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PLOS ONE  2013 

Gene Expression in Brain and Liver Produced by Three Different Regimens of Alcohol Consumption in Mice: Comparison with Immune Activation

DOI: 10.1371/journal.pone.0059870

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Abstract:

Chronically available alcohol escalates drinking in mice and a single injection of the immune activator lipopolysaccharide can mimic this effect and result in a persistent increase in alcohol consumption. We hypothesized that chronic alcohol drinking and lipopolysaccharide injections will produce some similar molecular changes that play a role in regulation of alcohol intake. We investigated the molecular mechanisms of chronic alcohol consumption or lipopolysaccharide insult by gene expression profiling in prefrontal cortex and liver of C57BL/6J mice. We identified similar patterns of transcriptional changes among four groups of animals, three consuming alcohol (vs water) in different consumption tests and one injected with lipopolysaccharide (vs. vehicle). The three tests of alcohol consumption are the continuous chronic two bottle choice (Chronic), two bottle choice available every other day (Chronic Intermittent) and limited access to one bottle of ethanol (Drinking in the Dark). Gene expression changes were more numerous and marked in liver than in prefrontal cortex for the alcohol treatments and similar in the two tissues for lipopolysaccharide. Many of the changes were unique to each treatment, but there was significant overlap in prefrontal cortex for Chronic-Chronic Intermittent and for Chronic Intermittent-lipopolysaccharide and in liver all pairs showed overlap. In silico cell-type analysis indicated that lipopolysaccharide had strongest effects on brain microglia and liver Kupffer cells. Pathway analysis detected a prefrontal cortex-based dopamine-related (PPP1R1B, DRD1, DRD2, FOSB, PDNY) network that was highly over-represented in the Chronic Intermittent group, with several genes from the network being also regulated in the Chronic and lipopolysaccharide (but not Drinking in the Dark) groups. Liver showed a CYP and GST centered metabolic network shared in part by all four treatments. We demonstrate common consequences of chronic alcohol consumption and immune activation in both liver and brain and show distinct genomic consequences of different types of alcohol consumption.

