Behavior Genetics

, Volume 44, Issue 5, pp 516–534 | Cite as

Behavioral and Pharmacological Evaluation of a Selectively Bred Mouse Model of Home Cage Hyperactivity

  • Petra MajdakEmail author
  • Paula J. Bucko
  • Ashley L. Holloway
  • Tushar K. Bhattacharya
  • Erin K. DeYoung
  • Chessa N. Kilby
  • Jonathan A. Zombeck
  • Justin S. Rhodes
Original Research


Daily levels of physical activity vary greatly across individuals and are strongly influenced by genetic background. While moderate levels of physical activity are associated with improved physical and mental health, extremely high levels of physical activity are associated with behavioral disorders such as attention deficit hyperactivity disorder (ADHD). However, the genetic and neurobiological mechanisms relating hyperactivity to ADHD or other behavioral disorders remain unclear. Therefore, we conducted a selective breeding experiment for increased home cage activity starting with a highly genetically variable population of house mice and evaluated the line for correlated responses in other relevant phenotypes. Here we report results through Generation 10. Relative to the Control line, the High-Active line traveled approximately 4 times as far in the home cage (on days 5 and 6 of a 6-day test), displayed reduced body mass at maturity, reduced reproductive success, increased wheel running and open field behavior, decreased performance on the rotarod, decreased performance on the Morris water maze that was not rescued by acute administration of d-amphetamine, reduced hyperactivity from chronically administered low clinical doses of d-amphetamine, and increased numbers of new cells and neuronal activation of the dentate gyrus. Standardized phenotypic differences between the lines were compared to estimates expected from genetic drift to evaluate whether the line differences could have resulted from random effects as opposed to correlated responses to selection. Results indicated line differences in body mass and locomotor responses to low doses of amphetamine were more likely due to selection than drift. The efficacy of low doses of d-amphetamine in ameliorating hyperactivity support the High-Active line as a useful model for exploring the etiology of hyperactivity-associated comorbid behavioral disorders.


ADHD Artificial selection Genetic drift Collaborative cross Home cage activity Heritability Amphetamine 



Special thanks to Elissa Chesler for providing the original G2:F1 Collaborative Cross mice. This work was supported by Grants from National Institutes of Health, MH083807 and DA027487.

Conflict of Interest

Petra Majdak, Paula J. Bucko, Ashley L. Holloway, Tushar K. Bhattacharya, Erin K. DeYoung, Jonathan A. Zombeck, and Justin S. Rhodes declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

All institutional and national guidelines for the care and use of laboratory animals were followed.


