What can we learn on rodent fearfulness/anxiety from the genetically heterogeneous NIH-HS rat stock?

Abstract

The “National Institutes of Health” genetically heterogeneous (NIH-HS) rat stock was created in the 1980s through an eight-way cross of as much as possible separate inbred rat strains (i.e. the MR/N, WN/N, WKY/N, M520/N, F344/N, ACI/N, BN/SsN and BUF/N strains) which were readily available at that time. Hansen and Spuhler [1] developed a more naturalistic, genetically heterogeneous rat stock with the aim of optimizing the distribution of genotypic frequencies and recombination and under the hypothesis that the NIH-HS stock could yield a broad-range distribution of responses (broader than commonly used laboratory rat strains) to experimental conditions, and thus serve as a base population for selection studies. Along the last decade, in a series of studies we have phenotypically characterized the NIH-HS rat stock (a colony exists at our laboratory since 2004) for their anxiety/fearfulness profiles (using a battery of both unconditioned and conditioned tests/tasks), as well as regarding their stress-induced hormonal responses, coping style under inescapable stress and spatial learning ability. We have also compared the phenotypic profiles of NIH-HS rats with those of the low anxious RHA-I and the high anxious RLA-I rat strains. The NIH-HS rat stock is, as a population, a rather anxious type of rat, with predominantly reactive/passive coping style in unlearned and learned anxiety/fear tests, and elevated stress hormone responses (as well as enhanced “depressive” symptoms in the forced swimming test). Genetic studies currently under way have thus far revealed that the genetically heterogeneous NIH-HS rat stock constitutes a unique tool for fine mapping of QTL (for multiple behavioural and biological complex traits) to megabase resolution levels, thus enabling candidate gene identification. We give some examples of this in the present paper, while also highlighting that microarray gene expression studies reveal that HPA-axis- and prolactin-related genes (among others) in the amygdala appear to be related with (or associated to) the coping style and anxiety/fearfulness responses of NIH-HS rats.

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Díaz-Morán, S. , Martínez-Membrives, E. , López-Aumatell, R. , Cañete, T. , Blázquez, G. , Palencia, M. , Mont-Cardona, C. , Estanislau, C. , Tobeña, A. and Fernández-Teruel, A. (2013) What can we learn on rodent fearfulness/anxiety from the genetically heterogeneous NIH-HS rat stock?. Open Journal of Psychiatry, 3, 238-250. doi: 10.4236/ojpsych.2013.32022.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Hansen, C. and Spuhler, K. (1984) Development of the National Institutes of Health genetically heterogeneous stock. Alcoholism: Clinical and Experimental Research, 8, 477-479. doi:10.1111/j.1530- 0277.1984.tb05706.x
[2] Spuhler, K. and Dietrich, R.A. (1984) Correlative analysis of ethanol-related phenotypes in rat inbred strains. Alcoholism: Clinical and Experimental Research, 8, 480-484. doi:10.1111/j.1530-0277. 1984.tb05707.x
[3] Draski, L.J., Spuhler, K.P., Erwin, V.G., Baker, R.C. and Dietrich, R.A. (1992) Selective breeding of rats differing in sensitivity to the effects of acute ethanol administration. Alcoholism: Clinical and Experimental Research, 16, 48-54. doi:10.1111/j.1530-0277.1992.tb00634.x
[4] Koch, L.G. and Britton, S.L. (2001) Artificial selection for intrinsic aerobic endurance running capacity in rats. Physiological Genomics, 5, 45-52.
[5] Troxell, M.L., Loyal Britton, S. and Koch, L.G. (2003) Genetic models in applied physiology: Selected contribution: Variation and heritability for the adaptational response to exercise in genetically heterogeneous rats. Journal of Applied Physiology, 94, 1674-1681.
