Skip to main content
Log in

Genetic Control of the Behavior of ISIAH Rats in the Open Field Test

  • ANIMAL GENETICS
  • Published:
Russian Journal of Genetics Aims and scope Submit manuscript

Abstract

Genetic control of behavior in ISIAH rats with inherited stress-induced arterial hypertension in an open field test was investigated. Genome scanning (QTL analysis) was carried out in a group of male F2 hybrids (ISIAH × WAG) at the age of 6 months using 149 microsatellite polymorphic markers. The following traits were studied: latent period of the onset of movement, locomotor activity (LA) in the first minute of the first open field test, LA on the periphery of the open field area, vertical activity (rearing) and grooming on the periphery of the open field area, defecation. The polygenic control of all studied traits has been determined. Various effects of ISIAH rat alleles in the found QTLs are shown: in some loci, the presence of ISIAH rat alleles leads to an increase in the trait value; in others, it leads to its decrease; and for a number of loci, the effects on the phenotype are shown in a heterozygous state. Among the found loci, 11 were described for the first time: three of them (on chromosomes 5, 11, and 18) are associated with the trait of locomotor activity in the first minute of the first open field test; one locus (on chromosome 14) is associated with locomotor activity at the periphery of the open field; one locus (on chromosome 17) is associated with grooming at the periphery of the open field; two loci (on chromosomes 17 and 18) are associated with rearing at the periphery of the open field; and four loci (on chromosomes 11, 12, 14, and 19) are associated with the level of defecation. Common loci associated with both behavior and previously studied traits that can influence behavior have been identified. On chromosome 5, a common locus associated with two behavioral traits and with a basal plasma corticosterone concentration has been described. On chromosome 8, a common locus associated with locomotor activity at the periphery of the open field area and with the concentration of dopamine in the brain stem was found. On chromosome 18, a common locus for four traits of behavior and the level of norepinephrine in the hypothalamus was identified. The results obtained contribute to the functional annotation of the rat genome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1.
Fig. 2.

Similar content being viewed by others

REFERENCES

  1. Kvetnansky, R., Sabban, E.L., and Palkovits, M., Catecholaminergic systems in stress: structural and molecular genetic approaches, Physiol. Rev., 2009, vol. 89, no. 2, pp. 535—606. https://doi.org/10.1152/physrev.00042.2006

    Article  CAS  PubMed  Google Scholar 

  2. Deshpande, R.P. and Babu, P.P., Anxiety, stress, and neurological dysfunction: from basic biology to present therapeutic interventions, in Application of Biomedical Engineering in Neuroscience, Singapore: Springer Nature Singapore, 2019, pp. 401—413.

    Google Scholar 

  3. Bussotti, M. and Sommaruga, M., Anxiety and depression in patients with pulmonary hypertension: impact and management challenges, Vasc. Health Risk Manag., 2018, vol. 14, pp. 349—360. https://doi.org/10.2147/VHRM.S147173

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hamam, M.S., Kunjummen, E., Hussain, M.S., et al., Anxiety, depression, and pain: considerations in the treatment of patients with uncontrolled hypertension, Curr. Hypertens. Rep., 2020, vol. 22, no. 12, p. 106. https://doi.org/10.1007/s11906-020-01117-2

    Article  PubMed  Google Scholar 

  5. Lim, L.F., Solmi, M., and Cortese, S., Association between anxiety and hypertension in adults: a systematic review and meta-analysis, Neurosci. Biobehav. Rev., 2021, vol. 131, pp. 96—119. https://doi.org/10.1016/j.neubiorev.2021.08.031

    Article  PubMed  Google Scholar 

  6. Roman, O., Seres, J., Pometlova, M., and Jurcovicova, J., Neuroendocrine or behavioral effects of acute or chronic emotional stress in Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats, Endocr. Regul., 2004, vol. 38, no. 4, pp. 151—155.

    PubMed  Google Scholar 

  7. Meier, S.M., Trontti, K., Purves, K.L., et al., Genetic variants associated with anxiety and stress-related disorders: a genome-wide association study and mouse-model study, JAMA Psychiatry, 2019, vol. 76, no. 9, pp. 924—932. https://doi.org/10.1001/jamapsychiatry.2019.1119

    Article  PubMed  PubMed Central  Google Scholar 

  8. Lin, W., Wang, W., and Shao, F., New animal model of emotional stress: behavioral, neuroendocrine and immunological consequences, Chin. Sci. Bull., 2003, vol. 48, no. 15, pp. 1565—1568. https://doi.org/10.1007/BF03183962

    Article  CAS  Google Scholar 

  9. Markel, A.L., Redina, O.E., Gilinsky, M.A., et al., Neuroendocrine profiling in inherited stress-induced arterial hypertension rat strain with stress-sensitive arterial hypertension, J. Endocrinol., 2007, vol. 195, no. 3, pp. 439—450. https://doi.org/10.1677/JOE-07-0254

    Article  CAS  PubMed  Google Scholar 

  10. Markel, A.L., Maslova, L.N., Shishkina, G.T., et al., Developmental influences on blood pressure regulation in ISIAH rats, in Development of the Hypertensive Phenotype: Basic and Clinical Studies, Amsterdam: Elsevier, 1999, pp. 493—526.

