Skip to main content

Advertisement

SpringerLink
Log in

An Animal Model of Oral Dysphagia in Amyotrophic Lateral Sclerosis

  • Original Article
  • Published:
Dysphagia Aims and scope Submit manuscript

Abstract

Relatively little is known about the underlying neuropathology of dysphagia in amyotrophic lateral sclerosis (ALS); thus, effective treatments remain elusive. Tremendous progress toward understanding and treating dysphagia in ALS may be possible through the use of an animal model of dysphagia in ALS research; however, no such animal model currently exists. The most logical candidate to consider is the SOD1-G93A transgenic mouse, the most widely investigated animal model of ALS. To investigate whether this animal model develops dysphagia, oral behaviors (lick and mastication rates) of SOD1-G93A transgenic mice (n = 30) were evaluated at three time points based on hind limb motor function: asymptomatic (60 days), disease onset (~110 days), and disease end-stage (~140 days). Age-matched nontransgenic littermates (n = 30) served as controls. At each time point, lick and mastication rates were significantly lower (p < 0.05) for transgenic mice compared with controls. Histologic analysis of the brainstem showed marked neurodegeneration (vacuolation) of the trigeminal and hypoglossal nuclei, two key motor components involved in mastication and licking behaviors. These results demonstrate a clinicopathologic correlation of oral dysfunction in SOD1-G93A transgenic mice, thereby establishing the SOD1-G93A transgenic mouse as a bona fide animal model of oral dysphagia in ALS.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Brownell B, Oppenheimer DR, Hughes JT. The central nervous system in motor neurone disease. J Neurol Neurosurg Psychiatry. 1970;33:338–57.

    Article  PubMed  CAS  Google Scholar 

  2. Charles T, Swash M. Amyotrophic lateral sclerosis: current understanding. J Neurosci Nurs. 2001;33:245–53.

    PubMed  CAS  Google Scholar 

  3. Hughes JT, Jerrome D. Ultrastructure of anterior horn motor neurones in the Hirano-Kurland-Sayre type of combined neurological system degeneration. J Neurol Sci. 1971;13:389–99. doi:10.1016/0022-510X(71)90002-5.

    Article  PubMed  CAS  Google Scholar 

  4. Lawyer T Jr, Netsky MG. Amyotrophic lateral sclerosis. AMA Arch Neurol Psychiatry. 1953;69:171–92.

    PubMed  Google Scholar 

  5. Rowland LP. Ten central themes in a decade of amyotrophic lateral sclerosis research. New York: Raven Press; 1991.

    Google Scholar 

  6. Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med. 2001;344:1688–700. doi:10.1056/NEJM200105313442207.

    Article  PubMed  CAS  Google Scholar 

  7. Talbot K. Motor neurone disease. Postgrad Med J. 2002;78:513–9. doi:10.1136/pmj.78.923.513.

    Article  PubMed  CAS  Google Scholar 

  8. Tandan R, Bradley WG. Amyotrophic lateral sclerosis: Part 1. Clinical features, pathology, and ethical issues in management. Ann Neurol. 1985;18:271–80. doi:10.1002/ana.410180302.

    Article  PubMed  CAS  Google Scholar 

  9. Walling AD. Amyotrophic lateral sclerosis: Lou Gehrig’s disease. Am Fam Physician. 1999;59:1489–96.

    PubMed  CAS  Google Scholar 

  10. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science. 1994;264:1772–5. doi:10.1126/science.8209258.

    Article  PubMed  CAS  Google Scholar 

  11. Gurney ME. Transgenic animal models of familial amyotrophic lateral sclerosis. J Neurol. 1997;244(Suppl 2):S15–20.

    Article  PubMed  Google Scholar 

  12. Gurney ME. The use of transgenic mouse models of amyotrophic lateral sclerosis in preclinical drug studies. J Neurol Sci. 1997;152(Suppl 1):S67–73. doi:10.1016/S0022-510X(97)00247-5.

    Article  PubMed  CAS  Google Scholar 

  13. Ripps ME, Huntley GW, Hof PR, Morrison JH, Gordon JW. Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA. 1995;92:689–93. doi:10.1073/pnas.92.3.689.

    Article  PubMed  CAS  Google Scholar 

  14. Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron. 1995;14:1105–16. doi:10.1016/0896-6273(95)90259-7.

    Article  PubMed  CAS  Google Scholar 

  15. Raoul C, Abbas-Terki T, Bensadoun JC, Guillot S, Haase G, Szulc J, et al. Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS. Nat Med. 2005;11:423–8. doi:10.1038/nm1207.

    Article  PubMed  CAS  Google Scholar 

  16. Sasaki S, Warita H, Abe K, Iwata M. Impairment of axonal transport in the axon hillock and the initial segment of anterior horn neurons in transgenic mice with a G93A mutant SOD1 gene. Acta Neuropathol. 2005;110:48–56. doi:10.1007/s00401-005-1021-9.

    Article  PubMed  CAS  Google Scholar 

  17. Zald DH, Pardo JV, The functional neuroanatomy of voluntary swallowing. Ann Neurol. 1999; 46:281–6. doi :10.1002/1531-8249(199909)46:3<281::AID-ANA2>3.0.CO;2-L.

  18. Weydt P, Hong SY, Kliot M, Moller T. Assessing disease onset and progression in the SOD1 mouse model of ALS. Neuroreport. 2003;14:1051–4. doi:10.1097/00001756-200305230-00029.

    Article  PubMed  Google Scholar 

  19. Newbery HJ, Abbott CM. Of mice, men and motor neurons. Trends Genet. 2001;17:S2–6. doi:10.1016/S0168-9525(01)02459-3.

