Abstract
Psychiatric diseases are very debilitating and some of them highly prevalent (e.g., depression or anxiety). The rat remains one model of choice in this discipline to investigate the neural mechanisms underlying normal and pathological traits. Genomic tools are now applied to identify genes involved in psychiatric illnesses and also to provide new biomarkers for diagnostic and prognosis, new targets for treatment and more generally to better understand the functioning of the brain. In this report, we will review rat models, behavioral approaches used to model psychiatry-related traits and the major studies published in the field including genetic mapping of quantitative trait loci (QTL), transcriptomics, proteomics and transgenic models.
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References
Mormede P, Courvoisier H, Ramos A, Marissal-Arvy N, Ousova O, Desautes C et al (2002) Molecular genetic approaches to investigate individual variations in behavioral and neuroendocrine stress responses. Psychoneuro-endocrinology 27:563–583
Kas MJ, Fernandes C, Schalkwyk LC, Collier DA (2007) Genetics of behavioural domains across the neuropsychiatric spectrum; of mice and men. Mol Psychiatry 12:324–330
Broadhurst PL (1975) The Maudsley reactive and nonreactive strains of rats: a survey. Behav Genet 5:299–319
Hendley ED, Ohlsson WG (1991) Two new inbred rat strains derived from SHR: WKHA, hyperactive, and WKHT, hypertensive, rats. Amer J Physiol 261:H583–H589
Moisan MP, Courvoisier H, Bihoreau MT, Gauguier D, Hendley ED, Lathrop M et al (1996) A major quantitative trait locus influences hyperactivity in the WKHA rat. Nat Genet 14:471–473
Moisan MP, Llamas B, Cook MN, Mormede P (2003) Further dissection of a genomic locus associated with behavioral activity in the Wistar-Kyoto hyperactive rat, an animal model of hyperkinesis. Mol Psychiatry 8:348–352
Fernandez-Teruel A, Escorihuela RM, Gray JA, Aguilar R, Gil L, Gimenez-Llort L et al (2002) A quantitative trait locus influencing anxiety in the laboratory rat. Genome Res 12:618–626
Carr LG, Foroud T, Bice P, Gobbett T, Ivashina J, Edenberg H et al (1998) A quantitative trait locus for alcohol consumption in selectively bred rat lines. Alcohol Clin Exp Res 22:884–887
Bice P, Foroud T, Bo R, Castelluccio P, Lumeng L, Li TK et al (1998) Genomic screen for QTLs underlying alcohol consumption in the P and NP rat lines. Mamm Genome 9:949–955
Radcliffe RA, Erwin VG, Draski L, Hoffmann S, Edwards J, Deng XS et al (2004) Quantitative trait loci mapping for ethanol sensitivity and neurotensin receptor density in an F2 intercross derived from inbred high and low alcohol sensitivity selectively bred rat lines. Alcohol Clin Exp Res 28:1796–1804
Ramos A, Moisan MP, Chaouloff F, de C, de P (1999) Identification of female-specific QTLs affecting an emotionality-related behavior in rats. Mol Psychiatry 4:453–462
Ahmadiyeh N, Churchill GA, Shimomura K, Solberg LC, Takahashi JS, Redei EE (2003) X-linked and lineage-dependent inheritance of coping responses to stress. Mamm Genome 14:748–757
Terenina-Rigaldie E, Moisan MP, Colas A, Beauge F, Shah KV, Jones BC et al (2003) Genetics of behaviour: phenotypic and molecular study of rats derived from high- and low-alcohol consuming lines. Pharmacogenetics 13:543–554
Bielavska E, Kren V, Musilova A, Zidek V, Pravenec M (2002) Genome scanning of the HXB/BXH sets of recombinant inbred strains of the rat for quantitative trait loci associated with conditioned taste aversion. Behav Genet 32:51–56