References

[1]  Farris SP, Wolen AR, Miles MF (2010) Using expression genetics to study the neurobiology of ethanol and alcoholism. Int Rev Neurobiol 91: 95–128.
[2]  Robison AJ, Nestler EJ (2011) Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci 12: 623–637.
[3]  Liu J, Lewohl JM, Harris RA, Iyer VR, Dodd PR, et al. (2006) Patterns of gene expression in the frontal cortex discriminate alcoholic from nonalcoholic individuals. Neuropsychopharmacology 31: 1574–1582.
[4]  Mayfield RD, Harris RA, Schuckit MA (2008) Genetic factors influencing alcohol dependence. Br J Pharmacol 154: 275–287.
[5]  Zhou Z, Yuan Q, Mash DC, Goldman D (2011) Substance-specific and shared transcription and epigenetic changes in the human hippocampus chronically exposed to cocaine and alcohol. Proc Natl Acad Sci U S A 108: 6626–6631.
[6]  Bell RL, Kimpel MW, McClintick JN, Strother WN, Carr LG, et al. (2009) Gene expression changes in the nucleus accumbens of alcohol-preferring rats following chronic ethanol consumption. Pharmacol Biochem Behav 94: 131–147.
[7]  McBride WJ, Kimpel MW, Schultz JA, McClintick JN, Edenberg HJ, et al. (2010) Changes in gene expression in regions of the extended amygdala of alcohol-preferring rats after binge-like alcohol drinking. Alcohol 44: 171–183.
[8]  Rodd ZA, Kimpel MW, Edenberg HJ, Bell RL, Strother WN, et al. (2008) Differential gene expression in the nucleus accumbens with ethanol self-administration in inbred alcohol-preferring rats. Pharmacol Biochem Behav 89: 481–498.
[9]  Mulligan MK, Rhodes JS, Crabbe JC, Mayfield RD, Adron Harris R, et al. (2011) Molecular profiles of drinking alcohol to intoxication in C57BL/6J mice. Alcohol Clin Exp Res 35: 659–670.
[10]  Wolstenholme JT, Warner JA, Capparuccini MI, Archer KJ, Shelton KL, et al. (2011) Genomic analysis of individual differences in ethanol drinking: evidence for non-genetic factors in C57BL/6 mice. PLoS One 6: e21100.
[11]  Ponomarev I, Wang S, Zhang L, Harris RA, Mayfield RD (2012) Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence. J Neurosci 32: 1884–1897.
[12]  Crews FT, Qin L, Sheedy D, Vetreno RP, Zou J (2012) High Mobility Group Box 1/Toll-like Receptor Danger Signaling Increases Brain Neuroimmune Activation in Alcohol Dependence. Biol Psychiatry 10.1016/j.biopsych.2012.09.030.
[13]  Mulligan MK, Ponomarev I, Hitzemann RJ, Belknap JK, Tabakoff B, et al. (2006) Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis. Proc Natl Acad Sci U S A 103: 6368–6373.
[14]  Blednov YA, Benavidez JM, Geil C, Perra S, Morikawa H, et al. (2011) Activation of inflammatory signaling by lipopolysaccharide produces a prolonged increase of voluntary alcohol intake in mice. Brain Behav Immun 25 Suppl 1S92–S105.
[15]  Crabbe JC, Harris RA, Koob GF (2011) Preclinical studies of alcohol binge drinking. Ann N Y Acad Sci 1216: 24–40.
[16]  Deaciuc IV, Doherty DE, Burikhanov R, Lee EY, Stromberg AJ, et al. (2004) Large-scale gene profiling of the liver in a mouse model of chronic, intragastric ethanol infusion. J Hepatol 40: 219–227.
[17]  Yin HQ, Je YT, Kim M, Kim JH, Kong G, et al. (2009) Analysis of hepatic gene expression during fatty liver change due to chronic ethanol administration in mice. Toxicol Appl Pharmacol 235: 312–320.
[18]  Crews FT, Boettiger CA (2009) Impulsivity, frontal lobes and risk for addiction. Pharmacol Biochem Behav 93: 237–247.
[19]  Pfefferbaum A, Sullivan EV, Rosenbloom MJ, Mathalon DH, Lim KO (1998) A controlled study of cortical gray matter and ventricular changes in alcoholic men over a 5-year interval. Arch Gen Psychiatry 55: 905–912.
[20]  Leeman RF, Heilig M, Cunningham CL, Stephens DN, Duka T, et al. (2010) Ethanol consumption: how should we measure it? Achieving consilience between human and animal phenotypes. Addict Biol 15: 109–124.
[21]  Wahlsten D, Bachmanov A, Finn DA, Crabbe JC (2006) Stability of inbred mouse strain differences in behavior and brain size between laboratories and across decades. Proc Natl Acad Sci U S A 103: 16364–16369.
