Advertisement

Behavior Genetics

, Volume 37, Issue 2, pp 388–398 | Cite as

Chronobiometry of Behavioral Activity in the Ts65Dn Model of Down Syndrome

  • Lee S. Stewart
  • Michael A. Persinger
  • Miguel A. Cortez
  • O. Carter SneadIII
Original Paper

Abstract

Disruption of the sleep-wake cycle has been reported among individuals with Down syndrome (DS). Here we studied behavioral rhythms in adult male and female Ts65Dn mice, a model of DS. The overall behavioral activity of Ts65Dn and diploid (2N) littermates as defined by total movements (TM), movement time (MT), ambulatory movement time (AMT), time spent in center of arena (CT), jumps (JFP), rotational behavior (TURNS), and wheel-running activity (WRA) was recorded under a 12 h:12 h light–dark photocycle. During the light phase, Ts65Dn mice exhibited higher TM, MT, CT, JFP, and WRA compared to 2N littermates. During the dark phase, Ts65Dn and 2N mice differed only in CT and WRA, with the Ts65Dn group engaging in higher levels of both. There were no gender differences for any of the behavioral variables studied. Non-linear least-squares (Cosinor) analysis of the distribution of total behavioral activity (TM) indicated that Ts65Dn mice exhibited a slightly higher mean oscillation (i.e., mesor), but significantly lower amplitude in comparison to 2N mice, suggesting that levels of TM were elevated in trisomic mice but were relatively constant throughout the photocycle. The peak of the Ts65Dn TM rhythm was significantly phase-advanced, occurring approximately 4 h earlier than 2N mice. Overall, Ts65Dn mice were hyperactive and differed significantly in daily patterns of specific behaviors from those of 2N littermates. To control for the potential confound of retinal degeneration in Ts65Dn and 2N mice, we compared and found no difference between the TM rhythm parameters of 2N and non-retinally degenerate C57/129Sv mice, suggesting that abnormal behavioral rhythmicity in Ts65Dn mice may not due to the absence of rod and cone photoreceptors. These results serve as a starting point for further investigations into the physiological basis of sleep–wake disturbances in DS patients.

Keywords

Behavioral rhythms Rest-activity cycle MMU16 Trisomy Retina APP Mouse 

Notes

Acknowledgments

The authors thank Dr. Zhengpheng Jia, Zarko Todorovski, Ilyas Aleem, and the Laboratory Animal Services at the Hospital for Sick Children for assistance. We also thank Dr. Lily Shen for the breeding and genotyping of the Ts65Dn mouse line. This work was supported by grants from The Hospital for Sick Children Down Syndrome Fund (#3217656151) to M.A.C. and The Canadian Institutes of Health Research (#3210016078) to O.C.S., III. L.S.S. is the recipient of a postdoctoral fellowship (#PDF-313950-2005) from the Natural Sciences and Engineering Research Council of Canada.