    Google Scholar 

  11. Tamashiro, K.L., Nguyen, M.M., Ostrander, M.M., et al., Social stress and recovery: implications for body weight and body composition, Am. J. Physiol. Regul. Integr. Comp. Physiol., 2007, vol. 293, no. 5, pp. R1864—R1874. https://doi.org/10.1152/ajpregu.00371.2007

    Article  CAS  PubMed  Google Scholar 

  12. de Souza, D.B., Silva, D., Silva, C.M.C., et al., Effects of immobilization stress on kidneys of Wistar male rats: a morphometrical and stereological analysis, Kidney Blood Press Res., 2011, vol. 34, no. 6, pp. 424—429. https://doi.org/10.1159/000328331

    Article  Google Scholar 

  13. Bohus, B., Benus, R.F., Fokkema, D.S., et al., Neuroendocrine states and behavioral and physiological stress responses, Prog. Brain Res., 1987, vol. 72, pp. 57—70. https://doi.org/10.1016/s0079-6123(08)60196-x

    Article  CAS  PubMed  Google Scholar 

  14. Mormede, P., Courvoisier, H., Ramos, A., et al., Molecular genetic approaches to investigate individual variations in behavioral and neuroendocrine stress responses, Psychoneuroendocrinology, 2002, vol. 27, no. 5, pp. 563—583. https://doi.org/10.1016/s0306-4530(01)00093-2

    Article  CAS  PubMed  Google Scholar 

  15. Flint, J., Animal models of anxiety and their molecular dissection, Semin. Cell Dev. Biol., 2003, vol. 14, no. 1, pp. 37—42. https://doi.org/10.1016/s1084-9521(02)00170-2

    Article  CAS  PubMed  Google Scholar 

  16. Bailey, J.S., Grabowski-Boase, L., Steffy, B.M., et al., Identification of quantitative trait loci for locomotor activation and anxiety using closely related inbred strains, Genes Brain Behav., 2008, vol. 7, no. 7, pp. 761—769. https://doi.org/10.1111/j.1601-183x.2008.00415.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fernandez-Teruel, A., Escorihuela, R.M., Gray, J.A., et al., A quantitative trait locus influencing anxiety in the laboratory rat, Genome Res., 2002, vol. 12, no. 4, pp. 618—626. https://doi.org/10.1101/gr.203402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ahmadiyeh, N., Churchill, G.A., Solberg, L.C., et al., Lineage is an epigenetic modifier of QTL influencing behavioral coping with stress, Behav. Genet., 2005, vol. 35, no. 2, pp. 189—198. https://doi.org/10.1007/s10519-004-1018-5

    Article  PubMed  PubMed Central  Google Scholar 

  19. Markel, A.L., Development of a new strain of rats with inherited stress-induced arterial hypertension, in Genetic Hypertension, Paris: Colloque INSERM, 1992, pp. 405—407.

  20. Adarichev, V.A., Korokhov, N.P., Ostapchuk, V., et al., Characterization of normotensive and hypertensive rat lines by the DNA fingerprinting method, Rus. J. Genet., 1996, vol. 32, no. 12, pp. 1453—1456.

    CAS  Google Scholar 

  21. Meshkov, I.O., Alekhina, T.A., Moreva, T.A., and Markel, A.L., Behavioral characterictics of ISIAH rat strain, Zh. Vyssh. Nerv. Deyat. im. I.P. Pavlova, 2012, vol. 62, no. 2, pp. 233—242.

