Abstract
Searches for the identity of genes that influence the levels of alcohol consumption by humans and other animals have often been driven by presupposition of the importance of particular gene products in determining positively or negatively reinforcing effects of ethanol. We have taken an unbiased approach and performed a meta-analysis across three types of mouse populations to correlate brain gene expression with levels of alcohol intake. Our studies, using filtering procedures based on QTL analysis, produced a list of eight candidate genes with highly heritable expression, which could explain a significant amount of the variance in alcohol preference in mice. Using the Allen Brain Atlas for gene expression, we noted that the candidate genes’ expression was localized to the olfactory and limbic areas as well as to the orbitofrontal cortex. Informatics techniques and pathway analysis illustrated the role of the candidate genes in neuronal migration, differentiation, and synaptic remodeling. The importance of olfactory cues, learning and memory formation (Pavlovian conditioning), and cortical executive function, for regulating alcohol intake by animals (including humans), is discussed.
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References
American Psychiatric Associaton (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DC
Anderson AK, Christoff K, Stappen I, Panitz D, Ghahremani DG et al (2003) Dissociated neural representations of intensity and valence in human olfaction. Nat Neurosci 6:196–202
Bachmanov AA, Kiefer SW, Molina JC, Tordoff MG, Duffy VB et al (2003) Chemosensory factors influencing alcohol perception, preferences, and consumption. Alcohol Clin Exp Res 27:220–231
Belknap JK, Belknap ND, Berg JH, Coleman R (1977) Preabsorptive vs. postabsorptive control of ethanol intake in C57BL/6J and DBA/2J mice. Behav Genet 7:413–425
Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc B 57:289–300
Bergen AW, Yang XR, Bai Y, Beerman MB, Goldstein AM et al (2003) Genomic regions linked to alcohol consumption in the Framingham Heart Study. BMC Genet 4(Suppl 1):S101
Bergen AW, Baccarelli A, McDaniel TK, Kuhn K, Pfeiffer R et al (2007) Cis sequence effects on gene expression. BMC Genomics 8:296
Bhave SV, Hoffman PL, Lassen N, Vasiliou V, Saba L et al (2006) Gene array profiles of alcohol and aldehyde metabolizing enzymes in brains of C57BL/6 and DBA/2 mice. Alcohol Clin Exp Res 30:1659–1669
Bhave SV, Hornbaker C, Phang TL, Saba L, Lapadat R et al (2007) The PhenoGen informatics website: tools for analyses of complex traits. BMC Genet 8:59
Chaillan FA, Roman FS, Soumireu-Mourat B (1996) Modulation of synaptic plasticity in the hippocampus and piriform cortex by physiologically meaningful olfactory cues in an olfactory association task. J Physiol Paris 90:343–347
Chesler EJ, Lu L, Shou S, Qu Y, Gu J et al (2005) Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat Genet 37:233–242
Chiang E, Strowbridge BW (2007) Diversity of neural signals mediated by multiple burst-firing mechanisms in rat olfactory tubercle neurons. J Neurophysiol 98:2716–2728
Connolly JB, Tully T (1998) Integrins: a role for adhesion molecules in olfactory memory. Curr Biol 8:R386–R389
Cowen MS, Djouma E, Lawrence AJ (2005) The metabotropic glutamate 5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine reduces ethanol self-administration in multiple strains of alcohol-preferring rats and regulates olfactory glutamatergic systems. J Pharmacol Exp Ther 315:590–600
de Anda FC, Pollarolo G, Da Silva JS, Camoletto PG, Feiguin F et al (2005) Centrosome localization determines neuronal polarity. Nature 436:704–708
Dodd J, Castellucci VF (1991) Smell and taste: the chemical senses. In: Kandel ER, Schwartz JH, Jessell TM (eds) Principles of neural science. Elsevier, New York, pp 512–529