[6] Overstreet, D.H., Rezvani, A.H., Pucilowski, O., Gause, L. and Janowsky, D.S. (1994) Rapid selection for serotonin-1A sensitivity in rats. Psychiatric Genetics, 4, 57-62. doi:10.1097/00041444- 199421000-00008
[7] Aitman, T.J., Critser, J.K., Cuppen, E., Dominiczak, A., Fernandez-Suarez, X.M., Flint, J., Gauguier, D., Geurts, A.M., Gould, M., Harris, P.C., Holmdahl, R., Hubner, N., Izsvák, Z., Jacob, H.J., Kuramoto, T., Kwitek, A.E., Marrone, A., Mashimo, T., Moreno, C., Mullins, J., Mullins, L., Olsson, T., Pravenec, M., Riley, L., Saar, K., Serikawa, T., Shull, J.D., Szpirer, C., Twigger, S.N., Voigt, B. and Worley, K. (2008) Progress and prospects in rat genetics: A community view. Nature Genetics, 40, 516-522. doi:10.1038/ng.147
[8] López-Aumatell, R., Guitart-Masip, M., Vicens-Costa, E., Gimenez-Llort, L., Valdar, W., Johannesson, M., et al. (2008) Fearfulness in a large N/NIH genetically heterogeneous rat stock: Differential profiles of timidity and defensive flight in males and females. Behavioural Brain Research, 188, 41-55. doi:10.1016/j.bbr.2007.10.015
[9] López-Aumatell, R. (2008) Temerositat en rates heterogènies N/NIH-HS: Vers els gens quantitatius de l’ansietat i la por. Ph.D. Thesis, Autonomous University of Barcelona, Barcelona.
[10] López-Aumatell, R., Vicens-Costa, E., Guitart-Masip, Martínez-Membrives, M., Valdar, W., Johannesson, M., Canete, T., Blázquez, G., Driscoll, P., Flint, J., Tobena, A. and Fernández-Teruel, A. (2009) Unlearned anxiety predicts learned fear: A comparison among heterogeneous rats and the Roman rat strains. Behavioural Brain Research, 202, 92-101. doi:10.1016/j.bbr.2009.03.024
[11] López-Aumatell, R., Vicens-Costa, E., Guitart-Masip, M., Martínez-Membrives, E., Valdar, W., Johannesson, M., Canete, T., Blázquez, G., Giménez-Llort, L., Flint, J., Tobena, A. and Fernández-Teruel, A. (2009) Ansiedad en ratas genéticamente heterogéneas: Hacia la identificación de genes para caracteres conductuales cuantitativos. Ansiedad y Estrés, 15, 67-84.
[12] López-Aumatell, R., Martínez-Membrives, E., VicensCosta, E., Canete, T., Blázquez, G., Mont-Cardona, C., Johannesson, M., Flint, J, Tobena, A. and FernándezTeruel, A. (2011) Effects of environmental and physiological covariates on sex differences in unconditioned and conditioned anxiety and fear in a large sample of genetically heterogeneous (N/NIH-HS) rats. Behavioral and Brain Functions, 7, 48. doi:10.1186/1744-9081-7-48
[13] Vicens-Costa, E., Martínez-Membrives, E., López-Aumatell, R., Guitart-Masip, M., Canete, T., Blázquez, G., Tobena, A. and Fernández-Teruel, A. (2011) Two-way avoidance acquisition is negatively related to conditioned freezing and positively associated with startle reactions: A dissection of anxiety and fear in genetically heterogeneous rats. Physiology & Behavior, 103, 148-156. doi:10.1016/j. physbeh.2010.12.009
[14] Ramos, A. and Mormede, P. (1998) Stress and emotionality: A multidimensional and genetic approach. Neuroscience & Biobehavioral Reviews, 22, 33-57. doi:10.1016/S0149-7634(97)00001-8
[15] Shepherd, J.K., Grewal, S.S., Fletcher, A., Bill, D.J. and Dourish, C.T. (1994) Behavioural and pharmacological characterisation of the elevated “zero-maze” as an animal model of anxiety. Psychopharmacology, 116, 56-64. doi:10.1007/BF02244871