[22]  Hopf FW, Simms JA, Chang SJ, Seif T, Bartlett SE, et al. (2011) Chlorzoxazone, an SK-type potassium channel activator used in humans, reduces excessive alcohol intake in rats. Biol Psychiatry 69: 618–624.
[23]  Simms JA, Steensland P, Medina B, Abernathy KE, Chandler LJ, et al. (2008) Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats. Alcohol Clin Exp Res 32: 1816–1823.
[24]  Szabo G, Mandrekar P, Petrasek J, Catalano D (2011) The unfolding web of innate immune dysregulation in alcoholic liver injury. Alcohol Clin Exp Res 35: 782–786.
[25]  Wang HJ, Gao B, Zakhari S, Nagy LE (2012) Inflammation in alcoholic liver disease. Annu Rev Nutr 32: 343–368.
[26]  Blednov YA, Ponomarev I, Geil C, Bergeson S, Koob GF, et al. (2012) Neuroimmune regulation of alcohol consumption: behavioral validation of genes obtained from genomic studies. Addict Biol 17: 108–120.
[27]  Crews FT, Zou J, Qin L (2011) Induction of innate immune genes in brain create the neurobiology of addiction. Brain Behav Immun 25 Suppl 1S4–S12.
[28]  Middaugh LD, Kelley BM, Bandy AL, McGroarty KK (1999) Ethanol consumption by C57BL/6 mice: influence of gender and procedural variables. Alcohol 17: 175–183.
[29]  Meliska CJ, Bartke A, McGlacken G, Jensen RA (1995) Ethanol, nicotine, amphetamine, and aspartame consumption and preferences in C57BL/6 and DBA/2 mice. Pharmacol Biochem Behav 50: 619–626.
[30]  Nocjar C, Middaugh LD, Tavernetti M (1999) Ethanol consumption and place-preference conditioning in the alcohol-preferring C57BL/6 mouse: relationship with motor activity patterns. Alcohol Clin Exp Res 23: 683–692.
[31]  Rhodes JS, Best K, Belknap JK, Finn DA, Crabbe JC (2005) Evaluation of a simple model of ethanol drinking to intoxication in C57BL/6J mice. Physiol Behav 84: 53–63.
[32]  Dantzer R (2001) Cytokine-induced sickness behavior: where do we stand? Brain Behav Immun 15: 7–24.
[33]  Ponomarev I, Rau V, Eger EI, Harris RA, Fanselow MS (2010) Amygdala transcriptome and cellular mechanisms underlying stress-enhanced fear learning in a rat model of posttraumatic stress disorder. Neuropsychopharmacology 35: 1402–1411.
[34]  Harris RA, Osterndorff-Kahanek E, Ponomarev I, Homanics GE, Blednov YA (2011) Testing the silence of mutations: Transcriptomic and behavioral studies of GABA(A) receptor alpha1 and alpha2 subunit knock-in mice. Neurosci Lett 488: 31–35.
[35]  R-Development TC (2011) R: A language and environment for statistical computing. Vienna, Austria: R. Foundation for Statistical Computing.
[36]  Lin SM, Du P, Huber W, Kibbe WA (2008) Model-based variance-stabilizing transformation for Illumina microarray data. Nucleic Acids Res 36: e11.
[37]  Bolstad BM, Irizarry RA, Astrand M, Speed TP (2003) A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19: 185–193.
[38]  Du P, Kibbe WA, Lin SM (2008) lumi: a pipeline for processing Illumina microarray. Bioinformatics 24: 1547–1548.
[39]  Smyth GK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3: Article3.
[40]  Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, et al. (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28: 264–278.
[41]  Oldham MC, Konopka G, Iwamoto K, Langfelder P, Kato T, et al. (2008) Functional organization of the transcriptome in human brain. Nat Neurosci 11: 1271–1282.
[42]  Takahara Y, Takahashi M, Wagatsuma H, Yokoya F, Zhang QW, et al. (2006) Gene expression profiles of hepatic cell-type specific marker genes in progression of liver fibrosis. World J Gastroenterol 12: 6473–6499.
[43]  Huang DW, Sherman BT, Lempicki RA (2009a) Systematic and integrative analysis of large gene lists using DAVID Bioinformatics Resources. Nature Protoc 4: 44–57.
[44]  Huang DW, Sherman BT, Lempicki RA (2009b) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37: 1–13.
[45]  Rosenwasser AM, Fixaris MC, Crabbe JC, Brooks PC, Ascheid S (2012) Escalation of intake under intermittent ethanol access in diverse mouse genotypes. Addict Biol 10 (1111/j.1369–1600.2012.00481): x.
[46]  Becker HC, Lopez MF (2004) Increased ethanol drinking after repeated chronic ethanol exposure and withdrawal experience in C57BL/6 mice. Alcohol Clin Exp Res 28: 1829–1838.