  1. Alexander RC, Wright R, Freed W (1996) Quantitative trait loci contributing to phencyclidine-induced and amphetamine-induced locomotor behavior in inbred mice. Neuropsychopharmacology 15:484–490PubMedCrossRefGoogle Scholar
  2. Allen G, Buxton RB, Wong EC, Courchesne E (1997) Attentional activation of the cerebellum independent of motor involvement. Science 275:1940–1943PubMedCrossRefGoogle Scholar
  3. Arnsten AF (2009) Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs 23(Suppl 1):33–41PubMedCrossRefGoogle Scholar
  4. Bari A, Robbins TW (2013) Inhibition and impulsivity: behavioral and neural basis of response control. Prog Neurobiol 108:44–79PubMedCrossRefGoogle Scholar
  5. Belknap JK, Crabbe JC, Young ER (1993) Voluntary consumption of ethanol in 15 inbred mouse strains. Psychopharmacology 112:503–510PubMedCrossRefGoogle Scholar
  6. Bledsoe J, Semrud-Clikeman M, Pliszka SR (2009) A magnetic resonance imaging study of the cerebellar vermis in chronically treated and treatment-naive children with attention-deficit/hyperactivity disorder combined type. Biol Psychiatry 65:620–624PubMedCentralPubMedCrossRefGoogle Scholar
  7. Brown RW, Bardo MT, Mace DD, Phillips SB, Kraemer PJ (2000) D-amphetamine facilitation of morris water task performance is blocked by eticlopride and correlated with increased dopamine synthesis in the prefrontal cortex. Behav Brain Res 114:135–143PubMedCrossRefGoogle Scholar
  8. Cherkasova MV, Hechtman L (2009) Neuroimaging in attention-deficit hyperactivity disorder: beyond the frontostriatal circuitry. Can J Psychiatry 54:651–664PubMedGoogle Scholar
  9. Chesler EJ, Miller DR, Branstetter LR, Galloway LD, Jackson BL, Philip VM, Voy BH, Culiat CT, Threadgill DW, Williams RW, Churchill GA, Johnson DK, Manly KF (2008) The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics. Mamm Genome 19:382–389PubMedCentralPubMedCrossRefGoogle Scholar
  10. Choh AC, Demerath EW, Lee M, Williams KD, Towne B, Siervogel RM, Cole SA, Czerwinski SA (2009) Genetic analysis of self-reported physical activity and adiposity: the Southwest Ohio Family Study. Public Health Nutr 12:1052–1060PubMedCentralPubMedCrossRefGoogle Scholar
  11. Choleris E, Thomas AW, Kavaliers M, Prato FS (2001) A detailed ethological analysis of the mouse open field test: effects of diazepam, chlordiazepoxide and an extremely low frequency pulsed magnetic field. Neurosci Biobehav Rev 25:235–260PubMedCrossRefGoogle Scholar
  12. Clark PJ, Brzezinska WJ, Thomas MW, Ryzhenko NA, Toshkov SA, Rhodes JS (2008) Intact neurogenesis is required for benefits of exercise on spatial memory but not motor performance or contextual fear conditioning in C57BL/6 J mice. Neuroscience 155:1048–1058PubMedCrossRefGoogle Scholar
  13. Clark PJ, Kohman RA, Miller DS, Bhattacharya TK, Brzezinska WJ, Rhodes JS (2011) Genetic influences on exercise-induced adult hippocampal neurogenesis across 12 divergent mouse strains. Genes Brain Behav 10:345–353PubMedCentralPubMedCrossRefGoogle Scholar
  14. Dabe EC, Majdak P, Bhattacharya TK, Miller DS, Rhodes JS (2013) Chronic D-amphetamine administered from childhood to adulthood dose-dependently increases the survival of new neurons in the hippocampus of male C57BL/6 J mice. Neuroscience 231:125–135PubMedCentralPubMedCrossRefGoogle Scholar
  15. DeFries JC, Wilson JR, McClearn GE (1970) Open-field behavior in mice: selection response and situational generality. Behav Genet 1:195–211PubMedCrossRefGoogle Scholar
  16. Demerath EW, Choh AC, Johnson W, Curran JE, Lee M, Bellis C, Dyer TD, Czerwinski SA, Blangero J, Towne B (2013) The positive association of obesity variants with adulthood adiposity strengthens over an 80-year period: a gene-by-birth year interaction. Hum Hered 75:175–185PubMedCrossRefGoogle Scholar
  17. Elia J, Sackett J, Turner T, Schardt M, Tang SC, Kurtz N, Dunfey M, McFarlane NA, Susi A, Danish D, Li A, Nissley-Tsiopinis J, Borgmann-Winter K (2012) Attention-deficit/hyperactivity disorder genomics: update for clinicians. Curr Psychiatry Rep 14:579–589PubMedCrossRefGoogle Scholar
  18. Falconer DS (1973) Replicated selection for body weight in mice. Genet Res 22:291–321PubMedCrossRefGoogle Scholar
  19. Fox KR (1999) The influence of physical activity on mental well-being. Public Health Nutr 2:411–418PubMedCrossRefGoogle Scholar
  20. Froehlich TE, McGough JJ, Stein MA (2010) Progress and promise of attention-deficit hyperactivity disorder pharmacogenetics. CNS Drugs 24:99–117PubMedCentralPubMedCrossRefGoogle Scholar
