Automated Operant Assessments of Huntington’s Disease Mouse Models

Part of the Methods in Molecular Biology book series (MIMB, volume 1780)


Huntington’s disease (HD) presents clinically with a triad of motor, cognitive, and psychiatric symptoms. Cognitive symptoms often occur early within the disease progression, prior to the onset of motor symptoms, and they are significantly burdensome to people who are affected by HD. In order to determine the suitability of mouse models of HD in recapitulating the human condition, these models must be behaviorally tested and characterized. Operant behavioral testing offers an automated and objective method of behaviorally profiling motor, cognitive, and psychiatric dysfunction in HD mice. Furthermore, operant testing can also be employed to determine any behavioral changes observed after any associated interventions or experimental therapeutics. We here present an overview of the most commonly used operant behavioral tests to dissociate motor, cognitive, and psychiatric aspects of mouse models of HD.


Huntington’s disease Mouse model Knockin Transgenic Cognition Behavior Operant 9-Hole box Skinner box Touch screen 



E.Y. is supported by a Health and Care Research Wales Health Fellowship award and has also received research funding from the Jacque and Gloria Gossweiler Foundation as well as a previous PhD studentship from the Medical Research Council (MRC), UK.

A.H. is supported by a scholarship of the Swedish Society for Medical research (SSMF) and a starting grant of the Swedish research council (Vetenskapsradet).

Both authors would like to acknowledge past and present members of the Brain Repair Group at Cardiff University and particularly the contribution of Professor Stephen B. Dunnett who has developed and refined these tasks over many decades. Furthermore, we would like to thank David H. Harrison for providing photographs of the operant equipment and Michael A. Yhnell for proofreading the content of this chapter.


  1. 1.
    MacDonald ME, Ambrose CM, Duyao MP et al (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983CrossRefGoogle Scholar
  2. 2.
    Jacobsen JC, Bawden CS, Rudiger SR et al (2010) An ovine transgenic Huntington’s disease model. Hum Mol Genet 19:1873–1882CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Yang D, Wang C-E, Zhao B et al (2010) Expression of Huntington’s disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Hum Mol Genet 19:3983–3994CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Yang S-H, Cheng P-H, Banta H et al (2008) Towards a transgenic model of Huntington’s disease in a non-human primate. Nature 453:921–924CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    von Hörsten S, Schmitt I, Nguyen HP et al (2003) Transgenic rat model of Huntington’s disease. Hum Mol Genet 12:617–624CrossRefGoogle Scholar
  6. 6.
    Faber PW, Alter JR, MacDonald ME et al (1999) Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc Natl Acad Sci U S A 96:179–184CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lunkes A, Mandel J-L (1998) A cellular model that recapitulates major pathogenic steps of Huntington’s disease. Hum Mol Genet 7:1355–1361CrossRefPubMedGoogle Scholar
  8. 8.
    Mangiarini L, Sathasivam K, Seller M et al (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506CrossRefPubMedGoogle Scholar
  9. 9.
    Brooks S, Higgs G, Jones L et al (2012) Longitudinal analysis of the behavioural phenotype in Hdh (CAG) 150 Huntington’s disease knock-in mice. Brain Res Bull 88:182–188CrossRefPubMedGoogle Scholar
  10. 10.
    Brooks SP, Janghra N, Workman VL et al (2012) Longitudinal analysis of the behavioural phenotype in R6/1 (C57BL/6J) Huntington’s disease transgenic mice. Brain Res Bull 88:94–103CrossRefPubMedGoogle Scholar
  11. 11.
    Brooks S, Higgs G, Janghra N et al (2012) Longitudinal analysis of the behavioural phenotype in YAC128 (C57BL/6J) Huntington's disease transgenic mice. Brain Res Bull 88:113–120CrossRefPubMedGoogle Scholar
  12. 12.
    Menalled L, El-Khodor BF, Patry M et al (2009) Systematic behavioral evaluation of Huntington’s disease transgenic and knock-in mouse models. Neurobiol Dis 35:319–336CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Rogers DC, Fisher E, Brown S et al (1997) Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm Genome 8:711–713CrossRefPubMedGoogle Scholar
  14. 14.