    CAS  Google Scholar 

  22. Redina, O.E., Smolenskaya, S.E., Maslova, L.N., and Markel, A.L., Genetic control of the corticosterone level at rest and under emotional stress in ISIAH rats with inherited stress-induced arterial hypertension, Clin. Exp. Hypertens., 2010, vol. 32, no. 6, pp. 364—371. https://doi.org/10.3109/10641961003628502

    Article  PubMed  Google Scholar 

  23. Redina, O.E., Smolenskaya, S.E., Maslova, L.N., and Markel, A.L., The genetic control of blood pressure and body composition in rats with stress-sensitive hypertension, Clin. Exp. Hypertens., 2013, vol. 35, no. 7, pp. 484—495. https://doi.org/10.3109/10641963.2012.758274

    Article  PubMed  Google Scholar 

  24. Redina, O.E., Smolenskaya, S.E., Abramova, T.O., and Markel, A.L., Genetic loci for spleen weight and blood pressure in ISIAH rats with inherited stress-induced arterial hypertension, Mol. Biol., 2014, vol. 48, no. 3, pp. 351—358. https://doi.org/10.1134/S0026893314030169

    Article  CAS  Google Scholar 

  25. Redina, O.E., Smolenskaya, S.E., and Markel, A.L., Dopamine level in the medulla oblongata is under the control of chromosome 8 locus in ISIAH rats, Dokl. Biol. Sci., 2010, vol. 431, pp. 100—102. https://doi.org/10.1134/s0012496610020080

    Article  CAS  PubMed  Google Scholar 

  26. Redina, O.E., Smolenskaya, S.E., Polityko, Y.K., et al., Hypothalamic norepinephrine concentration and heart mass in hypertensive ISIAH rats are associated with a genetic locus on chromosome 18, J. Pers. Med., 2021, vol. 11, no. 2, p. 67. https://doi.org/10.3390/jpm11020067

    Article  PubMed  PubMed Central  Google Scholar 

  27. Samani, N.J., Gauguier, D., Vincent, M., et al., Analysis of quantitative trait loci for blood pressure on rat chromosomes 2 and 13: age-related differences in effect, Hypertension, 1996, vol. 28, no. 6, pp. 1118—1122. https://doi.org/10.1161/01.hyp.28.6.1118

    Article  CAS  PubMed  Google Scholar 

  28. Kovacs, P., van den Brandt, J., and Kloting, I., Effects of quantitative trait loci for lipid phenotypes in the rat are influenced by age, Clin. Exp. Pharmacol. Physiol., 1998, vol. 25, no. 12, pp. 1004—1007. https://doi.org/10.1111/j.1440-1681.1998.tb02174.x

    Article  CAS  PubMed  Google Scholar 

  29. Redina, O.E., Smolenskaya, S.E., Maslova, L.N., et al., The characteristics of motor activity in ISIAH rats in an open field test are controlled by genes on chromosomes 2 and 16, Neurosci. Behav. Physiol., 2009, vol. 39, no. 1, pp. 57—64. https://doi.org/10.1007/s11055-008-9100-8

    Article  CAS  PubMed  Google Scholar 

  30. Garrett, M.R., Dene, H., and Rapp, J.P., Time-course genetic analysis of albuminuria in Dahl salt-sensitive rats on low-salt diet, J. Am. Soc. Nephrol., 2003, vol. 14, no. 5, pp. 1175—1187. https://doi.org/10.1097/01.asn.0000060572.13794.58

    Article  CAS  PubMed  Google Scholar 

  31. Markel, A.L., Galaktionov, Yu K., and Efimov, V.M., Factor analysis of rat behavior in an open field test, Neurosci. Behav. Physiol., 1989, vol. 19, no. 4, pp. 279—286. https://doi.org/10.1007/BF01236015

    Article  CAS  PubMed  Google Scholar 

  32. Sambrook, J., Fritsch, E.F., Maniatis, T., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Lab., 1989, 2nd ed.

  33. Lander, E.S., Green, P., Abrahamson, J., et al., MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations, Genomics, 1987, vol. 1, no. 2, pp. 174—181. https://doi.org/10.1016/0888-7543(87)90010-3

    Article  CAS  PubMed  Google Scholar 

  34. Basten, C.J., Weir, B.S., and Zeng, Z.-B., Zmap-a QTL cartographer, Computing Strategies and Software (Proc. 5th World Congress on Genetics Applied to Livestock Production, Guelph, Ontario, Canada), Guelph, 1994, pp. 65—66.

  35. Basten, C.J., Weir, B.S., and Zeng, Z.-B., QTL Cartographer: Version 1.17, North Raleigh, NC: Carolina State Univ., 2004.