[16] Steimer, T. and Driscoll, P. (2003) Divergent stress responses and coping styles in psychogenetically selected Roman high-(RHA) and low-(RLA) avoidance rats: Behavioural, neuroendocrine and developmental aspects. Stress, 6, 87-100. doi:10.1080/1025389031000111320
[17] Aguilar, R., Gil, L., Tobena, A., Escorihuela, R.M. and Fernández-Teruel, A. (2000) Differential effects of cohort removal stress on the acoustic startle response of the Roman/Verh rat strains. Behavior Genetics, 30, 71-75. doi:10.1023/A:100 2042711672
[18] Schwegler, H., Pilz, P.K.D., Koch, M., Fendt, M., Linke, R. and Driscoll, P. (1997) The acoustic startle response in inbred Roman highand low-avoidance rats. Behavior Genetics, 27, 579-582. doi:10.1023/A:1021465217299
[19] Davis, M., Falls, W.A., Campeau, S. and Kim, M. (1993) Fear-potentiated startle: A neural and pharmacological analysis. Behavioural Brain Research, 58, 175-198. doi:10.1016/0166- 4328(93)90102-V
[20] López-Aumatell, R., Blázquez, G., Gil, L., Aguilar, R., Canete, T., Giménez-Llort, L., Tobena, A. and Fernández-Teruel, A. (2009) The Roman high-and low-avoidance rat strains differ in fear-potentiated startle and classical aversive conditioning. Psicothema, 21, 27-32.
[21] Escorihuela, R.M., Fernández-Teruel, A., Zapata, A., Nunez, J.F. and Tobena, A. (1993) Flumazenil prevents the anxiolytic effects diazepam, alprazolam and adinazolam on the early acquisition of two-way active avoidance. Pharmacological Research, 28, 53-58. doi:10.1006/phrs.1993.1109
[22] Fernández-Teruel, A., Escorihuela, R.M., Boix, F. and Tobena, A. (1991) Effects of different handling-stimulation procedures and benzodiazepines on two-way active avoidance acquisition in rats. Pharmacological Research, 24, 273-282. doi:10.1016/1043-6618(91)90091-B
[23] Fernández-Teruel, A., Escorihuela, R.M., Nunez, J.F., Zapata, A., Boix, F., Salazar, W. and Tobena, A. (1991) The early acquisition of two-way (shuttle-box) avoidance as an anxiety-mediated behaviour: Psychopharmacological validation. Brain Research Bulletin, 26, 173-176. doi:10.1016/0361-9230(91)90205-X
[24] Fernández-Teruel, A., Escorihuela, R.M., Tobena, A. and Driscoll, P. (1991) Stress and putative endogenous ligands for benzodiazepine receptors: The importance of characteristics of the aversive situation and of differential emotionality in experimental animals. Experientia, 47, 1051-1056. doi:10.1007/BF01923340
[25] Fernández-Teruel, A., Escorihuela, R.M., Gray, J.A., Aguilar, R., Gil, L., Giménez-Llort, L., Tobena, A., Bhomra, A., Nicod, A., Mott, R., Driscoll, P., Dawson, GR. and Flint, J. (2002) A quantitative trait locus influencing anxiety in the laboratory rat. Genome Research, 12, 618-626.
[26] Prunell, M., Escorihuela, R.M., Fernández-Teruel, A., Nunez, J.F. and Tobena, A. (1994) Differential interactions between ethanol and Ro 15-4513 on two anxiety tests in rats. Pharmacology Biochemistry and Behavior, 47, 147-151. doi:10.1016/0091-3057(94)90124-4
[27] Prunell, M., Escorihuela, R.M., Fernández-Teruel, A., Nunez, J.F. and Tobena, A. (1994) Anxiolytic profiles of alprazolam and ethanol in the elevated plus-maze test and the early acquisition of shuttlebox avoidance. Pharmacological Research, 29, 37-45. doi:10.1016/1043-6618(94)80096-0
[28] Díaz-Morán, S. (2012) Temerosidad en ratas heterogéneas (N/NIH-HS) y Romanas (RHA/RLA): Estudios hormonales y de expresión génica diferencial. Ph.D. Thesis, Autonomous University of Barcelona, Barcelona.