Enoch MA, Goldman D (2001) The genetics of alcoholism and alcohol abuse. Curr Psychiatry Rep 3:144–151
Fedulov V, Rex CS, Simmons DA, Palmer L, Gall CM et al (2007) Evidence that long-term potentiation occurs within individual hippocampal synapses during learning. J Neurosci 27:8031–8039
Field AP (2001) Meta-analysis of correlation coefficients: a Monte Carlo comparison of fixed- and random-effects methods. Psychol Methods 6:161–180
Gerrow K, El-Husseini A (2007) Receptors look outward: revealing signals that bring excitation to synapses. Sci STKE 2007:pe56
Goldin AL (2003) Mechanisms of sodium channel inactivation. Curr Opin Neurobiol 13:284–290
Gould E (2007) How widespread is adult neurogenesis in mammals? Nat Rev Neurosci 8:481–488
Grahame NJ, Li TK, Lumeng L (1999) Selective breeding for high and low alcohol preference in mice. Behav Genet 29:47–57
Grieco TM, Malhotra JD, Chen C, Isom LL, Raman IM (2005) Open-channel block by the cytoplasmic tail of sodium channel beta4 as a mechanism for resurgent sodium current. Neuron 45:233–244
Guerrini I, Cook CC, Kest W, Devitgh A, McQuillin A et al (2005) Genetic linkage analysis supports the presence of two susceptibility loci for alcoholism and heavy drinking on chromosome 1p22.1-11.2 and 1q21.3–24.2. BMC Genet 6:11
He JC, Neves SR, Jordan JD, Iyengar R (2006) Role of the Go/i signaling network in the regulation of neurite outgrowth. Can J Physiol Pharmacol 84:687–694
Hedges LV, Vevea JL (1998) Fixed- and random-effects models in meta-analysis. Psychol Methods 3:486–504
Higginbotham HR, Gleeson JG (2007) The centrosome in neuronal development. Trends Neurosci 30:276–283
Hishimoto A, Liu QR, Drgon T, Pletnikova O, Walther D et al (2007) Neurexin 3 polymorphisms are associated with alcohol dependence and altered expression of specific isoforms. Hum Mol Genet 16:2880–2891
Kalant H, LeBlanc AE, Gibbins RJ (1971) Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacol Rev 23:135–191
Kampov-Polevoy AB, Kasheffskaya OP, Sinclair JD (1990) Initial acceptance of ethanol: gustatory factors and patterns of alcohol drinking. Alcohol 7:83–85
Lander ES, Botstein D (1989) Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121:185–199
Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A et al (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168–176
Li TK, Hewitt BG, Grant BF (2007) The alcohol dependence syndrome, 30 years later: a commentary. the 2006 H. David Archibald lecture. Addiction 102:1522–1530
Liang JJ, Cockett M, Khawaja XZ (1998) Immunohistochemical localization of G protein beta1, beta2, beta3, beta4, beta5, and gamma3 subunits in the adult rat brain. J Neurochem 71:345–355
Liu QR, Drgon T, Johnson C, Walther D, Hess J et al (2006) Addiction molecular genetics: 639,401 SNP whole genome association identifies many “cell adhesion” genes. Am J Med Genet B Neuropsychiatr Genet 141:918–925
Ma JY, Catterall WA, Scheuer T (1997) Persistent sodium currents through brain sodium channels induced by G protein betagamma subunits. Neuron 19:443–452
Maccioni P, Orrú A, Korkosz A, Gessa GL, Carai MA et al (2007) Cue-induced reinstatement of ethanol seeking in Sardinian alcohol-preferring rats. Alcohol 41:31–39
Mantegazza M, Yu FH, Powell AJ, Clare JJ, Catterall WA et al (2005) Molecular determinants for modulation of persistent sodium current by G-protein betagamma subunits. J Neurosci 25:3341–3349
Mantovani A, Garlanda C, Doni A, Bottazzi B (2008) Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3. J Clin Immunol 28:1–13
Martin C, Beshel J, Kay LM (2007) An olfacto-hippocampal network is dynamically involved in odor-discrimination learning. J Neurophysiol 98:2196–2205
Matys V, Kel-Margoulis OV, Fricke E, Liebich I, Land S et al (2006) TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes. Nucleic Acids Res 34:D108–D110