  21. Gainetdinov RR (2008) Dopamine transporter mutant mice in experimental neuropharmacology. Naunyn Schmiedebergs Arch Pharmacol 377:301–313PubMedCrossRefGoogle Scholar
  22. Galsworthy MJ, Paya-Cano JL, Liu L, Monleon S, Gregoryan G, Fernandes C, Schalkwyk LC, Plomin R (2005) Assessing reliability, heritability and general cognitive ability in a battery of cognitive tasks for laboratory mice. Behav Genet 35:675–692PubMedCrossRefGoogle Scholar
  23. Gammie SC, Edelmann MN, Mandel-Brehm C, D’Anna KL, Auger AP, Stevenson SA (2008) Altered dopamine signaling in naturally occurring maternal neglect. PLoS ONE 3:e1974PubMedCentralPubMedCrossRefGoogle Scholar
  24. Garland T Jr, Kelly SA, Malisch JL, Kolb EM, Hannon RM, Keeney BK, Van Cleave SL, Middleton KM (2011a) How to run far: multiple solutions and sex-specific responses to selective breeding for high voluntary activity levels. Proc Biol Sci 278:574–581PubMedCentralPubMedCrossRefGoogle Scholar
  25. Garland T Jr, Schutz H, Chappell MA, Keeney BK, Meek TH, Copes LE, Acosta W, Drenowatz C, Maciel RC, van Dijk G, Kotz CM, Eisenmann JC (2011b) The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives. J Exp Biol 214:206–229PubMedCentralPubMedCrossRefGoogle Scholar
  26. Gaub M, Carlson CL (1997) Gender differences in ADHD: a meta-analysis and critical review. J Am Acad Child Adolesc Psychiatry 36:1036–1045PubMedCrossRefGoogle Scholar
  27. Gershon J (2002) A meta-analytic review of gender differences in ADHD. J Atten Disord 5:143–154PubMedCrossRefGoogle Scholar
  28. Goddyn H, Leo S, Meert T, D’Hooge R (2006) Differences in behavioural test battery performance between mice with hippocampal and cerebellar lesions. Behav Brain Res 173:138–147PubMedCrossRefGoogle Scholar
  29. Greven CU, Asherson P, Rijsdijk FV, Plomin R (2011) A longitudinal twin study on the association between inattentive and hyperactive-impulsive ADHD symptoms. J Abnorm Child Psychol 39:623–632PubMedCrossRefGoogle Scholar
  30. Henderson ND (1989) Interpreting studies that compare high- and low-selected lines on new characters. Behav Genet 19:473–502PubMedCrossRefGoogle Scholar
  31. Henderson ND (1997) Spurious associations in unreplicated selected lines. Behav Genet 27:145–154PubMedCrossRefGoogle Scholar
  32. Houle-Leroy P, Guderley H, Swallow JG, Garland T Jr (2003) Artificial selection for high activity favors mighty mini-muscles in house mice. Am J Physiol Regul Integr Comp Physiol 284:R433–R443PubMedGoogle Scholar
  33. Kolb EM, Rezende EL, Holness L, Radtke A, Lee SK, Obenaus A, Garland T Jr (2013) Mice selectively bred for high voluntary wheel running have larger midbrains: support for the mosaic model of brain evolution. J Exp Biol 216:515–523PubMedCrossRefGoogle Scholar
  34. Konarzewski M, Ksiazek A, Lapo IB (2005) Artificial selection on metabolic rates and related traits in rodents. Integr Comp Biol 45:416–425PubMedCrossRefGoogle Scholar
  35. Krain AL, Castellanos FX (2006) Brain development and ADHD. Clin Psychol Rev 26:433–444PubMedCrossRefGoogle Scholar
  36. Lahti J, Raikkonen K, Kajantie E, Heinonen K, Pesonen AK, Jarvenpaa AL, Strandberg T (2006) Small body size at birth and behavioural symptoms of ADHD in children aged five to six years. J Child Psychol Psychiatry 47:1167–1174PubMedCrossRefGoogle Scholar
  37. Mackie S, Shaw P, Lenroot R, Pierson R, Greenstein DK, Nugent TF 3rd, Sharp WS, Giedd JN, Rapoport JL (2007) Cerebellar development and clinical outcome in attention deficit hyperactivity disorder. Am J Psychiatry 164:647–655PubMedCrossRefGoogle Scholar
  38. McLoughlin G, Ronald A, Kuntsi J, Asherson P, Plomin R (2007) Genetic support for the dual nature of attention deficit hyperactivity disorder: substantial genetic overlap between the inattentive and hyperactive-impulsive components. J Abnorm Child Psychol 35:999–1008PubMedCentralPubMedCrossRefGoogle Scholar
  39. Mick E, Biederman J, Prince J, Fischer MJ, Faraone SV (2002) Impact of low birth weight on attention-deficit hyperactivity disorder. J Dev Behav Pediatr 23:16–22PubMedCrossRefGoogle Scholar
  40. Moschak TM, Mitchell SH (2012) Acute ethanol administration and reinforcer magnitude reduction both reduce responding and increase response latency in a go/no-go task. Alcohol Clin Exp Res 36:1803–1810PubMedCentralPubMedCrossRefGoogle Scholar