McEwen BS (2003) Mood disorders and allostatic load. Biol Psychiatry 54:200–207
Hall CS (1934) Emotional behavior in the rat I. Defecation and urination as measures of individual differences in emotionality. J Comp Psychol 18:385–395
Carobrez AP, Bertoglio LJ (2005) Ethological and temporal analyses of anxiety-like behavior: the elevated plus-maze model 20 years on. Neurosci Biobehav Rev 29:1193–1205
Lister RG (1990) Ethologically-based animal models of anxiety disorders. Pharmacol Ther 46:321–340
Fernandez-Teruel A, Gimenez-Llort L, Escorihuela RM, Gil L, Aguilar R, Steimer T et al (2002) Early-life handling stimulation and environmental enrichment: are some of their effects mediated by similar neural mechanisms? Pharmacol Biochem Behav 73:233–245
Ramos A, Mormède P (1998) Stress and emotionality: a multidimensional and genetic approach. Neurosci Biobehav Rev 22:33–57
Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33
El Yacoubi M, Vaugeois JM (2007) Genetic rodent models of depression. Curr Opin Pharmacol 7:3–7
Sousa N, Almeida OF, Wotjak CT (2006) A hitchhiker’s guide to behavioral analysis in laboratory rodents. Genes Brain Behav 5(Suppl 2):5–24
Crabbe JC, Phillips TJ (2004) Pharmacogenetic studies of alcohol self-administration and withdrawal. Psychopharmacology (Berl) 174:539–560
Rodd ZA, Bertsch BA, Strother WN, Le Niculescu H, Balaraman Y, Hayden E et al (2007) Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach. Pharmacogenomics J 7:222–256
Overstreet DH, Rezvani AH, Djouma E, Parsian A, Lawrence AJ (2007) Depressive-like behavior and high alcohol drinking co-occur in the FH/WJD rat but appear to be under independent genetic control. Neurosci Biobehav Rev 31:103–114
Colombo G, Lobina C, Carai MA, Gessa GL (2006) Phenotypic characterization of genetically selected Sardinian alcohol-preferring (sP) and -non-preferring (sNP) rats. Addict Biol 11:324–338
Baum AE, Solberg LC, Churchill GA, Ahmadiyeh N, Takahashi JS, Redei EE (2006) Test- and behavior-specific genetic factors affect WKY hypoactivity in tests of emotionality. Behav Brain Res 169:220–230
Liang T, Spence J, Liu L, Strother WN, Chang HW, Ellison JA et al (2003) alpha-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats. Proc Natl Acad Sci USA 100:4690–4695
Chiavegatto S, Izidio GS, Mendes-Lana A, Aneas I, Freitas TA, Torrao AS et al (2009) Expression of alpha-synuclein is increased in the hippocampus of rats with high levels of innate anxiety. Mol Psychiatry 14: 894–905
Foroud T, Wetherill LF, Liang T, Dick DM, Hesselbrock V, Kramer J et al (2007) Association of alcohol craving with alpha-synuclein (SNCA). Alcohol Clin Exp Res 31:537–545
Pandey SC, Zhang H, Roy A, Xu T (2005) Deficits in amygdaloid cAMP-responsive element-binding protein signaling play a role in genetic predisposition to anxiety and alcoholism. J Clin Invest 115:2762–2773
Primeaux SD, Wilson SP, Bray GA, York DA, Wilson MA (2006) Overexpression of neuropeptide Y in the central nucleus of the amygdala decreases ethanol self-administration in “anxious” rats. Alcohol Clin Exp Res 30:791–801
Kimpel MW, Strother WN, McClintick JN, Carr LG, Liang T, Edenberg HJ et al (2007) Functional gene expression differences between inbred alcohol-preferring and -non-preferring rats in five brain regions. Alcohol 41:95–132
Mottagui-Tabar S, Prince JA, Wahlestedt C, Zhu G, Goldman D, Heilig M (2005) A novel single nucleotide polymorphism of the neuropeptide Y (NPY) gene associated with alcohol dependence. Alcohol Clin Exp Res 29:702–707
