Abstract
It seems that the genetic basis of common psychiatric diseases such as schizophrenia and manic-depressive psychosis is amenable to the genetic mapping strategies that have been successful in other complex disorders such as diabetes. The next challenge is the genetic dissection of quantitative behavioural traits such as mood, personality and intelligence. Quantitative traits pose new problems for gene cloning experiments. We argue that one way forward is by using animal models. One of the features of quantitative traits is that the DNA sequence variants which are responsible for them are unlikely to be immediately recognizable. In contrast to many qualitative traits where a discrete phenotypic difference is often the consequence of an inactivating mutation, the allelic variation responsible for quantitative traits probably has a more subtle basis. This distinction means that strategies to clone the genetic basis of quantitative behavioural traits will have to rely on functional assays of alleles thought to be important in determining the phenotype. We suggest that an efficient strategy for detecting sequences that give rise to quantitative behavioural traits can be devised in the mouse. The importance and utility of the mouse for quantitative trait analysis make it worthwhile to investigate mouse models of human behaviour; these advantages outweigh the difficulties that arise in attempts to validate the animal models. As an example we review the evidence that validates rodent emotionality as an animal model for susceptibility to human anxiety. We show that there is good evidence that rodent emotionality is a central nervous system state with a genetic basis, and that there are neuropharmacological and neuroanatomical parallels with human anxiety. Furthermore, our own work has shown that the genetic basis of the trait is relatively simple, and that the task of characterizing it at a molecular level is feasible. We expect that future experiments will show us how genetic variation gives rise to quantitative behavioural traits.
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Abbreviations
- MR :
-
Maudsley reactive
- MNR :
-
Maudsleynon-reactive
- OFA :
-
Open-field activity
- OFD :
-
Open-field defecation
- RHA :
-
Roman high-avoidance
- RLA :
-
Roman low-avoidance
References
Lander ES, Schork NJ (1994) Genetic dissection of complex traits. Science 265:2037–2048
Dubay C (1993) Genetic determinants of diastolic and pulse pressure map to different loci in Lyon hypertensive rats. Nature Genet 3:354–357
Gauguier D, Froguel P, Parent V, Bernard C, Bihoreau M, Portha B, James MR, Penicaud L, Lathrop M, Ktorza A (1996) Chromosomal mapping of genetic loci associated with non-in-sulin dependent diabetes in the GK rat. Nature Genet 12:38–43
Moises HW, Yang L, Kristbjarnarson H, Wiese C, Byerley W, Macciardi F, Arolt V, Blackwood D, Lio X, B. Sjögren, Aschauer HN, Hwu H-G, Jang K, Livesley WJ, Kennedy JL, Zoega T, Ivarsson O, Bui M-T, Yu M-H, Havsteen B, Commenges D, Weissenbach J, Schwinger E, Gottesman II, Pakstis AJ, Wetterberg L, Kidd KK, Helgason T (1995) An international two-stage genome wide search for schizophrenia susceptibility genes. Nature Genet 11:321–324
Antonarakis SE, Blouin J-L, Pulver AE, Wolyniec P, Lasseter VK, Nestadt G, Kasch L, Babb R, Kazazian HH, Dombroski B, Ott J, Karayiorgou M, C.J. MacLean (1995) Schizophrenia susceptibility and chromosome 6p24–22. Nature Genet 11:235–236
Berrettini WH, Ferraro TN, Goldin LR, Weeks DE, DeteraWadleigh S, Nurnberger JI, Gershon ES (1994) Chromosome 18 DNA markers and manic depressive illness. Evidence for a susceptibility locus. Proc Natl Acad Sci USA 91:5918–5921
Schwab SG, Albus M, Hallmayer J, Honig S, Borrmann M, Lichtermann D, Ebstein RP, Ackenheil M, Lerer B, Risch N, Maier W, Wildenauer DB (1995) Evaluation of a susceptibilitygene for schizophrenia on chromsome 6p by multipoint affected sib-pair linkage analysis. Nature Genet 11:325–326