    Baldo B, Petersén Å (2015) Chapter 35: Analysis of nonmotor features in murine models of Huntington disease A2. In: LeDoux MS (ed) Movement disorders, 2nd edn. Academic Press, Boston, pp 583–602CrossRefGoogle Scholar
  15. 15.
    Brooks SP, Dunnett SB (2009) Tests to assess motor phenotype in mice: a user’s guide. Nat Rev Neurosci 10:519–529CrossRefPubMedGoogle Scholar
  16. 16.
    Crawley JN (2008) Behavioral phenotyping strategies for mutant mice. Neuron 57:809–818CrossRefPubMedGoogle Scholar
  17. 17.
    Yue F, Cheng Y, Breschi A et al (2014) A comparative encyclopedia of DNA elements in the mouse genome. Nature 515:355–364CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Huntington G (1872) Medical and surgical reporter. On Chorea:320–321Google Scholar
  19. 19.
    Thompson P, Berardelli A, Rothwell J et al (1988) The coexistence of bradykinesia and chorea in Huntington’s disease and its implications for theories of basal ganglia control of movement. Brain 111:223–244CrossRefPubMedGoogle Scholar
  20. 20.
    Diamond R, White RF, Myers RH et al (1992) Evidence of presymptomatic cognitive decline in Huntington’s disease. J Clin Exp Neuropsychol 14:961–975CrossRefPubMedGoogle Scholar
  21. 21.
    Lawrence AD, Hodges JR, Rosser AE et al (1998) Evidence for specific cognitive deficits in preclinical Huntington’s disease. Brain 121:1329–1341CrossRefPubMedGoogle Scholar
  22. 22.
    Kirkwood S, Siemers E, Hodes M et al (2000) Subtle changes among presymptomatic carriers of the Huntington’s disease gene. J Neurol Neurosurg Psychiatry 69:773–779CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Robins Wahlin T-B, Lundin A, Dear K (2007) Early cognitive deficits in Swedish gene carriers of Huntington’s disease. Neuropsychology 21:31CrossRefPubMedGoogle Scholar
  24. 24.
    Paulsen J, Langbehn D, Stout J et al (2008) Detection of Huntington’s disease decades before diagnosis: the predict-HD study. J Neurol Neurosurg Psychiatry 79:874–880CrossRefPubMedGoogle Scholar
  25. 25.
    Tabrizi SJ, Langbehn DR, Leavitt BR et al (2009) Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 8:791–801CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Tabrizi SJ, Scahill RI, Durr A et al (2011) Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol 10:31–42CrossRefPubMedGoogle Scholar
  27. 27.
    Tabrizi SJ, Scahill RI, Owen G et al (2013) Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol 12:637–649CrossRefPubMedGoogle Scholar
  28. 28.
    Craufurd D, Thompson JC, Snowden JS (2001) Behavioral changes in Huntington disease. Neuropsychiatry Neuropsychol Behav Neurol 14:219–226PubMedGoogle Scholar
  29. 29.
    Thompson JC, Snowden JS, Craufurd D et al (2002) Behavior in Huntington’s disease: dissociating cognition-based and mood-based changes. J Neuropsychiatry Clin Neurosci 14:37–43CrossRefPubMedGoogle Scholar
  30. 30.
    Lawrence AD, Sahakian B, Rogers R et al (1999) Discrimination, reversal, and shift learning in Huntington’s disease: mechanisms of impaired response selection. Neuropsychologia 37:1359–1374CrossRefPubMedGoogle Scholar
  31. 31.
    Josiassen RC, Curry LM, Mancall EL (1983) Development of neuropsychological deficits in Huntington’s disease. Arch Neurol 40:791–796CrossRefPubMedGoogle Scholar
  32. 32.
    Snowden J, Austin N, Sembi S et al (2008) Emotion recognition in Huntington’s disease and frontotemporal dementia. Neuropsychologia 46:2638–2649CrossRefPubMedGoogle Scholar
  33. 33.