    Google Scholar 

  36. Churchill, G.A. and Doerge, R.W., Empirical threshold values for quantitative trait mapping, Genetics, 1994, vol. 138, pp. 963—971. https://doi.org/10.1093/genetics/138.3.963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lander, E. and Kruglyak, L., Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results, Nat. Genet., 1995, vol. 11, no. 3, pp. 241—247. https://doi.org/10.1038/ng1195-241

    Article  CAS  PubMed  Google Scholar 

  38. Gray, J.A., Flint, J., Dawson, G.R., and Fulker, D.W., A strategy to home-in on polygenes influencing susceptibility to anxiety, Hum. Psychopharmacol. Clin. Exp., 1999, vol. 14, no. S1, pp. S3—S10. https://doi.org/10.1002/(SICI)1099-1077(199908)14:1+<S3::AID-HUP111>3.0.CO;2-8

    Article  Google Scholar 

  39. Sousa, N., Almeida, O.F., and Wotjak, C.T., A hitchhiker’s guide to behavioral analysis in laboratory rodents, Genes Brain Behav., 2006, vol. 5, suppl. 2, pp. 5—24. https://doi.org/10.1111/j.1601-183X.2006.00228.x

    Article  PubMed  Google Scholar 

  40. Nosek, K., Dennis, K., Andrus, B.M., et al., Context and strain-dependent behavioral response to stress, Behav. Brain Funct., 2008, vol. 4, p. 23. https://doi.org/10.1186/1744-9081-4-23

    Article  PubMed  PubMed Central  Google Scholar 

  41. Moisan, M.P., Courvoisier, H., Bihoreau, M.T., et al., A major quantitative trait locus influences hyperactivity in the WKHA rat, Nat. Genet., 1996, vol. 14, no. 4, pp. 471—473. https://doi.org/10.1038/ng1296-471

    Article  CAS  PubMed  Google Scholar 

  42. Ramos, A., Moisan, M.P., Chaouloff, F., et al., Identification of female-specific QTLs affecting an emotionality-related behavior in rats, Mol. Psychiatry, 1999, vol. 4, no. 5, pp. 453—462. https://doi.org/10.1038/sj.mp.4000546

    Article  CAS  PubMed  Google Scholar 

  43. Conti, L.H., Jirout, M., Breen, L., et al., Identification of quantitative trait loci for anxiety and locomotion phenotypes in rat recombinant inbred strains, Behav. Genet., 2004, vol. 34, no. 1, pp. 93—103. https://doi.org/10.1023/B:BEGE.0000009479.02183.1f

    Article  PubMed  Google Scholar 

  44. Solberg, L.C., Baum, A.E., Ahmadiyeh, N., et al., Sex- and lineage-specific inheritance of depression-like behavior in the rat, Mamm. Genome, 2004, vol. 15, no. 8, pp. 648—662. https://doi.org/10.1007/s00335-004-2326-z

    Article  PubMed  PubMed Central  Google Scholar 

  45. Redina, O.E., Devyatkin, V.A., Ershov, N.I., and Markel, A.L., Genetic polymorphism of experimentally produced forms of arterial hypertension, Russ. J. Genet., 2020, vol. 56, no. 2, pp. 213—225. https://doi.org/10.1134/S1022795420020106

    Article  CAS  Google Scholar 

  46. Coll, A.P., Challis, B.G., Yeo, G.S., et al., The effects of proopiomelanocortin deficiency on murine adrenal development and responsiveness to adrenocorticotropin, Endocrinology, 2004, vol. 145, no. 10, pp. 4721—4727. https://doi.org/10.1210/en.2004-0491

    Article  CAS  PubMed  Google Scholar 

  47. Mitra, R. and Sapolsky, R.M., Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy, Proc. Natl. Acad. Sci. U.S.A., 2008, vol. 105, no. 14, pp. 5573—5578. https://doi.org/10.1073/pnas.0705615105

    Article  PubMed  PubMed Central  Google Scholar 

  48. Burford, N.G., Webster, N.A., and Cruz-Topete, D., Hypothalamic-pituitary-adrenal axis modulation of glucocorticoids in the cardiovascular system, Int. J. Mol. Sci., 2017, vol. 18, no. 10, p. pii: E2150. https://doi.org/10.3390/ijms18102150

  49. Sutton, R.E., Koob, G.F., Le Moal, M., et al., Corticotropin releasing factor produces behavioural activation in rats, Nature, 1982, vol. 297, no. 5864, pp. 331—333. https://doi.org/10.1038/297331a0

    Article  CAS  PubMed  Google Scholar 

  50. Boyer, P., Do anxiety and depression have a common pathophysiological mechanism?, Acta. Psychiatr. Scand. Suppl., 2000, no. 406, pp. 24—29.