Straub RE, MacLean C. J. A. O, Burke J, Murphy B, Duke F, Shinkwin R, Webb BT, Zhang J, Walsh D, Kendler KS (1995) A potential vulnerability locus for schizophrenia on chromsome 6p24–22: evidence for genetic heterogeneity. Nature Genet 11:287–292
Stine OC, Xu J, Koskela R, McMahon FJ, Gschwend M, Friddle C, Clark CD, McInnis MG, Simpson SG, Breschel TS, Vishio E, Riskin K, Feilcotter H, Chen E, Shen S, Folstein S, Meyers DA, Botstein D, Marr TG, DePaulo JR (1995) Evidence for linkage of bipolar disorder to chromosome 18 with aparent-of-origin effect. Am J Hum Genet 57:1384–1394
Ross CA, McInnis MG, Margolis RL, Li SH (1993) Genes with triplet repeats: candidate mediators of neuropsychiatric disorders. Trends Neurosci 16:254–260
Copeman JB, Cucca F, Hearne CM, Cornall RJ, Reed PW, Ronningen KS, Undlien DE, Nistico L, Tosi R, Pociot F, Nerup J, Cornelis F, Barnett AH, Bain SC, Todd JA (1995) Linkage disequilibrium mapping of a type 1 diabetes susceptibilitygene (IDDM7) to chromosome 2q31-q33. Nature Genet 9:80–85
Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus. Am J Hum Genet 52:506–516
Willner P (1990) Animal models for clinical psychopharmacology: depression, anxiety, schizophrenia. Int Rev Psychiatry 2:253–276
Collins F (1995) Positional cloning moves from perditional to traditional. Nature Genet 9:347–350
Hall CS (1934) Emotional behaviour in the rat. I. Defecation and urination as measures of individual differences in emotionality. J Comp Psychol 22:345–352
Stouffer SA, Lumsdaine AA, Lumsdaine MH, Williams RN, Smith MB, Janis IL, Star SA, Cottrell LS (1949) Studies in social psychology in World War II: the American soldier: combat and its aftermath. Princeton Unviersity Press Princeton
Archer J (1973) Tests for emotionality in rats and mice: A review. Anim Behav 21:205–235
Gray JA (1982) The neuropsychology of anxiety: an enquiry into the function of the septo-hippocampal system. Oxford University Press, Oxford
Gray JA (1987) The psychology of fear and stress. Cambridge University Press, Cambridge
DeFries JC, Gervais MC, Thomas EA (1978) Response to 30 generations of selection for open field activity in laboratory mice. Behav Genet 5:3–213
Levine S, Broadhurst PL (1963) Genetic and ontogenetic influences on later emotionality in the rat. J Comp Physiol Psychol 56:423–428
Owen S (1962) The effect of avoidance response extinction in rats of CS and continuation and emotional constitution. J Genet Psychol 103:147–151
Broadhurst PL (1960) Application of biometrical genetics to the inheritance of behaviour. In: Eysenck HJ (eds) Experiments in personality. Routledge and Kegan Paul, London, pp 3–102
Bignami G (1965) Selection for high rates and low rates of avoidance conditioning in the rat. Behav Res Ther 2:273–280
Broadhurst PL, Bignami G(1965) Correlative effect of psychogenetic selection: a study of the Roman high and low avoidance strains of rats. Behav Res Ther 2:273–280
Driscoll P, Woodson P, Fuem H, Battig K (1980) Selection for two way avoidance deficit inhibits shock-induced fighting in the rat. Physiol Behav 24:793–795
Chamove AS, Sanders DC (1980) Emotional correlates of selection for avoidance learning in rats. Biol Psychiatry 10:41–55
Driscoll P, Battig K (1982) Behavioral, emotional and neurochemical profiles of rats selected for extreme differences in active two way avoidance. In: Lieblich eds Genetics of the brain. Elsevier, Amsterdam, pp 95–123
Gentsch C, Lichtsteiner M, Feer H (1981) Locomoter activity, defecation score and corticosterone levels during an open-field exposure: a comparison among individually and group-housed rats, and genetically selected rat lines. Physiol Behav 27:183–186
Rawlins JNP, Feldon J, Tonkiss J, Coffey PJ (1989)The role of subicular outputs in the development of the partial reinforcement extinction effect. Exp Brain Res 77:153–160
Gray JA, McNaughton N (1983) Comparison between the ‘behavioural’ effects of septal and hippocampal lesions: a review. Neurosci Biobehav Rev 7:119–188
Schwegler H, Lipp H-P (1983) Hereditary covariations of neuronal circuitry and behaviour: correlations between the proportions of hippocampal synaptic fields in the regio inferior and two-way avoidance in mice and rats. Behav Brain Res 7:1–39