McBride WJ, Li TK (1998) Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents. Crit Rev Neurobiol 12:339–369
McEwen DP, Koenekoop RK, Khanna H, Jenkins PM, Lopez I et al (2007) Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons. Proc Natl Acad Sci USA 104:15917–15922
Melendez RI, Middaugh LD, Kalivas PW (2006) Development of an alcohol deprivation and escalation effect in C57BL/6J mice. Alcohol Clin Exp Res 30:2017–2025
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 USA 103:6368–6373
Newlin DB, Hotchkiss B, Cox WM, Rauscher F, Li TK (1989) Autonomic and subjective responses to alcohol stimuli with appropriate control stimuli. Addict Behav 14:625–630
Oyama F, Miyazaki H, Sakamoto N, Becquet C, Machida Y et al (2006) Sodium channel beta4 subunit: down-regulation and possible involvement in neuritic degeneration in Huntington’s disease transgenic mice. J Neurochem 98:518–529
Reid MS, Flammino F, Starosta A, Palamar J, Franck J (2006) Physiological and subjective responding to alcohol cue exposure in alcoholics and control subjects: evidence for appetitive responding. J Neural Transm 113:1519–1535
Ritzmann RF, Tabakoff B (1976) Body temperature in mice: a quantitative measure of alcohol tolerance and physical dependence. J Pharmacol Exp Ther 199:158–170
Rodriguez LA, Plomin R, Blizard DA, Jones BC, McClearn GE (1994) Alcohol acceptance, preference, and sensitivity in mice. I. Quantitative genetic analysis using BXD recombinant inbred strains. Alcohol Clin Exp Res 18:1416–1422
Saba L, Bhave SV, Grahame N, Bice P, Lapadat R et al (2006) Candidate genes and their regulatory elements: alcohol preference and tolerance. Mamm Genome 17:669–688
Schroeder JP, Overstreet DH, Hodge CW (2005) The mGluR5 antagonist MPEP decreases operant ethanol self-administration during maintenance and after repeated alcohol deprivations in alcohol-preferring (P) rats. Psychopharmacology (Berl) 179:262–270
Sia GM, Beique JC, Rumbaugh G, Cho R, Worley PF et al (2007) Interaction of the N-terminal domain of the AMPA receptor GluR4 subunit with the neuronal pentraxin NP1 mediates GluR4 synaptic recruitment. Neuron 55:87–102
Tsui CC, Copeland NG, Gilbert DJ, Jenkins NA, Barnes C et al (1996) Narp, a novel member of the pentraxin family, promotes neurite outgrowth and is dynamically regulated by neuronal activity. J Neurosci 16:2463–2478
Visscher PM, Thompson R, Haley CS (1996) Confidence intervals in QTL mapping by bootstrapping. Genetics 143:1013–1020
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 USA 103:16364–16369
Walter NA, McWeeney SK, Peters ST, Belknap JK, Hitzemann R et al (2007) SNPs matter: impact on detection of differential expression. Nat Methods 4:679–680
Whitfield JB, Zhu G, Madden PA, Neale MC, Heath AC et al (2004) The genetics of alcohol intake and of alcohol dependence. Alcohol Clin Exp Res 28:1153–1160
World Health Organization (2005) International statistical classification of diseases and health related problems, 2nd edn. WHO, ICD-10, Geneva
Yoneyama N, Crabbe JC, Ford MM, Murillo A, Finn DA (2008) Voluntary ethanol consumption in 22 inbred mouse strains. Alcohol 42:149–160
Zutter MM, Edelson BT (2007) The alpha2beta1 integrin: a novel collectin/C1q receptor. Immunobiology 212:343–353
Acknowledgments
This work was supported in part by NIAAA, NIH (U01 AA016649-INIA Project; U01 AA016663-INIA Project; U01 AA013478-INIA Project; R24 AA013162), and the Banbury Fund.
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Tabakoff, B., Saba, L., Kechris, K. et al. The genomic determinants of alcohol preference in mice. Mamm Genome 19, 352–365 (2008). https://doi.org/10.1007/s00335-008-9115-z
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DOI: https://doi.org/10.1007/s00335-008-9115-z