Llamas B, Contesse V, Guyonnet-Duperat V, Vaudry H, Mormede P, Moisan MP (2005) QTL mapping for traits associated with stress neuroendocrine reactivity in rats. Mamm Genome 16:505–515
Solberg LC, Baum AE, Ahmadiyeh N, Shimomura K, Li R, Turek FW et al (2006) Genetic analysis of the stress-responsive adrenocortical axis. Physiol Genomics 27:362–369
Ousova O, Guyonnet-Duperat V, Iannuccelli N, Bidanel JP, Milan D, Genet C et al (2004) Corticosteroid binding globulin: a new target for cortisol-driven obesity. Mol Endocrinol 18:1687–1696
Carr LG, Kimpel MW, Liang T, McClintick JN, McCall K, Morse M et al (2007) Identification of candidate genes for alcohol preference by expression profiling of congenic rat strains. Alcohol Clin Exp Res 31:1089–1098
Kobeissy FH, Sadasivan S, Liu J, Gold MS, Wang KK (2008) Psychiatric research: psychoproteomics, degradomics and systems biology. Expert Rev Proteomics 5:293–314
Nestler EJ (2001) Psychogenomics: opportunities for understanding addiction. J Neurosci 21:8324–8327
Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ et al (2007) Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131:391–404
McClung CA, Nestler EJ (2008) Neuroplasticity mediated by altered gene expression. Neuropsychopharmacology 33:3–17
Teague CR, Dhabhar FS, Barton RH, Beckwith-Hall B, Powell J, Cobain M et al (2007) Metabonomic studies on the physiological effects of acute and chronic psychological stress in Sprague-Dawley rats. J Proteome Res 6:2080–2093
Ruiz-Opazo N, Kosik KS, Lopez LV, Bagamasbad P, Ponce LR, Herrera VL (2004) Attenuated hippocampus-dependent learning and memory decline in transgenic TgAPPswe Fischer-344 rats. Mol Med 10:36–44
Gimenez-Llort L, Schiffmann SN, Shmidt T, Canela L, Camon L, Wassholm M et al (2007) Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain. Neurobiol Learn Mem 87:42–56
Homberg JR, Olivier JD, Smits BM, Mul JD, Mudde J, Verheul M et al (2007) Characterization of the serotonin transporter knockout rat: a selective change in the functioning of the serotonergic system. Neuroscience 146:1662–1676
Olivier JD, Van Der Hart MG, Van Swelm RP, Dederen PJ, Homberg JR, Cremers T et al (2008) A study in male and female 5-HT transporter knockout rats: an animal model for anxiety and depression disorders. Neuroscience 152:573–584
Potenza MN, Brodkin ES, Joe B, Luo X, Remmers EF, Wilder RL et al (2004) Genomic regions controlling corticosterone levels in rats. Biol Psychiatry 55:634–641
Bilusic M, Bataillard A, Tschannen MR, Gao L, Barreto NE, Vincent M et al (2004) Mapping the genetic determinants of hypertension, metabolic diseases, and related phenotypes in the lyon hypertensive rat. Hypertension 44:695–701
Marissal-Arvy N, Lombes M, Petterson J, Moisan MP, Mormede P (2004) Gain of function mutation in the mineralocorticoid receptor of the Brown Norway rat. J Biol Chem 279:39232–39239
Klimes I, Weston K, Gasperikova D, Kovacs P, Kvetnansky R, Jezova D et al (2005) Mapping of genetic determinants of the sympathoneural response to stress. Physiol Genomics 20:183–187
Cui ZH, Ikeda K, Kawakami K, Gonda T, Nabika T, Masuda J (2003) Exaggerated response to restraint stress in rats congenic for the chromosome 1 blood pressure quantitative trait locus. Clin Exp Pharmacol Physiol 30:464–469
Conti LH, Jirout M, Breen L, Vanella JJ, Schork NJ, Printz MP (2004) Identification of quantitative trait Loci for anxiety and locomotion phenotypes in rat recombinant inbred strains. Behav Genet 34:93–103