[29] Díaz-Morán, S., Mont-Cardona, C., Canete, T., Blázquez, G., Martínez-Membrives, E., López-Aumatell, R., Tobena, A. and Fernández-Teruel, A. (2012) Coping style and stress hormone responses in genetically heterogeneous rats: Comparison with the Roman rat strains. Behavioural Brain Research, 228, 203-210. doi:10.1016/j.bbr.2011.12.002
[30] Martinez-Membrives, E. (2012) Susceptibility to experimental autoimmune encephalomyelitis (model of multiple sclerosis) and anxiety in heterogeneous rats. Ph.D. Thesis, Autonomous University of Barcelona, Barcelona.
[31] Blanchard, R.J., Blanchard, D.C., Rodgers, J. and Weiss, S.M. (1990) The characterization and modeling of antipredator defensive behavior. Neuroscience & Biobehavioral Reviews, 14, 463-472. doi:10.1016/S0149-7634(05)80069-7
[32] Blanchard, R.J., Yudko, E.B., Rodgers, J. and Blanchard, D.C. (1993) Defense system psychopharmacology: An ethological approach to the pharmacology of fear and anxiety. Behavioural Brain Research, 58, 155-165. doi:10.1016/0166-4328(93)90100-5
[33] Gray, J.A. and McNaughton, N. (2000) The neuropsychology of anxiety: An enquiry into the functions of the septo-hippocampal system. 2nd Edition, Oxford University Press, Oxford.
[34] McNaughton, N. and Gray, J.A. (2000) Anxiolytic action on the behavioural inhibition system implies multiple types of arousal contribute to anxiety. Journal of Affective Disorders, 61, 161-176. doi:10.1016/S0165-0327(00)00344-X
[35] Boix, F., Fernández-Teruel, A. and Tobena, A. (1988) The anxiolytic action of benzodiazepines is not present in handling-habituated rats. Pharmacology Biochemistry and Behavior, 31, 541-546. doi:10.1016/0091-3057(88)90228-6
[36] Gray, J.A. (1982) The neuropsychology of anxiety: An enquiry into the functions of the septo-hippocampal system. Oxford University Press, Oxford.
[37] Carrasco, J., Márquez, C., Nadal, R., Tobena, A., Fernández-Teruel, A. and Armario, A. (2008) Characterization of central and peripheral components of the hypothalamus-pituitary-adrenal axis in the inbred Roman rat strains. Psychoneuroendocrinology, 33, 437-445. doi:10.1016/j. psyneuen.2008.01.001
[38] Steimer, T. and Driscoll, P. (2005) Inter-individual vs. line/strain differences in psychogenetically selected Roman high-(RHA) and low-(RLA) avoidance rats: Neuroendocrine and behavioural aspects. Neuroscience & Biobehavioral Reviews, 29, 99-112. doi:10.1016/j.neubiorev.2004.07.002
[39] Piras, G., Barbato, A., Giorgi, O. and Corda, M. (2010) Effects of antidepressants on the performance in the forced swim test of two psychogenetically selected lines of rats that differ in coping strategies to aversive condictions. Psychopharmacology (Berlin), 211, 403-414. doi:10.1007/s00213-010-1904-x
[40] Freeman, M.E., Kanyicska, B., Lerant, A. and Nagy, G. (2001) Prolactin: Structure, function and regulation of secretion. Physiological Reviews, 80, 1523-1631.