References

  1. Ambree O, Touma C, Gortz N, Keyvani K, Paulus W, Palme R, Sachser N (2006) Acitivty changes and marked stereotypic behavior precede Aβ pathology in TgCRND8 Alzheimer mice. Neurobiol. Aging 27:955–964PubMedCrossRefGoogle Scholar
  2. Belichenko PV, Masliah E, Kleschevnikov AM, Villar AJ, Epstein CJ, Salehi A, Mobley WC (2004) Synaptic structural abnormalities in the Ts65Dn mouse model of Down Syndrome. J Comp Neurol 480:281–298PubMedCrossRefGoogle Scholar
  3. Benavides-Piccione R, Ballesteros-Yanez I, de Lagran MM, Elston G, Estivill X, Fillat C, Defelipe J, Dierssen M (2004) On dendrites in Down syndrome and DS murine models: a spiny way to learn. Prog Neurobiol 74:111–126PubMedCrossRefGoogle Scholar
  4. Bimonte-Nelson HA, Hunter CL, Nelson ME, Granholm AC (2003) Frontal cortex BDNF levels correlate with working memory in an animal model of Down syndrome. Behav Brain Res 139:7–57CrossRefGoogle Scholar
  5. Chang B, Hawes NL, Hurd RE, Davisson, MT, Nusinowitz S, Heckenlively JR (2002) Retinal degeneration mutants in the mouse. Vision Res 42:517–525PubMedCrossRefGoogle Scholar
  6. Cooper SA, Prasher VP (1998) Maladaptive behaviours and symptoms of dementia in adults with Down syndrome compared with adults with intellectual disability of other etiologies. J Intellect Disabil Res 42:293–300PubMedCrossRefGoogle Scholar
  7. Cotton S, Richdale A (2006) Parental descriptions of sleep problems in children with autism, Down syndrome, and Prader–Willi syndrome. Res Dev Disabil 27:151–161PubMedCrossRefGoogle Scholar
  8. Coussons-Read ME, Crnic LS (1996) Behavioral assessment of the Ts65Dn mouse, a model for Down syndrome: altered behavior in the elevated plus maze and open field. Behav Genet 26:7–13PubMedCrossRefGoogle Scholar
  9. Costa AC, Walsh K, Davisson MT (1999) Motor dysfunction in a mouse model for Down syndrome. Physiol Behav 68:211–220PubMedCrossRefGoogle Scholar
  10. Dahlqvist A, Rask E, Rosenqvist CJ, Sahlin C, Franklin KA (2003) Sleep apnea and Down syndrome. Acta Otolaryngol 123:1094–1097PubMedCrossRefGoogle Scholar
  11. Davisson MT, Schmidt C, Akeson EC (1990) Segmental trisomy of murine chromosome 16: a new system for studying Down syndrome. In: Patteron D, Epstein CJ (eds) Molecular genetics of chromosome 21 and Down syndrome. Wiley-Liss, New York, pp. 263–280Google Scholar
  12. Demas GE, Nelson RJ, Krueger BK, Yarowsky PJ (1996) Spatial memory deficits in segmental trisomic Ts65Dn mice. Behav Brain Res 2:5–92Google Scholar
  13. Driscoll LL, Carroll JC, Moon J, Crnic LS, Levitsky DA, Strupp BJ (2004) Impaired sustained attention and error-induced stereotypy in the aged Ts65Dn mouse: a model of Down syndrome and Alzheimer’s disease. Behav Neurosci 118:1196–1205PubMedCrossRefGoogle Scholar
  14. Easton A, Meerlo P, Bergmann B, Turek FW (2004) The suprachiasmatic nucleus regulates sleep timing and amount in mice. Sleep 27:1307–1318PubMedGoogle Scholar
  15. Escorihuela RM, Fernandez-Teruel A, Vallina IF, Baamonde C, Lumbreras MA, Dierssen M, Tobena A, Florez J (1995) A behavioral assessment of Ts65Dn mice: a putative Down syndrome model. Neurosci Lett 199:43–146CrossRefGoogle Scholar
  16. Escorihuela RM, Vallina IF, Martinez-Cue C, Baamonde C, Dierssen M, Tobena A, Florez J, Fernandez-Teruel A (1998) Impaired short-and long-term memory in Ts65Dn mice, a model for Down syndrome. Neurosci Lett 247:171–174PubMedCrossRefGoogle Scholar
  17. Ferguson SA, Kenneway DJ, Moyer RW (1999) Nicotine phase shifts the 6-sulphatoxymelatonin rhythm and induces c-Fos in the SCN of rats. Brain Res Bull 48:527–538PubMedCrossRefGoogle Scholar
  18. Finkel SI (2003) Behavioral and psychological symptoms of dementia. Clin. Geriatr Med 19:799–824PubMedCrossRefGoogle Scholar
