-Keuls' post hoc test. Gene expression profile was assessed 24 h after the last conditioning session that corresponded to 48 h after last cocaine exposure, when drug has been eliminated from the body and transient transcriptional changes are likely to be minimal. Therefore, changes in gene expression at this time-point are likely to reflect longer lasting adaptations that may account for maintenance of cocaine-induced memories. The complete lists of normalized gene expression values for the frontal cortex of saline-treated, cocaine non-paired and cocaine-paired groups are presented. Differences in the expression of 39 transcripts in the frontal cortex were related to the conditioned place preference paradigm. These include increases in the level of 22 genes and decreases in 17 genes. (NIF Table ID 130.3 [83.5])
Authors:
Krasnova IN, Li SM, Wood WH, McCoy MT, Prabhu VV, Becker KG, Katz JL, Cadet JL
Chronic ethanol - Ethanol vs. Control DNA microarray Change in gene expression - Class II Alcoholics were classified based on the quantity of alcohol consumed, according to the National Health and Medical Research Council (NHMRC) (>80 g of alcohol per day), instead of the criteria established by the American Psychiatric Association (DSM-IV) or the World Health Organization (ICD-10). Many alcoholic patients in this study consumed significantly more than 80 g / day for most of their adult life. Cerebral atrophy was observed in three alcoholic cases. All alcoholic cases included in our Axon GenePix 4.0 software; partial least squares (PLS) statistical procedure; linear discriminant analysis (LDA) procedure for prediction analysis. PLS and LDA analysis were performed using in JMP IN software; principal component analysis (PCA) used STATISTICA software. Results reflect the combined dataset: Class I genes were qualitatively different, that is, they were predominantly detected in one group but not the other. They represent those that were more likely turned off or turned on as a result of alcohol abuse. Class II genes were consistently detected in both groups. They represent consistently expressed genes for which quantitative differences in expression could be determined. (NIF Method ID 157)
Genes associated with Homo sapiens that interact with the MeSH term 'RS 17053' (C099495). Incorporates data from 222 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Oryctolagus cuniculus that interact with the MeSH term 'chromium hexavalent ion' (C074702). Incorporates data from 1 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Homo sapiens that interact with the MeSH term 'resveratrol' (C059514). Incorporates data from 16 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Homo sapiens that interact with the MeSH term 'vorinostat' (C111237). Incorporates data from 13 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
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