    Kipps C, Duggins A, McCusker E et al (2007) Disgust and happiness recognition correlate with anteroventral insula and amygdala volume respectively in preclinical Huntington’s disease. J Cogn Neurosci 19:1206–1217CrossRefPubMedGoogle Scholar
  34. 34.
    Johnson SA, Stout JC, Solomon AC et al (2007) Beyond disgust: impaired recognition of negative emotions prior to diagnosis in Huntington’s disease. Brain 130:1732–1744CrossRefPubMedGoogle Scholar
  35. 35.
    Helder D, Kaptein A, Van Kempen G et al (2001) Impact of Huntington’s disease on quality of life. Mov Diskord 16:325–330CrossRefGoogle Scholar
  36. 36.
    Ready RE, Mathews M, Leserman A et al (2008) Patient and caregiver quality of life in Huntington’s disease. Mov Disord 23:721–726CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Mitchell AJ, Kemp S, Benito-León J et al (2010) The influence of cognitive impairment on health-related quality of life in neurological disease. Acta Neuropsychiatr 22:2–13CrossRefGoogle Scholar
  38. 38.
    Burns A, Folstein S, Brandt J et al (1990) Clinical assessment of irritability, aggression, and apathy in Huntington and Alzheimer disease. J Nerv Ment Dis 178:20–26CrossRefPubMedGoogle Scholar
  39. 39.
    Gusella JF, Macdonald ME, Duff K et al (2007) Psychiatric symptoms in Huntington’s disease before diagnosis: the predict-HD study. Biol Psychiatry 62:1340CrossRefPubMedGoogle Scholar
  40. 40.
    Julien CL, Thompson JC, Wild S et al (2007) Psychiatric disorders in preclinical Huntington’s disease. J Neurol Neurosurg Psychiatry 78:939–943CrossRefPubMedGoogle Scholar
  41. 41.
    Klöppel S, Stonnington CM, Petrovic P et al (2010) Irritability in pre-clinical Huntington’s disease. Neuropsychologia 48:549–557CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Baudic S, Maison P, Dolbeau G et al (2006) Cognitive impairment related to apathy in early Huntington’s disease. Dement Geriatr Cogn Disord 21:316–321CrossRefPubMedGoogle Scholar
  43. 43.
    Paulsen JS, Nehl C, Hoth KF et al (2005) Depression and stages of Huntington’s disease. J Neuropsychiatry Clin Neurosci 17:496–502CrossRefPubMedGoogle Scholar
  44. 44.
    Slaughter JR, Martens MP, Slaughter KA (2001) Depression and Huntington’s disease: prevalence, clinical manifestations, etiology, and treatment. CNS Spectr 6:306–308. 325–326CrossRefPubMedGoogle Scholar
  45. 45.
    Brooks SP, Jones L, Dunnett SB (2012) Longitudinal analyses of operant performance on the serial implicit learning task (SILT) in the YAC128 Huntington’s disease mouse line. Brain Res Bull 88:130–136CrossRefPubMedGoogle Scholar
  46. 46.
    Takao K, Miyakawa T (2006) Light/dark transition test for mice. J Vis Exp (1):e104Google Scholar
  47. 47.
    Brasted PJ, Döbrössy MD, Robbins TW et al (1998) Striatal lesions produce distinctive impairments in reaction time performance in two different operant chambers. Brain Res Bull 46:487–493CrossRefPubMedGoogle Scholar
  48. 48.
    Spaulding WD, Storms L, Goodrich V, Sullivan M (1986) Applications of experimental psychopathology in psychiatric rehabilitation. Schizophr Bull 12:560–577CrossRefPubMedGoogle Scholar
  49. 49.
    Skinner B (1938) The behavior of organisms. Appleton-Century-Crofts, New YorkGoogle Scholar
  50. 50.
    Yhnell E, Dunnett SB, Brooks SP (2016) The utilisation of operant delayed matching and non-matching to position for probing cognitive flexibility and working memory in mouse models of Huntington’s disease. J Neurosci Methods 265:72–80CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Carli M, Robbins T, Evenden J et al (1983) Effects of lesions to ascending noradrenergic neurones on performance of a 5-choice serial reaction task in rats; implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal. Behav Brain Res 9:361–380CrossRefPubMedGoogle Scholar
  52. 52.