[41] Castanon, N., Pérez-Díaz, F. and Mormede, P. (1995) Genetic analysis of the relationship between behavioral and neuroendocrine traits in Roman high and low avoidance rat lines. Behavior Genetics, 25, 371-383. doi:10.1007/BF02197288
[42] Steimer, T., la Fleur, S. and Schulz, P.E. (1997) Neuroendocrine correlates of emotional reactivity and coping in male rats from the Roman High (RHA/Verh)and Low (RLA/Verh)-Avoidance lines. Behavior Genetics, 27, 503-512. doi:10.1023/A:1021448713665
[43] Castanon, N., Dulluc, J., Le Moal, M. and Mormêde, P. (1992) Prolactin as a link between behavioral and immune differences between the Roman rat lines. Physiology & Behavior, 51, 1235-1241. doi:10.1016/0031-9384(92)90314-R
[44] Sabariego, M., Gómez, M.J., Morón, I., Torres, C., Fernández-Teruel, A., Tobena, A., Canete, T., MartínezConejero, J.A., Horcajadas, J.A. and Esteban, F.J. (2011) Differential gene expression between inbred Roman high(RHA-I) and low-(RLA-I) avoidance rats. Neuroscience Letters, 504, 265-270. doi:10.1016/j.neulet.2011.09.044
[45] Armario, A., Gabaldá, A. and Martí, J. (1994) Comparison of the behavioural and endocrine response to forced swimming stress in five inbred strains of rats. Psychoneuroendocrinology, 20, 879-890. doi:10.1016/0306-4530(95)00018-6
[46] Braw, Y., Malkesman, O., Dagan, M., Bercovich, A., Lavi-Avnon, Y., Schroeder, M., et al. (2006) Anxietylike behaviours in pre-pubertal rats of the flinders sensitive lines (FSL) and Wistar-Kyoto (WKY) animal models of depression. Behavioural Brain Research, 167, 261-219. doi:10.1016/j. bbr.2005.09.013
[47] Malkesman, O., Braw, Y., Zagoory-Sharon, O., Golan, O., Lavi-Avnon, Y., Schroeder, M., et al. (2005) Reward and anxiety in genetic animal models of childhood depression. Behavioural Brain Research, 164, 1-10. doi:10.1016/j.bbr.2005.04.023
[48] Malkesman, O., Braw, Y., Maayan, R., Weizman, A., Overstreet, D.H., Shabat-Simon, M., et al. (2006) Two different putative genetic animal models of childhood depression. Biological Psychiatry, 59, 17-23. doi:10.1016/j.biopsych.2005.05.039
[49] Paré, W.P. (1989) Behavioral despair test predicts stress ulcer in WKY rats. Physiology & Behavior, 46, 483-487. doi:10.1016/0031-9384(89)90025-5
[50] Paré, W.P. (1989) Stress ulcer susceptibility and depression in wistar Kyoto (WKY) rats. Physiology & Behavior, 46, 993-998. doi:10.1016/0031-9384(89)90203-5
[51] Paré, W.P. (1992) The performance of WKY rats on three tests of emotional behaviour. Physiology & Behavior, 51, 1051-1056. doi:10.1016/0031-9384(92)90091-F
[52] Paré, W.P. (1994) Open field, learned helplessness, conditioned defensive burying, and forced swim test in WKY rats. Physiology & Behavior, 55, 433-439. doi:10.1016/0031-9384(94)90097-3
[53] Solberg, L.C., Olson, S.L., Turek, F.W. and Redei, E. (2001) Altered hormone levels and circadian rhythm of activity in the WKY rat, a putative animal model of depression. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 281, R786-R794.
[54] Athey, G.R. and Iams, S.G. (1981) Cold-restraint induced gastric lesions in normotensive and spontaneously hypertensive rats. Life Science, 28, 889-894. doi:10.1016/0024-3205(81)90050-3
[55] Gomez, F., Lahmame, A., de Kloet, E.R. and Armario, A. (1996) Hypothalamic-pituitary-adrenal response to chronic stress in five inbred rat strains: differential responses are mainly located at the adrenocortical level. Neuroendocrinology, 63, 327-337. doi:10.1159/000126973
[56] Lahmame, A., Grigoriadis, D.E., De Souza, E.B. and Armario, A. (1997) Brain corticotropinreleasing factor immunoreactivity and receptors in five inbred rat strains: Relationship to forced swimming behaviour. Brain Research, 750, 285-292. doi:10.1016/S0006-8993(96)01368-6
[57] Ledoux, J.E., Sakaguchi, A. and Reis, D.J. (1983) Strain differences in fear between spontaneously hypertensive and normotensive rats. Brain Research, 277, 137-143. doi:10.1016/0006-8993 (83)90915-0
[58] Paré, W.P. and Redei, E. (1993) Depressive behaviour and stress ulcer in Wistar-Kyoto rats. Journal of Physiology-Paris, 87, 229-238. doi:10.1016/0928-4257(93)90010-Q
[59] Redei, E., Paré, W.P., Aird, F. and Klucynski, J. (1994) Strain differences in hypothalamic-pituitary-adrenal activity and stress ulcer. American Journal of Physiology, 266, R353-R360.