  19. Hampton TG, Stasko MR, Kale A, Amende I, Costa AC (2004) Gait dynamics in trisomic mice: quantitative neurological traits of Down syndrome. Physiol Behav 82:381–389PubMedCrossRefGoogle Scholar
  20. Hastings M, Maywood ES (2000) Circadian clocks in the mammalian brain. BioEssays 22:23–31PubMedCrossRefGoogle Scholar
  21. Holtzman DM, Santucci D, Killbridge J, Chua-Couzens J, Fontana DJ, Daniels SE, Johnson RM, Chen K, Sun Y, Carlson E, Alleva E, Epstein CJ, Mobley WC (1996) Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proc Natl Acad Sci USA 93:13333–13338PubMedCrossRefGoogle Scholar
  22. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, A-beta elevation, and amyloid plaques in transgenic mice. Science 274:99–102PubMedCrossRefGoogle Scholar
  23. Hunter CL, Isacson O, Nelson M, Bimonte-Nelson H, Seo H, Lin L, Ford K, Kindy MS, Granholm A-C (2003) Regional alterations in amyloid precursor protein and nerve growth factor across age in a mouse model of Down’s syndrome. Neurosci Res 45:437–445PubMedCrossRefGoogle Scholar
  24. Klein SL, Kriegsfeld LJ, Hairston JE, Rau V, Nelson RJ, Yarowsky PJ (1996) Characterization of sensorimotor performance, reproductive and aggressive behaviors in segmental trisomic 16 (Ts65Dn) mice. Physiol Behav 60:1159–1164PubMedCrossRefGoogle Scholar
  25. Krout KE, Kawano J, Mettenleiter TC, Loewy AD (2002) CNS inputs to the suprachiasmatic nucleus of the rat. Neuroscience 110:73–92PubMedCrossRefGoogle Scholar
  26. Lalonde R, Dumont M, Staufenbiel M, Sturchler-Pierrat C, Strazielle C (2002) Spatial learning, exploration, anxiety, motor coordination in female APP23 transgenic mice with the Swedish mutation. Brain Res 956:36–44PubMedCrossRefGoogle Scholar
  27. Levanon A, Tarasiuk A, Tal A (1999) Sleep characteristics in children with Down syndrome. J Pediatr 134:755–760PubMedCrossRefGoogle Scholar
  28. Low-Zeddies SS, Takahashi JS (2001) Chimera analysis of the Clock mutation in mice shows that complex cellular integration determines circadian behavior. Cell 105:25–42PubMedCrossRefGoogle Scholar
  29. Liu DP, Schnidt C, Billings T, Davisson MT (2003) Quantitative PCR genotyping assay for the Ts65Dn mouse model of Down syndrome. Biotechniques 35:1–7Google Scholar
  30. Marashi V, Barnekow A, Ossendorf E, Sachser N (2003) Effects of different forms of environmental enrichment on behavioral, endocrinological, and immunological parameters in male mice. Horm Behav 43:281–292PubMedCrossRefGoogle Scholar
  31. Martinez-Cue C, Baamonde C, Lumbreras M, Paz J, Davisson MT, Schmidt C, Diersson M, Florez J (2002) Differential effects of environmental enrichment on behavior and learning of male and female Ts65Dn mice, a model for Down syndrome. Behav Brain Res 134:185–200PubMedCrossRefGoogle Scholar
  32. Moore RY (1996) Entrainment pathways and the functional organization of the circadian system. Prog Brain Res 111:103–119PubMedCrossRefGoogle Scholar
  33. Mrak RE, Griffin WS (2004) Trisomy 21 and the brain. J Neuropathol Exp Neurol 63:679–85PubMedGoogle Scholar
  34. Mrosovsky N (2003) Contribution of classic photoreceptors to entrainment. J Comp Physiol A 189:69–73Google Scholar
  35. Mrosovsky N (2003) Aschoff’s rule in retinally degenerate mice. J Comp Physiol A 189:75–78Google Scholar
  36. Niedermayer E (2001) Frontal lobe disinhibition, Rett syndrome and attention deficit hyperactivity disorder. Clin Electroencephalogr 32:20–23Google Scholar
  37. Nelson DL, Gibbs RA (2004) The critical region in Trisomy 21. Science 306:619–621PubMedCrossRefGoogle Scholar
  38. Pitovcakova J, Makatsori A, Sulcova A, Jezova D (2005) Felbamate reduces hormone release and locomotor hypoactivity induced by repeated stress of social defeat in mice. Eur Neuropsychopharmacol 15:153–158CrossRefGoogle Scholar