Mormede P, Moneva E, Bruneval C, Chaouloff F, Moisan MP (2002) Marker-assisted selection of a neuro-behavioural trait related to behavioural inhibition in the SHR strain. an animal model of ADHD. Genes Brain Behav 1:111–116
Terenina-Rigaldie E, Jones BC, Mormede P (2003) Pleiotropic effect of a locus on chromosome 4 influencing alcohol drinking and emotional reactivity in rats. Genes Brain Behav 2:125–131
Vendruscolo LF, Terenina-Rigaldie E, Raba F, Ramos A, Takahashi RN, Mormede P (2006) Evidence for a female-specific effect of a chromosome 4 locus on anxiety-related behaviors and ethanol drinking in rats. Genes Brain Behav 5:441–450
Ahmadiyeh N, Churchill GA, Solberg LC, Baum AE, Shimomura K, Takahashi JS et al (2005) Lineage is an epigenetic modifier of QTL influencing behavioral coping with stress. Behav Genet 35:189–198
Solberg LC, Baum AE, Ahmadiyeh N, Shimomura K, Li R, Turek FW et al (2004) Sex- and lineage-specific inheritance of depression-like behavior in the rat. Mamm Genome 15:648–662
Palmer AA, Breen LL, Flodman P, Conti LH, Spence MA, Printz MP (2003) Identification of quantitative trait loci for prepulse inhibition in rats. Psychopharmacology (Berl) 165:270–279
Vendruscolo LF, Terenina-Rigaldie E, Raba F, Ramos A, Takahashi RN, Mormede P (2006) A QTL on rat chromosome 7 modulates prepulse inhibition, a neuro-behavioral trait of ADHD, in a Lewis × SHR intercross. Behav Brain Funct 2:21
Ruiz-Opazo N, Tonkiss J (2006) Genome-wide scan for quantitative trait loci influencing spatial navigation and social recognition memory in Dahl rats. Physiol Genomics 26:145–151
Carr LG, Habegger K, Spence JP, Liu L, Lumeng L, Foroud T (2006) Development of congenic rat strains for alcohol consumption derived from the alcohol-preferring and nonpreferring rats. Behav Genet 36:285–290
Foroud T, Bice P, Castelluccio P, Bo R, Miller L, Ritchotte A et al (2000) Identification of quantitative trait loci influencing alcohol consumption in the high alcohol drinking and low alcohol drinking rat lines. Behav Genet 30:131–140
Foroud T, Bice P, Castelluccio P, Bo R, Ritchotte A, Stewart R et al (2002) Mapping of QTL influencing saccharin consumption in the selectively bred alcohol-preferring and -nonpreferring rat lines. Behav Genet 32:57–67
Foroud T, Ritchotte A, Spence J, Liu L, Lumeng L, Li TK et al (2003) Confirmation of alcohol preference quantitative trait loci in the replicate high alcohol drinking and low alcohol drinking rat lines. Psychiatr Genet 13:155–161
Radcliffe RA, Bludeau P, Deng XS, Erwin VG, Deitrich RA (2007) Short-term selection for acute ethanol tolerance and sensitization from an F2 population derived from the high and low alcohol-sensitive selectively bred rat lines. Alcohol 41:557–566
Radcliffe RA, Bludeau P, Asperi W, Fay T, Deng XS, Erwin VG et al (2006) Confirmation of quantitative trait loci for ethanol sensitivity and neurotensin receptor density in crosses derived from the inbred high and low alcohol sensitive selectively bred rat lines. Psychopharmacology (Berl) 188:343–354
Nakatani N, Aburatani H, Nishimura K, Semba J, Yoshikawa T (2004) Comprehensive expression analysis of a rat depression model. Pharmacogenomics J 4:114–126
Kohen R, Kirov S, Navaja GP, Happe HK, Hamblin MW, Snoddy JR et al (2005) Gene expression profiling in the hippocampus of learned helpless and nonhelpless rats. Pharmacogenomics J 5:278–291
Kroes RA, Panksepp J, Burgdorf J, Otto NJ, Moskal JR (2006) Modeling depression: social dominance-submission gene expression patterns in rat neocortex. Neuroscience 137:37–49