[60] Servatius, R.J., Ottenweller, J.E., Beldowizc, D., Guo, W., Zhu, G. and Natelson, B.H. (1998) Persistenly exaggerated startle responses in rats treated with pyridostigmine bromide. Journal of Pharmacology and Experimental Therapeutics, 287, 1020-1028.
[61] Aguilar, R., Gil, L., Flint, J., Gray, J.A., Dawson, G.R., Driscoll, P., et al. (2002) Learned fear, emotional reactivity and fear of heights: A factor analytic map from a large F2 intercross of Roman rat strains. Brain Research Bulletin, 57, 17-26. doi:10.1016/S0361-9230(01)00632-3
[62] Aguilar, R., Gil, L., Gray, J.A., Driscoll, P., Flint, J., Dawson, G.R., et al. (2003) Fearfulness and sex in F2 Roman rats: Males display more fear though both sexes share the same fearfulness traits. Physiology & Behavior, 78, 723-732. doi:10.1016/S0031-9384(03)00043-X
[63] Fernandes, C., González, M.I., Wilson, C. and File, S.E. (1999) Factor analysis shows that female rat behavior is characterized primarily by activity, male rats are driven by sex and anxiety. Pharmacology Biochemistry and Behavior, 64, 731-738. doi:10.1016/S0091-3057(99)00139-2
[64] Lehmann, J., Pryce, C.R. and Feldon, J. (1999) Sex differences in the acoustic startle response and prepulse inhibition in Wistar rats. Behavioural Brain Research, 104, 113-117. doi:10.1016/S0166-4328(99)00058-3
[65] Brush, F.R., Del Paine, S.L., Pellegrino, L.J., Rykazewwski, I.M., Dess, N.K. and Collins, P. (1988) CER suppression, passive-avoidance learning, and stress-suppression of drinking in the Siracuse highand low-avoidance strains of rats (Rattus norvegicus). Journal of Comparative Psychology, 102, 337-339. doi:10.1037/0735-7036.102.4.337
[66] Johnston, A.L. and File, S.E. (1991) Sex differences in animal tests of anxiety. Physiology & Behavior, 49, 245-250. doi:10.1016/0031-9384(91)90039-Q
[67] McNish, K.A., Gewirtz, J.C. and Davis, M. (1997) Evidence of contextual fear after lesions of the hippocampus: A disruption of freezing but not fear-potentiated startle. Journal of Neuroscience, 17, 9353-9260.
[68] Phillips, R.G. and LeDoux, J.E. (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behavioral Neuroscience, 106, 274-285. doi:10.1037/0735-7044.106.2.274
[69] Phillips, R.G. and LeDoux, J.E. (1994) Lesions of the dorsal hippocampal formation interfere with background but no foreground contextual fear conditioning. Learning & Memory, 1, 34-44.