  41. Napolitano F, Bonito-Oliva A, Federici M, Carta M, Errico F, Magara S, Martella G, Nistico R, Centonze D, Pisani A, Gu HH, Mercuri NB, Usiello A (2010) Role of aberrant striatal dopamine D1 receptor/cAMP/protein kinase A/DARPP32 signaling in the paradoxical calming effect of amphetamine. J Neurosci 30:11043–11056PubMedCrossRefGoogle Scholar
  42. Rhodes JS, Garland T (2003) Differential sensitivity to acute administration of Ritalin, apomorphine, SCH 23390, but not raclopride in mice selectively bred for hyperactive wheel-running behavior. Psychopharmacology 167:242–250PubMedGoogle Scholar
  43. Rhodes JS, Hosack GR, Girard I, Kelley AE, Mitchell GS, Garland T Jr (2001) Differential sensitivity to acute administration of cocaine, GBR 12909, and fluoxetine in mice selectively bred for hyperactive wheel-running behavior. Psychopharmacology 158:120–131PubMedCrossRefGoogle Scholar
  44. Rhodes JS, van Praag H, Jeffrey S, Girard I, Mitchell GS, Garland T Jr, Gage FH (2003) Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running. Behav Neurosci 117:1006–1016PubMedCrossRefGoogle Scholar
  45. Rhodes JS, Gammie SC, Garland T Jr (2005) Neurobiology of Mice Selected for High Voluntary Wheel-running Activity. Integr Comp Biol 45:438–455PubMedCrossRefGoogle Scholar
  46. Rucklidge JJ (2010) Gender differences in attention-deficit/hyperactivity disorder. Psychiatr Clin North Am 33:357–373PubMedCrossRefGoogle Scholar
  47. Rustay NR, Wahlsten D, Crabbe JC (2003) Assessment of genetic susceptibility to ethanol intoxication in mice. Proc Natl Acad Sci U S A 100:2917–2922PubMedCentralPubMedCrossRefGoogle Scholar
  48. Sharp SI, McQuillin A, Gurling HM (2009) Genetics of attention-deficit hyperactivity disorder (ADHD). Neuropharmacology 57:590–600PubMedCrossRefGoogle Scholar
  49. Strang-Karlsson S, Raikkonen K, Pesonen AK, Kajantie E, Paavonen EJ, Lahti J, Hovi P, Heinonen K, Jarvenpaa AL, Eriksson JG, Andersson S (2008) Very low birth weight and behavioral symptoms of attention deficit hyperactivity disorder in young adulthood: the Helsinki study of very-low-birth-weight adults. Am J Psychiatry 165:1345–1353PubMedCrossRefGoogle Scholar
  50. Swallow JG, Carter PA, Garland T Jr (1998) Artificial selection for increased wheel-running behavior in house mice. Behav Genet 28:227–237PubMedCrossRefGoogle Scholar
  51. Swallow JG, Koteja P, Carter PA, Garland T (1999) Artificial selection for increased wheel-running activity in house mice results in decreased body mass at maturity. J Exp Biol 202:2513–2520PubMedGoogle Scholar
  52. Swallow JG, Koteja P, Carter PA, Garland T Jr (2001) Food consumption and body composition in mice selected for high wheel-running activity. J Comp Physiol B 171:651–659PubMedCrossRefGoogle Scholar
  53. Thapar A, Cooper M, Eyre O, Langley K (2013) What have we learnt about the causes of ADHD? J Child Psychol Psychiatry 54:3–16PubMedCentralPubMedCrossRefGoogle Scholar
  54. Trost SG, Kerr LM, Ward DS, Pate RR (2001) Physical activity and determinants of physical activity in obese and non-obese children. Int J Obes Relat Metab Disord 25:822–829PubMedCrossRefGoogle Scholar
  55. Zombeck JA, Chen GT, Johnson ZV, Rosenberg DM, Craig AB, Rhodes JS (2008) Neuroanatomical specificity of conditioned responses to cocaine versus food in mice. Physiol Behav 93:637–650PubMedCrossRefGoogle Scholar
  56. Zombeck JA, Lewicki AD, Patel K, Gupta T, Rhodes JS (2010) Patterns of neural activity associated with differential acute locomotor stimulation to cocaine and methamphetamine in adolescent versus adult male C57BL/6 J mice. Neuroscience 165:1087–1099PubMedCentralPubMedCrossRefGoogle Scholar
  57. Zombeck JA, Deyoung EK, Brzezinska WJ, Rhodes JS (2011) Selective breeding for increased home cage physical activity in collaborative cross and Hsd:ICR mice. Behav Genet 41:571–582PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Petra Majdak
    • 1
    Email author
  • Paula J. Bucko
    • 2
  • Ashley L. Holloway
    • 2
  • Tushar K. Bhattacharya
    • 2
  • Erin K. DeYoung
    • 2
  • Chessa N. Kilby
    • 2
  • Jonathan A. Zombeck
    • 3
  • Justin S. Rhodes
    • 2
  1. 1.Neuroscience Program, The Beckman InstituteUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  2. 2.Department of Psychology, The Beckman InstituteUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  3. 3.Biomodels, LLCWatertownUSA

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