[47]  Becker HC, Diaz-Granados JL, Hale RL (1997) Exacerbation of ethanol withdrawal seizures in mice with a history of multiple withdrawal experience. Pharmacol Biochem Behav 57: 179–183.
[48]  Vetreno PV, Crews FT (2013) Innate Immune Signaling and Alcoholism. In: Changhai Cui LG, Antonio Noronha, editor. Neural-Immune Interactions in Brain Function and Alcohol Related Disorders. New York: Springer, U.S. 251–278.
[49]  Alfonso-Loeches S, Pascual-Lucas M, Blanco AM, Sanchez-Vera I, Guerri C (2010) Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. J Neurosci 30: 8285–8295.
[50]  Blanco AM, Guerri C (2007) Ethanol intake enhances inflammatory mediators in brain: role of glial cells and TLR4/IL-1RI receptors. Front Biosci 12: 2616–2630.
[51]  Zou J, Crews F (2010) Induction of innate immune gene expression cascades in brain slice cultures by ethanol: key role of NF-kappaB and proinflammatory cytokines. Alcohol Clin Exp Res 34: 777–789.
[52]  Banks WA, Robinson SM (2010) Minimal penetration of lipopolysaccharide across the murine blood-brain barrier. Brain Behav Immun 24: 102–109.
[53]  Chen Z, Jalabi W, Shpargel KB, Farabaugh KT, Dutta R, et al. (2012) Lipopolysaccharide-Induced Microglial Activation and Neuroprotection against Experimental Brain Injury Is Independent of Hematogenous TLR4. J Neurosci 32: 11706–11715.
[54]  Kauer JA, Malenka RC (2007) Synaptic plasticity and addiction. Nat Rev Neurosci 8: 844–858.
[55]  Maldve RE, Zhang TA, Ferrani-Kile K, Schreiber SS, Lippmann MJ, et al. (2002) DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens. Nat Neurosci 5: 641–648.
[56]  Nuutinen S, Kiianmaa K, Panula P (2011) DARPP-32 and Akt regulation in ethanol-preferring AA and ethanol-avoiding ANA rats. Neurosci Lett 503: 31–36.
[57]  Nairn AC, Svenningsson P, Nishi A, Fisone G, Girault JA, et al. (2004) The role of DARPP-32 in the actions of drugs of abuse. Neuropharmacology 47 Suppl 114–23.
[58]  Femenia T, Manzanares J (2012) Increased ethanol intake in prodynorphin knockout mice is associated to changes in opioid receptor function and dopamine transmission. Addict Biol 17: 322–337.
[59]  Bazov I, Kononenko O, Watanabe H, Kuntic V, Sarkisyan D, et al. (2011) The endogenous opioid system in human alcoholics: molecular adaptations in brain areas involved in cognitive control of addiction. Addict Biol 10 (1111/j.1369–1600.2011.00366): x.
[60]  Taqi MM, Bazov I, Watanabe H, Sheedy D, Harper C, et al. (2011) Prodynorphin CpG-SNPs associated with alcohol dependence: elevated methylation in the brain of human alcoholics. Addict Biol 16: 499–509.
[61]  Clarke TK, Ambrose-Lanci L, Ferraro TN, Berrettini WH, Kampman KM, et al. (2012) Genetic association analyses of PDYN polymorphisms with heroin and cocaine addiction. Genes Brain Behav 11: 415–423.
[62]  Blednov YA, Walker D, Martinez M, Harris RA (2006) Reduced alcohol consumption in mice lacking preprodynorphin. Alcohol 40: 73–86.
[63]  Kovacs KM, Szakall I, O'Brien D, Wang R, Vinod KY, et al. (2005) Decreased oral self-administration of alcohol in kappa-opioid receptor knock-out mice. Alcohol Clin Exp Res 29: 730–738.
[64]  Nishi A, Kuroiwa M, Miller DB, O'Callaghan JP, Bateup HS, et al. (2008) Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. J Neurosci 28: 10460–10471.
[65]  Logrip ML, Zorrilla EP (2012) Stress history increases alcohol intake in relapse: relation to phosphodiesterase 10A. Addict Biol 10 (1111/j.1369–1600.2012.00460): x.
[66]  Contet C, Gardon O, Filliol D, Becker JA, Koob GF, et al. (2011) Identification of genes regulated in the mouse extended amygdala by excessive ethanol drinking associated with dependence. Addict Biol 16: 615–619.
[67]  Melendez RI, McGinty JF, Kalivas PW, Becker HC (2012) Brain region-specific gene expression changes after chronic intermittent ethanol exposure and early withdrawal in C57BL/6J mice. Addict Biol 17: 351–364.
[68]  Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, et al. (2012) Genomic analysis of reactive astrogliosis. J Neurosci 32: 6391–6410.

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