[70] Savonenko, A., Werka, T., Nikolaev, E., Zielinski, K. and Kaczmarek, L. (2003) Complex effects of NMDA recaptor antagonist AVP in the basolateral amygdala on acquisition of two-way avoidance reaction and long-term fear memory. Learning & Memory, 10, 293-303. doi:10.1101/lm.58803
[71] Werka, T. (1997) The effects of the medial and cortical amygdala lesions on poststress analgesia in rats. Behavioural Brain Research, 86, 59-65. doi:10.1016/S0166-4328(96)02244-9
[72] Werka, T. and Zielinski, K. (1998) CS modality transfer of two-way avoidance in rats with central and basolateral amygdala lesions. Behavioural Brain Research, 93, 11-24. doi:10.1016/S0166-4328(97) 00131-9
[73] Davis, M., Falls, W.A., Campeau, S. and Kim, M. (1993) Fear-potentiated startle: A neural and pharmacological analysis. Behavioural Brain Research, 58, 175-198. doi:10.1016/0166-4328(93) 90102-V
[74] Josselyn, S.A., Falls, W.A., Gewirtz, J.C., Pistell, P. and Davis, M. (2005) The nucleus accumbens is not critically involved in mediating the effects of a safety signal on behavior. Neuropsychopharmacology, 30, 17-26. doi:10.1038/sj.npp.1300530
[75] Oliveira, A.R., Reimer, A.E. and Brandao, M.L. (2006) Dopamine D2 receptor mechanisms in the expression of conditioned fear. Pharmacology Biochemistry and Behavior, 84, 102-111. doi:10.1016/j.pbb. 2006.04.012
[76] Reis, F.L.V., Masson, S., Oliveira, A.R. and Brandao, M.L. (2004) Dopaminergic mechanisms in the conditioned and unconditioned fear as assessed by the two-way avoidance and switch-off tests. Pharmacology Biochemistry and Behavior, 79, 359-365. doi:10.1016/j.pbb.2004.08.006
[77] Schultz, W. (2002) Getting formal with dopamine and reward. Neuron, 36, 241-263. doi:10.1016/S0896-6273 (02)00967-4
[78] Stark, H., Rothe, T., Wagner, T. and Scheich, H. (2004) Learning a new behavioral strategy in the shuttle-box increases prefrontal dopamine. Neuroscience, 126, 21-29. doi:10.1016/j.neuroscience. 2004.02.026
[79] Flint, J. and Mott, R. (2001) Finding the molecular basis of quantitative traits: successes and pitfalls. Nature Reviews Genetics, 2, 437-445. doi:10.1038/35076585
[80] Kwitek-Black, A.E. and Jacob, H.J. (2001) The use of designer rats in the genetic dissection of hypertension. Current Hypertension Reports, 3, 12-18. doi:10.1007/s11906-001-0072-0
[81] Mott. R., Talbot, C.J., Turri, M.G., Collins, A.C. and Flint, J. (2000) A method for fine mapping quantitative trait loci in outbred animal stocks. Proceedings of the National Academy of Sciences of the United States of America, 97, 12649-12654. doi:10.1073/pnas.230304397
[82] Mott, R. and Flint, J. (2002) Simultaneous detection and fine mapping of quantitative trait loci in mice using heterogeneous stocks. Genetics, 160, 1609-1618.
