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Acute and chronic alcohol exposure was analyzed in 534 (C57BL/6J x C3H/HeJ)F2 mice. Behavioral testing was done using 5 traits, acute drug effect, forced ethanol drinking, withdrawal studies ethanol preference and stress induced ethanol drinking. The following QTL were found in a genome wide scan: Following the QTL is the Chromosome , cM location, and LOD score, Eih1 (Chr 1, 85 cM, LOD 6.6), Eih2 (Chr 7, 10 cM, LOD 3.6), Ceih1 (Chr 3, 55 cM, LOD 4.1), Ceih2 (Chr 6, 24.7 cM, LOD 4.1), Ceih3 (Chr 13, 39 cM, LOD 4.1), Eia1(Chr 1, 65 cM, LOD 10.3 and 10.4), Eiwa1 (Chr 7, 50 cM, LOD 4.4), Eiwa2(Chr 11, 43.1 cM, LOD 4.1),Aldd1(Chr 5, 42 cM, LOD 13.2), Aldd2(Chr 12, 18 cM, LOD 5.3),Eiwax1(Chr 1, 79 cM, LOD 6.5), Eiwax2(Chr 5, 59 cM, LOD 15.0), Eiwax3(Chr 12, 21 cM, LOD 3.6), Methp1(Chr 16, 31.4 cM, LOD 4.3), Mec1(Chr 16, 19.4 cM, LOD 5.1), Epbs1(Chr 16, 33 cM, LOD 4.1), Ecbs1(Chr 16, 29.4 cM, LOD 4.8), Mec2(Chr 1, 109 cM, LOD 3.9), Mec3(Chr 2, 109 cM, LOD 4.3), Mec4(Chr 5, 29 cM, LOD 3.9), Mec5(Chr 10, 2 cM, LOD 5.0), Mec6(Chr 15, 49 cM, LOD 5.2, 95% CI 6.7–56.7).
Authors:
Drews E, Rcz I, Lacava AD, Barth A, Bilkei-Gorz A, Wienker TF, Zimmer A
Ethanol Preference from BXD lines span 58586243-108586243. This interval was obtained by using an arbitrary interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org). Marker Loci associated with 10% Ethanol Preferences Drinking at p<0.05 (Two Tailed) in the BXD RI set and the Correlation Coefficient, p and Estimated LOD. D15Mit33 (83586243 NCBI 37) p=0.05, LOD=0.08 overall LOD BXD & Select Line 2.4.
QTL for Voluntary Ethanol Consumption on LS x SS RI lines spans 43765164-93765164 .This interval was obtained by using an arbitrary interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org). Chr 15 D15Mit3 39 cM VEC (females) 0.02
In the present study Aaq1, a previously mapped QTL on mouse Chromosome 15 linked to alcohol acceptance, is confirmed using a (C57BL/6J x DBA/2J)F2 population. Aaq1 mapped to 15 cM (D15Mit60)- 48 cM (D15Mit34) on mouse Chromosome 15 with a peak LOD score of 3.8 at approximately 30 cM. C57BL/6J-derived alleles confer increased alcohol acceptance in a dominant fashion at Aaq1. A potential candidate gene for Aaq1 is the peripheral benzodiazepine receptor gene, Bzrp.
Authors:
McClearn GE, Tarantino LM, Rodriguez LA, Jones BC, Blizard DA, Plomin R
QTL mapping results for B6D2F2 mice in regions provisionally identified in BXD RI mice for free-choice ethanol consumption. Peak D15Mit33 58586243-108586243. This interval was obtained by using an arbitrary interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org)
Analysis of 2 Lore5 interval specific congenic strains (ISCS) excluded Mapk8ip as a candidate gene for Lore5. The Lore5 interval appears to be localized between D15Mit94 (29 cM) and D15Mit93 (43.7).
Authors:
Ehringer MA, Thompson J, Conroy O, Yang F, Hink R, Bennett B, Johnson TE, Sikela JM
Alcohol use disorder (AUD) is a complex psychiatric disorder with strong genetic and environmental risk factors. We studied the molecular perturbations underlying risky drinking behavior by measuring transcriptome changes across the neurocircuitry of addiction in a genetic mouse model of binge drinking. Sixteen generations of selective breeding for high blood alcohol levels after a binge drinking session produced global changes in brain gene expression in alcohol-naïve High Drinking in the Dark (HDID-1) mice. Using gene expression profiles to generate circuit-level hypotheses, we developed a systems approach that integrated regulation of gene coexpression networks across multiple brain regions, neuron-specific transcriptional signatures, and knowledgebase analytics. Whole-cell, voltage-clamp recordings from nucleus accumbens shell neurons projecting to the ventral tegmental area showed differential ethanol-induced plasticity in HDID-1 and control mice and provided support for one of the hypotheses. There were similarities in gene networks between HDID-1 mouse brains and postmortem brains of human alcoholics, suggesting that some gene expression patterns associated with high alcohol consumption are conserved across species. This study demonstrated the value of gene networks for data integration across biological modalities and species to study mechanisms of disease.
Authors:
Laura B Ferguson, Lingling Zhang, Daniel Kircher, Shi Wang, R Dayne Mayfield, John C Crabbe, Richard A Morrisett, R Adron Harris, Igor Ponomarev
Alcohol use disorder (AUD) is a complex psychiatric disorder with strong genetic and environmental risk factors. We studied the molecular perturbations underlying risky drinking behavior by measuring transcriptome changes across the neurocircuitry of addiction in a genetic mouse model of binge drinking. Sixteen generations of selective breeding for high blood alcohol levels after a binge drinking session produced global changes in brain gene expression in alcohol-naïve High Drinking in the Dark (HDID-1) mice. Using gene expression profiles to generate circuit-level hypotheses, we developed a systems approach that integrated regulation of gene coexpression networks across multiple brain regions, neuron-specific transcriptional signatures, and knowledgebase analytics. Whole-cell, voltage-clamp recordings from nucleus accumbens shell neurons projecting to the ventral tegmental area showed differential ethanol-induced plasticity in HDID-1 and control mice and provided support for one of the hypotheses. There were similarities in gene networks between HDID-1 mouse brains and postmortem brains of human alcoholics, suggesting that some gene expression patterns associated with high alcohol consumption are conserved across species. This study demonstrated the value of gene networks for data integration across biological modalities and species to study mechanisms of disease.
Authors:
Laura B Ferguson, Lingling Zhang, Daniel Kircher, Shi Wang, R Dayne Mayfield, John C Crabbe, Richard A Morrisett, R Adron Harris, Igor Ponomarev
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We tested three PPAR agonists in a continuous access two-bottle choice (2BC) drinking paradigm and found that tesaglitazar (PPARα/γ; 1.5 mg/kg) and fenofibrate (PPARα; 150 mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPARα/γ/β; 75 mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co-expression network analysis (WGCNA) revealed co-expression of treatment-significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior.
Authors:
Laura B Ferguson, Dana Most, Yuri A Blednov, R Adron Harris
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We tested three PPAR agonists in a continuous access two-bottle choice (2BC) drinking paradigm and found that tesaglitazar (PPARα/γ; 1.5 mg/kg) and fenofibrate (PPARα; 150 mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPARα/γ/β; 75 mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co-expression network analysis (WGCNA) revealed co-expression of treatment-significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior.
Authors:
Laura B Ferguson, Dana Most, Yuri A Blednov, R Adron Harris
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