Pearson KA, Stephen A, Beck SG, Valentino RJ (2006) Identifying genes in monoamine nuclei that may determine stress vulnerability and depressive behavior in Wistar-Kyoto rats. Neuropsychopharmacology 31:2449–2461
Orsetti M, Di Brisco F, Canonico PL, Genazzani AA, Ghi P (2008) Gene regulation in the frontal cortex of rats exposed to the chronic mild stress paradigm, an animal model of human depression. Eur J NeuroSci 27:2156–2164
Gass JT, Olive MF (2008) Transcriptional profiling of the rat frontal cortex following administration of the mGlu5 receptor antagonists MPEP and MTEP. Eur J Pharmacol 584:253–262
Khawaja X, Xu J, Liang JJ, Barrett JE (2004) Proteomic analysis of protein changes developing in rat hippocampus after chronic antidepressant treatment: Implications for depressive disorders and future therapies. J Neurosci Res 75:451–460
Carboni L, Vighini M, Piubelli C, Castelletti L, Milli A, Domenici E (2006) Proteomic analysis of rat hippocampus and frontal cortex after chronic treatment with fluoxetine or putative novel antidepressants: CRF1 and NK1 receptor antagonists. Eur Neuropsycho-pharmacol 16:521–537
Mu J, Xie P, Yang ZS, Yang DL, Lv FJ, Luo TY et al (2007) Neurogenesis and major depression: implications from proteomic analyses of hippocampal proteins in a rat depression model. Neurosci Lett 416:252–256
Kim HG, Kim KL (2007) Decreased hippocampal cholinergic neurostimulating peptide precursor protein associated with stress exposure in rat brain by proteomic analysis. J Neurosci Res 85:2898–2908
Worst TJ, Tan JC, Robertson DJ, Freeman WM, Hyytia P, Kiianmaa K et al (2005) Transcriptome analysis of frontal cortex in alcohol-preferring and nonpreferring rats. J Neurosci Res 80:529–538
Edenberg HJ, Strother WN, McClintick JN, Tian H, Stephens M, Jerome RE et al (2005) Gene expression in the hippocampus of inbred alcohol-preferring and -nonpreferring rats. Genes Brain Behav 4:20–30
Hargreaves GA, Quinn H, Kashem MA, Matsumoto I, McGregor IS (2008) Proteomic analysis demonstrates adolescent vulnerability to lasting hippocampal changes following chronic alcohol consumption. Alcohol Clin Exp Res 33:86–94
Kabbaj M, Evans S, Watson SJ, Akil H (2004) The search for the neurobiological basis of vulnerability to drug abuse: using microarrays to investigate the role of stress and individual differences. Neuropharmacology 47(Suppl. 1):111–122
Ahmed SH, Lutjens R, van der Stap LD, Lekic D, Romano-Spica V, Morales M et al (2005) Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction. Proc Natl Acad Sci USA 102:11533–11538
McClung CA, Nestler EJ, Zachariou V (2005) Regulation of gene expression by chronic morphine and morphine withdrawal in the locus ceruleus and ventral tegmental area. J Neurosci 25:6005–6015
Kobeissy FH, Warren MW, Ottens AK, Sadasivan S, Zhang Z, Gold MS et al (2008) Psychoproteomic analysis of rat cortex following acute methamphetamine exposure. J Proteome Res 7:1971–1983
Li X, Wang H, Qiu P, Luo H (2008) Proteomic profiling of proteins associated with methamphetamine-induced neurotoxicity in different regions of rat brain. Neurochem Int 52:256–264
Burger C, Lopez MC, Baker HV, Mandel RJ, Muzyczka N (2008) Genome-wide analysis of aging and learning-related genes in the hippocampal dentate gyrus. Neurobiol Learn Mem 89:379–396
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Moisan, MP., Ramos, A. (2010). Rat Genomics Applied to Psychiatric Research. In: Anegon, I. (eds) Rat Genomics. Methods in Molecular Biology, vol 597. Humana Press. https://doi.org/10.1007/978-1-60327-389-3_25
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