[83] Valdar, W., Solberg, L.C., Gauguier, D., Burnett, S., Klenerman, P., Cookson, W.O., Taylor, M.S., Rawlins, J.N., Mott, R. and Flint, J. (2006) Genome-wide genetic association of complex traits in heterogeneous stock mice. Nature Genetics, 38, 879-887. doi:10.1038/ng1840
[84] Yalcin, B., Willis-Owen, S.A., Fullerton, J., Meesaq, A., Deacon, R.M., Rawlins, J.N., Copley, R.R., Morris, A.P., Flint, J. and Mott, R. (2004) Genetic dissection of a behavioral quantitative trait locus shows that Rgs2 modulates anxiety in mice. Nature Genetics, 36, 1197-1202. doi:10.1038/ng1450
[85] Boucher, W. and Cotterman, C.W. (1990) On the classification of regular systems of inbreeding. Journal of Mathematical Biology, 28, 293-305. doi:10.1007/BF00178778
[86] Johannesson, M., López-Aumatell, R., Stridh, P., Diez, M., Tuncel, J., Blázquez, G., Martinez-Membrives, E., Canete, T., Vicens-Costa, E., Graham, D., Copley, R.R., Hernandez-Pliego, P., Beyeen, A.D., Ockinger, J., Fernández-Santamaría, C., Gulko, P.S., Brenner, M., Tobena, A., Guitart-Masip, M., Giménez-Llort, L., Dominiczak, A., Holmdahl, R., Gauguier, D., Olsson, T., Mott, R., Valdar, W., Redei, E.E., Fernández-Teruel, A. and Flint, J. (2009) A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: The NIH heterogeneous stock. Genome Research, 19, 150-158. doi:10.1101/gr.081497.108
[87] Flint, J. (2004) The genetic basis of neuroticism. Neuroscience & Biobehavioral Reviews, 28, 307-316. doi:10.1016/j.neubiorev.2004.01.004
[88] Solberg Woods, L.C., Stelloh, C., Regner, K.R., Schwabe, T., Eisenhauer, J. and Garrett, M.R. (2010) Heterogeneous stock rats: A new model to study the genetics of renal phenotypes. American Journal of Physiology—Renal Physiology, 298, 1484-1491. doi:10.1152/ajprenal.00002.2010
[89] Solberg Woods, L.C., Holl, K.L., Oreper, D., Xie, Y., Tsaih, S.W. and Valdar, W. (2012) Fine-mapping diabetes-related traits, including insulin resistance, in heterogeneous stock rats. Physiological Genomics, 44, 1013-1026. doi:10.1152/physiolgenomics.00040.2012
[90] Solberg Woods, L.C., Holl, K., Tschannen, M. and Valdar, W. (2010) Fine-mapping a locus for glucose tolerance using heterogeneous stock rats. Physiological Genomics, 41, 102-108. doi:10.1152/physiol genomics.00178.2009
[91] Alam, I., Koller, D.L., Sun, Q., Roeder, R.K., Ca?ete, T., Blázquez, G., López-Aumatell, R., Martínez-Membrives, E., Vicens-Costa, E., Mont, C., Díaz, S., Tobe?a, A., Fernández-Teruel, A., Whitley, A., Strid, P., Diez, M., Johannesson, M., Flint, J., Econs, M.J., Turner, C.H. and Foroud, T. (2011) Heterogeneous stock rat: A unique animal model for mapping genes influencing bone fragility. Bone, 48, 1169-1177. doi:10.1016/j.bone.2011.02.009
[92] Stridh, P. (2010) Inheritance of autoimmune neuroinflammation. Ph.D. Thesis, Karolinska Institutet, Stockholm.
[93] Barabási, A.L. and Oltvai, Z.N. (2004) Network biology: Understanding the cell’s functional organization. Nature Reviews Genetics, 5, 101-113. doi:10.1038/nrg1272
[94] Hartwell, L.H., Hopfield, J.J., Leibler, S. and Murray, A.W. (1999) From molecular to modular cell biology. Nature, 402, C47-C52. doi:10.1038/35011540
[95] Díaz-Morán, S., Palència, M., Canete, T., Blázquez, G., Morón, I., Sabariego, M., Donaire, R., Torres, C., MontCardona, C., Martínez-Membrives, E., López-Aumatell, R., Martínez-Conejero, J.A., Tobena, A. and FernándezTeruel, A. (2012) Aplicabilidad del análisis de microarray en la detección de patrones de expresión genética diferencial en procesos psicológicos: Expresión genética amigdalar en ratas N/NIH-HS extremas en ansiedad. Iniciación a la investigación, 6, 1-8.
[96] Huang, G., Shifman, S., Valdar, W., Johannesson, M., Yalcin, B., Taylor, M.S., Taylor, J.M., Mott, R. and Flint, J. (2009) High resolution mapping of expression QTLs in heterogeneous stock mice in multiple tissues. Genome Research, 19, 1133-1140. doi:10.1101/gr.088120.108
[97] Flint, J. and Eskin, E. (2012) Genome-wide association studies in mice. Nature Reviews Genetics, 13, 807-816. doi:10.1038/nrg3335

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