  51. Binder E.B. and Nemeroff, C.B., The CRF system, stress, depression and anxiety-insights from human genetic studies, Mol. Psychiatry, 2010, vol. 15, no. 6, pp. 574—588. https://doi.org/10.1038/mp.2009.141

    Article  CAS  PubMed  Google Scholar 

  52. Hata, T., Kita, T., Kamanaka, Y., et al., Catecholamine levels in the brain of SART (repeated cold)-stressed rats, J. Auton. Pharmacol., 1987, vol. 7, no. 3, pp. 257—266. https://doi.org/10.1111/j.1474-8673.1987.tb00154.x

    Article  CAS  PubMed  Google Scholar 

  53. Hata, T., Nishimura, Y., Kita, T., et al., The abnormal open-field behavior of SART-stressed rats and effects of some drugs on it, Jpn. J. Pharmacol., 1988, vol. 48, no. 4, pp. 479—490. https://doi.org/10.1254/jjp.48.479

    Article  CAS  PubMed  Google Scholar 

  54. Lambert, G.W. and Jonsdottir, I.H., Influence of voluntary exercise on hypothalamic norepinephrine, J. Appl. Physiol. (1985), 1998, vol. 85, no. 3, pp. 962—966. https://doi.org/10.1152/jappl.1998.85.3.962

  55. Baum, A.E., Solberg, L.C., Churchill, G.A., et al., Test- and behavior-specific genetic factors affect WKY hypoactivity in tests of emotionality, Behav. Brain. Res., 2006, vol. 169, no. 2, pp. 220—230. https://doi.org/10.1016/j.bbr.2006.01.007

    Article  PubMed  PubMed Central  Google Scholar 

  56. Eisener-Dorman, A.F., Grabowski-Boase, L., Steffy, B.M., et al., Quantitative trait locus and haplotype mapping in closely related inbred strains identifies a locus for open field behavior, Mamm. Genome, 2010, vol. 21, nos. 5—6, pp. 231—246. https://doi.org/10.1007/s00335-010-9260-z

    Article  PubMed  Google Scholar 

  57. Carlborg, O., Kerje, S., Schütz, K., et al., A global search reveals epistatic interaction between QTL for early growth in the chicken, Genome Res., 2003, vol. 13, no. 3, pp. 413—421. https://doi.org/10.1101/gr.528003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Beck, S.R., Brown, W.M., Williams, A.H., et al., Age-stratified QTL genome scan analyses for anthropometric measures, BMC Genet., 2003, vol. 4, suppl. 1, p. S31. https://doi.org/10.1186/1471-2156-4-S1-S31

    Article  PubMed  PubMed Central  Google Scholar 

  59. Legare, M.E., Bartlett, F.S., and Frankel, W.N., A major effect QTL determined by multiple genes in epileptic EL mice, Genome Res., 2000, vol. 10, no. 1, pp. 42—48.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Morel, L., Blenman, K.R., Croker, B.P., and Wakeland, E.K., The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes, Proc. Natl. Acad. Sci. U.S.A., 2001, vol. 98, no. 4, pp. 1787—1792. https://doi.org/10.1073/pnas.031336098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yagil, C., Hubner, N., Monti, J., et al., Identification of hypertension-related genes through an integrated genomic-transcriptomic approach, Circ. Res., 2005, vol. 96, no. 6, pp. 617—625. https://doi.org/10.1161/01.RES.0000160556.52369.61

    Article  CAS  PubMed  Google Scholar 

  62. Izídio, G.S., Oliveira, L.C., Oliveira, L.F., et al., The influence of sex and estrous cycle on QTL for emotionality and ethanol consumption, Mamm. Genome, 2011, vol. 22, nos. 5—6, pp. 329—340. https://doi.org/10.1007/s00335-011-9327-5

    Article  CAS  PubMed  Google Scholar 

  63. Terenina-Rigaldie, E., Moisan, M.P., Colas, A., et al., Genetics of behaviour: phenotypic and molecular study of rats derived from high- and low-alcohol consuming lines, Pharmacogenetics, 2003, vol. 13, no. 9, pp. 543—554. https://doi.org/10.1097/01.fpc.0000054120.14659.8c

    Article  PubMed  Google Scholar 

Download references

Funding

Genotyping was supported by budget project FWNR-2022-0019. Mathematical processing of the data obtained and preparation of the results for publication was supported by the Russian Foundation for Basic Research, grant no. 20-04-00119a.

Author information

Authors and Affiliations

Authors

Contributions

The authors made equal contributions.

Corresponding author

Correspondence to O. E. Redina.

Ethics declarations

Conflict of interest. The authors declare that they have no conflict of interest.

Statement on the welfare of animals. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Additional information

Translated by E. Makeeva

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Redina, O.E., Smolenskaya, S.E. & Markel, A.L. Genetic Control of the Behavior of ISIAH Rats in the Open Field Test. Russ J Genet 58, 791–803 (2022). https://doi.org/10.1134/S1022795422070146

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1022795422070146

Keywords:

Navigation