  39. Provencio I, Wong S, Lederman AB, Argamaso SM, Foster RG (1994) Visual and circadian responses to light in aged retinally degenerate mice. Vision Res 34:1799–1806PubMedCrossRefGoogle Scholar
  40. Provencio I, Cooper HM, Foster RG (1998) Retinal projections in mice with inherited retinal degeneration: implications for circadian photoentrainment. J Comp Neurol 395:417–439PubMedCrossRefGoogle Scholar
  41. Ralph MR, Foster RG, Davis FC, Menaker M (1990) Transplanted suprachiasmatic nucleus determines circadian period. Science 247:975–978PubMedCrossRefGoogle Scholar
  42. Richtsmeier JT, Zumwalt A, Carlson EJ, Epstein CJ, Reeves RH (2002) Craniofacial phenotypes in segmentally trisomic mouse models for Down syndrome. Am J Med Genet 107:317–324PubMedCrossRefGoogle Scholar
  43. Sancar A (2000) Cryptochrome: the second photoactive pigment in the eye and its role in circadian photoreception. Annu Rev Biochem 69:31–67PubMedCrossRefGoogle Scholar
  44. Selby CP, Thompson C, Schmitz TM, van Gelder RN, Sancar A (2000) Functional redundancy of cryptochromes and classical photoreceptors for nonvisual ocular photoreception in mice. Proc Natl Acad Sci USA 97:14697–14702PubMedCrossRefGoogle Scholar
  45. Seo H, Isacson O (2005) Abnormal APP, cholinergic and cognitive function in Ts65Dn Down’s model mice. Exp Neurol 193:469–480PubMedCrossRefGoogle Scholar
  46. Stewart LS, Potok A, Camper SA, Stifani S (2005) Runx1 expression defines a subpopulation of displaced amacrine cells in the developing mouse retina. J Neurochem 94:1739–1745PubMedCrossRefGoogle Scholar
  47. Tate B, Aboody-Guterman KS, Morris AM, Walcott EC, Majocha RE, Marotta CA (1992) Disruption of circadian regulation by brain grafts that overexpress Alzheimer beta/A4 amyloid. Proc Natl Acad Sci USA 89:7090–7094PubMedCrossRefGoogle Scholar
  48. Teipel SJ, Hampel H (2006) Neuroanatomy of Down syndrome in vivo: a model of preclinical Alzheimer’s disease. Behav Genet 36:405–415PubMedCrossRefGoogle Scholar
  49. Teicher MH, Barber NI (1990) COSIFIT: an interactive program for simultaneous multioscillator Cosinor analysis of time-series data. Comp Biomed Res 23:283–295CrossRefGoogle Scholar
  50. Tsiouris JA, Brown WT (2004) Neuropyschiatric symptoms of fragile X syndrome: pathophysiology and pharmacotherapy. CNS Drugs 18:687–703PubMedCrossRefGoogle Scholar
  51. Turek FW (1985) Circadian neural rhythms in mammals. Ann Rev Physiol 47:49–64CrossRefGoogle Scholar
  52. Turner CA, Presti MF, Newman HA, Bugenhagen P, Crnic L, Lewis MH (2001) Spontaneous stereotypy in an animal model of Down syndrome: Ts65Dn mice. Behav Genet 31:393–400PubMedCrossRefGoogle Scholar
  53. Vicari S (2006) Motor development and neuropsychological patterns in persons with Down syndrome. Behav Genet 36:355–364PubMedCrossRefGoogle Scholar
  54. Vitiello MV, Prinz PN (1989) Alzheimer’s disease. Sleep and sleep/wake patterns. Clin Geriatr Med 5:289–299PubMedGoogle Scholar
  55. Wilsor JP, Edgar DM, Yesavage J, Ryan HS, McCormick CM, Lapustea N, Murphy GM (2005) Sleep and circadian abnormalities in a transgenic mouse model of Alzheimer’s disease: a role for cholinergic transmission. Neuroscience 131:375–385CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Lee S. Stewart
    • 1
  • Michael A. Persinger
    • 4
  • Miguel A. Cortez
    • 1
    • 2
    • 3
  • O. Carter SneadIII
    • 1
    • 2
    • 3
  1. 1.Brain and Behavior Research ProgramThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Division of NeurologyThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of Pediatrics, Faculty of MedicineThe University of TorontoTorontoCanada
  4. 4.Department of PsychologyLaurentian UniversitySudburyCanada

Personalised recommendations