Schwegler H, Lipp H-P, van der Loos H, Buselmaier W (1981) Individual hippocampal mossy fibre distribution in mice correlates with two-way avoidance performance. Science 214:817–819
Redmond DE (1985) Neurochemical basis for anxiety and anxiety based disorders: evidence from drugs which decrease human fear or anxiety. In: Tuma AH, Maser JD eds Anxiety and the anxiety disorders. Erlbaum, Hillsdale, pp 530–555
Soubrie P (1986) Reconciling the role of serotonin neurons in human and animal behaviour. Behav Brain Sci 9:319–363
Redmond DE(1986) The possible role of locus coeruleus noradrenergic activity in anxiety-panic. Clin Neuropharmacol 9: 40–42
Flint J, Corley R, DeFries JC, Fulker DW, Gray JA, Miller S, Collins AC (1995) A simple genetic basis for a complex psychological trait in laboratory mice. Science 269:1432–1435
Pellow S, Chopin P, File S, Briley M (1985) Validation of open:closed arms entries in an elevated plus maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167
Pellow S, File SE (1986) Anxiolytic and anxiogenic drug effects in exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmacol Biochem Behav 24:525
Plomin R, Owen M, McGuffin P (1994). The genetic basis of complex human behaviours. Science 264:1733–1739
Crabbe J, Belknap JK, Buck KJ (1994) Genetic animal models of alcohol and drug abuse. Science 264:1715–1723
McCouch, SR, Doerge RW (1995) QTL mapping in rice. Trends Genet 11:482–487
Frankel WN (1995) Taking stock of complex trait genetics in mice. Trends Genet 11:471–477
Stuber CW (1995) Mapping and manipulating quantitative traits in maize. Trends Genet 11:477–481
Risch N, Ghosh S, Todd JA (1993) Statistical evaluation of multiple-locus linkage data in experimental species and its relevance to human studies: application to nonobese diabetic (NOD) mouse and human insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 53:702–714
Paterson AH, Lin Y-R, Li Z, Schertz KF, Doebley JF, Pinsn SRM, Liu S-C, Stansel JW, Irvine JE (1995) Convergent domestication of cereal crops by indepencent mutations at corresponding genetic loci. Science 269:1714–1718
Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S, Muuler U, Agyet M, Babinet C, Shih JC, DeMaeyer E (1995) Aggressive behaviour and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268:1763–1766
Nelson RJ, Demas GE, Huang PL, Fishman MC, Dawson VL, Dawson TM, Snyder SH (1995) Behavioural abnormalities in male mice lacking neuronal nitric oxide synthase. Nature 378:383–386
Brunner HG, Nelen MR, van Zandvoort P, Abeling NGGM, vanGennip AH, Wolters EC, Kuiper MA, Ropers HH, vanOost BA (1993a) X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localizaion, and evidence for disturbed monoamine metabolism. Am J Hum Genet 52:1032–1039
Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA (1993b) Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 262:578–580
Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ (1994) Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79:59–68
Huang Y-Y, Li X-C, Kandel ER (1994) cAMP contributes to mossy fiber LTP by initiating both a covalently mediated early phase and macromolecular synthesis-dependent late phase. Cell 79:69–79
Grant SGN, O'Dell TJ, Karl KA, Stein PL, Soriano P, Kandel ER (1992) Impaired long-term potentiation, spatial learning and hippocampal development in fyn mutant mice. Science 258:1903–1910
Silva AJ, Stevens CF, Tonegawa S, Wang Y (1992a) Deficient hippocampal long-term potentiation in α-calcium-calmodulin kinase II mutant mice. Science 257:201–206
Silva AJ, Paylor R, Wehner JM, Tonegawa S(1992b) Impaired spatial learning in a-calcium-calmodulin kinase II mutant mice. Science 257:206–211
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Flint, J., Corley, R. Do animal models have a place in the genetic analysis of quantitative human behavioural traits?. J Mol Med 74, 515–521 (1996). https://doi.org/10.1007/BF00204977
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DOI: https://doi.org/10.1007/BF00204977