    Robbins T (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology 163:362–380CrossRefPubMedGoogle Scholar
  53. 53.
    Humby T, Laird FM, Davies W et al (1999) Visuospatial attentional functioning in mice: interactions between cholinergic manipulations and genotype. Eur J Neurosci 11:2813–2823CrossRefPubMedGoogle Scholar
  54. 54.
    Bensadoun J-C, Brooks SP, Dunnett SB (2004) Free operant and discrete trial performance of mice in the nine-hole box apparatus: validation using amphetamine and scopolamine. Psychopharmacology 174:396–405CrossRefPubMedGoogle Scholar
  55. 55.
    Trueman RC, Dunnett SB, Jones L et al (2012) Five choice serial reaction time performance in the Hdh Q92 mouse model of Huntington’s disease. Brain Res Bull 88:163–170CrossRefPubMedGoogle Scholar
  56. 56.
    Yhnell E, Dunnett SB, Brooks SP (2016) A longitudinal operant assessment of cognitive and behavioural changes in the Hdh Q111 mouse model of Huntington’s disease. PLoS One 11:e0164072CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Horner AE, Heath CJ, Hvoslef-Eide M et al (2013) The touchscreen operant platform for testing learning and memory in rats and mice. Nat Protoc 8:1961–1984CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Morton AJ, Skillings E, Bussey TJ et al (2006) Measuring cognitive deficits in disabled mice using an automated interactive touchscreen system. Nat Methods 3:767CrossRefPubMedGoogle Scholar
  59. 59.
    Clelland C, Choi M, Romberg C et al (2009) A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325:210–213CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    McTighe SM, Mar AC, Romberg C et al (2009) A new touchscreen test of pattern separation: effect of hippocampal lesions. Neuroreport 20:881–885CrossRefPubMedGoogle Scholar
  61. 61.
    Talpos J, McTighe S, Dias R et al (2010) Trial-unique, delayed nonmatching-to-location (TUNL): a novel, highly hippocampus-dependent automated touchscreen test of location memory and pattern separation. Neurobiol Learn Mem 94:341–352CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Curtin PC, Farrar AM, Oakeshott S et al (2015) Cognitive training at a young age attenuates deficits in the zQ175 mouse model of HD. Front Behav Neurosci 9:361PubMedGoogle Scholar
  63. 63.
    Oakeshott S, Port R, Cummins-Sutphen J, et al (2012) A mixed fixed ratio/progressive ratio procedure reveals an apathy phenotype in the BAC HD and the z_Q175 KI mouse models of Huntington’s disease. PLoS Curr Huntington Disease 5.
  64. 64.
    Yhnell E, Lelos MJ, Dunnett SB et al (2016) Cognitive training modifies disease symptoms in a mouse model of Huntington’s disease. Exp Neurol 282:19–26CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Trueman RC, Brooks SP, Jones L et al (2007) The operant serial implicit learning task reveals early onset motor learning deficits in the HdhQ92 knock-in mouse model of Huntington’s disease. Eur J Neurosci 25:551–558CrossRefPubMedGoogle Scholar
  66. 66.
    Trueman RC, Brooks SP, Jones L et al (2008) Time course of choice reaction time deficits in the Hdh Q92 knock-in mouse model of Huntington's disease in the operant Serial Implicit Learning Task (SILT). Behav Brain Res 189:317–324CrossRefPubMedGoogle Scholar
  67. 67.
    Dunnett SB, Rogers DC, Jones GH (1989) Effects of nucleus basalis magnocellularis lesions in rats on delayed matching and non-matching to position tasks. Eur J Neurosci 1:395–406CrossRefPubMedGoogle Scholar
  68. 68.
    D’amato M (1973) Delayed matching and short-term memory in monkeys. Psych Learn Motiv 7:227–269CrossRefGoogle Scholar
  69. 69.
    Döbrössy MD, Dunnett SB (1998) Striatal grafts alleviate deficits in response execution in a lateralised reaction time task. Brain Res Bull 47:585–593CrossRefPubMedGoogle Scholar
  70. 70.
    Dowd E, Dunnett SB (2004) Deficits in a lateralized associative learning task in dopamine-depleted rats with functional recovery by dopamine-rich transplants. Eur J Neurosci 20:1953–1959CrossRefPubMedGoogle Scholar
  71. 71.
    Trueman RC, Jones L, Dunnett SB et al (2012) Early onset deficits on the delayed alternation task in the Hdh Q92 knock-in mouse model of Huntington’s disease. Brain Res Bull 88:156–162CrossRefPubMedGoogle Scholar
  72. 72.
    Dunnett SB, White A (2006) Striatal grafts alleviate bilateral striatal lesion deficits in operant delayed alternation in the rat. Exp Neurol 199:479–489CrossRefPubMedGoogle Scholar
  73. 73.
    Trueman RC, Brooks SP, Jones L et al (2009) Rule learning, visuospatial function and motor performance in the Hdh Q92 knock-in mouse model of Huntington’s disease. Behav Brain Res 203:215–222CrossRefPubMedGoogle Scholar
  74. 74.
    Dunnett SB, Fuller A, Rosser AE et al (2012) A novel extended sequence learning task (ESLeT) for rodents: validation and the effects of amphetamine, scopolamine and striatal lesions. Brain Res Bull 88:237–250CrossRefPubMedGoogle Scholar
  75. 75.
    Kubota K, Niki H (1971) Prefrontal cortical unit activity and delayed alternation performance in monkeys. J Neurophysiol 34(3):337–347CrossRefPubMedGoogle Scholar
  76. 76.
    Jacobsen CF, Nissen H (1937) Studies of cerebral function in primates: IV. The effects of frontal lobe lesions on the delayed alternation habit in monkeys. J Comp Psychol 23:101CrossRefGoogle Scholar
  77. 77.
    Dunnett SB, Nathwani F, Brasted PJ (1999) Medial prefrontal and neostriatal lesions disrupt performance in an operant delayed alternation task in rats. Behav Brain Res 106:13–28CrossRefPubMedGoogle Scholar
  78. 78.
    Dunnett SB (1985) Comparative effects of cholinergic drugs and lesions of nucleus basalis or fimbria-fornix on delayed matching in rats. Psychopharmacology 87:357–363CrossRefPubMedGoogle Scholar
  79. 79.
    Carli M, Evenden J, Robbins T (1985) Depletion of unilateral striatal dopamine impairs initiation of contralateral actions and not sensory attention. Nature 313:679–682CrossRefPubMedGoogle Scholar
  80. 80.
    Döbrössy MD, Dunnett SB (1997) Unilateral striatal lesions impair response execution on a lateralised choice reaction time task. Behav Brain Res 87:159–171CrossRefPubMedGoogle Scholar
  81. 81.
    Dowd E, Dunnett SB (2005) Comparison of 6-hydroxydopamine-induced medial forebrain bundle and nigrostriatal terminal lesions in a lateralised nose-poking task in rats. Behav Brain Res 159:153–161CrossRefPubMedGoogle Scholar
  82. 82.
    Mayer E, Brown V, Dunnett S et al (1992) Striatal graft-associated recovery of a lesion-induced performance deficit in the rat requires learning to use the transplant. Eur J Neurosci 4:119–126CrossRefPubMedGoogle Scholar
  83. 83.
    Van Raamsdonk JM, Metzler M, Slow E et al (2007) Phenotypic abnormalities in the YAC128 mouse model of Huntington disease are penetrant on multiple genetic backgrounds and modulated by strain. Neurobiol Dis 26:189–200CrossRefPubMedGoogle Scholar
  84. 84.
    Tucci V, Hardy A, Nolan PM (2006) A comparison of physiological and behavioural parameters in C57BL/6J mice undergoing food or water restriction regimes. Behav Brain Res 173:22–29CrossRefPubMedGoogle Scholar
  85. 85.
    Duan W, Guo Z, Jiang H et al (2003) Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci U S A 100:2911–2916CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Neuroscience and Mental Health Research InstituteCardiff UniversityCardiffUK
  2. 2.Molecular Neuromodulation, Experimental MedicineLund UniversityLundSweden

Personalised recommendations