    Article  PubMed  CAS  Google Scholar 

  20. Howland DS, Liu J, She Y, Goad B, Maragakis NJ, Kim B, et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci USA. 2002;99:1604–9. doi:10.1073/pnas.032539299.

    Article  PubMed  CAS  Google Scholar 

  21. Bruijn LI, Miller TM, Cleveland DW. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci. 2004;27:723–49. doi:10.1146/annurev.neuro.27.070203.144244.

    Article  PubMed  CAS  Google Scholar 

  22. Ralph GS, Radcliffe PA, Day DM, Carthy JM, Leroux MA, Lee DC, et al. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat Med. 2005;11:429–33. doi:10.1038/nm1205.

    Article  PubMed  CAS  Google Scholar 

  23. Higo R, Tayama N, Watanabe T, Nitou T. Videomanofluorometric study in amyotrophic lateral sclerosis. Laryngoscope. 2002;112:911–7. doi:10.1097/00005537-200205000-00024.

    Article  PubMed  Google Scholar 

  24. Kawai S, Tsukuda M, Mochimatsu I, Enomoto H, Kagesato Y, Hirose H, et al. A study of the early stage of dysphagia in amyotrophic lateral sclerosis. Dysphagia. 2003;18:1–8. doi:10.1007/s00455-002-0074-3.

    Article  PubMed  Google Scholar 

  25. Hillel AD, Miller RM. Management of bulbar symptoms in amyotrophic lateral sclerosis. Adv Exp Med Biol. 1987;209:201–21.

    PubMed  CAS  Google Scholar 

  26. Tayama N. Dysphagia in amyotrophic lateral sclerosis–the mechanism and managements. Rinsho Shinkeigaku. 1995;35:1557–9.

    PubMed  CAS  Google Scholar 

  27. Ohkubo H. Dysphagia in amyotrophic lateral sclerosis–electromyographic and radiological investigations. Otol Fukuoka. 1980;26:44–78.

    Google Scholar 

  28. Hillel AD, Miller R. Bulbar amyotrophic lateral sclerosis: patterns of progression and clinical management. Head Neck. 1989;11:51–9. doi:10.1002/hed.2880110110.

    Article  PubMed  CAS  Google Scholar 

  29. Zang DW, Yang Q, Wang HX, Egan G, Lopes EC, Cheema SS. Magnetic resonance imaging reveals neuronal degeneration in the brainstem of the superoxide dismutase 1 transgenic mouse model of amyotrophic lateral sclerosis. Eur J Neurosci. 2004;20:1745–51. doi:10.1111/j.1460-9568.2004.03648.x.

    Article  PubMed  Google Scholar 

  30. Angenstein F, Niessen HG, Goldschmidt J, Vielhaber S, Ludolph AC, Scheich H. Age-dependent changes in MRI of motor brain stem nuclei in a mouse model of ALS. Neuroreport. 2004;15:2271–4. doi:10.1097/00001756-200410050-00026.

    Article  PubMed  Google Scholar 

  31. Gannon KS, Smith JC, Henderson R, Hendrick P. A system for studying the microstructure of ingestive behavior in mice. Physiol Behav. 1992;51:515–21. doi:10.1016/0031-9384(92)90173-Y.

    Article  PubMed  CAS  Google Scholar 

  32. Kobayashi M, Masuda Y, Fujimoto Y, Matsuya T, Yamamura K, Yamada Y, et al. Electrophysiological analysis of rhythmic jaw movements in the freely moving mouse. Physiol Behav. 2002;75:377–85. doi:10.1016/S0031-9384(01)00662-X.

    Article  PubMed  CAS  Google Scholar 

  33. Okayasu I, Yamada Y, Kohno S, Yoshida N. New animal model for studying mastication in oral motor disorders. J Dent Res. 2003;82:318–21.

    Article  PubMed  CAS  Google Scholar 

  34. Koga Y, Yoshida N, Kobayashi K, Ichiro O, Yamada Y. Development of a three-dimensional jaw-tracking system implanted in the freely moving mouse. Med Eng Phys. 2001;23:201–6. doi:10.1016/S1350-4533(01)00038-8.

    Article  PubMed  CAS  Google Scholar 

  35. Carvalho TC, Gerstner GE. Licking rate adaptations to increased mandibular weight in the adult rat. Physiol Behav. 2004;82:331–7. doi:10.1016/j.physbeh.2004.04.003.

    Article  PubMed  CAS  Google Scholar 

  36. Strand EA, Miller RM, Yorkston KM, Hillel AD. Management of oral-pharyngeal dysphagia symptoms in amyotrophic lateral sclerosis. Dysphagia. 1996;11:129–39. doi:10.1007/BF00417903.

    Article  PubMed  CAS  Google Scholar 

  37. Genotyping Protocol for SOD. Bar Harbor, ME: The Jackson Laboratory, 2005.

  38. Heiman-Patterson TD, Deitch JS, Blankenhorn EP, Erwin KL, Perreault MJ, Alexander BK, et al. Background and gender effects on survival in the TgN(SOD1–G93A)1Gur mouse model of ALS. J Neurol Sci. 2005;236:1–7. doi:10.1016/j.jns.2005.02.006.

    Article  PubMed  CAS  Google Scholar 

  39. Xu Z, Jung C, Higgins C, Levine J, Kong J. Mitochondrial degeneration in amyotrophic lateral sclerosis. J Bioenerg Biomembr. 2004;36:395–9. doi:10.1023/B:JOBB.0000041774.12654.e1.

    Article  PubMed  CAS  Google Scholar 

  40. Kong J, Xu Z. Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci. 1998;18:3241–50.

    PubMed  CAS  Google Scholar 

  41. Miana-Mena FJ, Munoz MJ, Yague G, Mendez M, Moreno M, Ciriza J, et al. Optimal methods to characterize the G93A mouse model of ALS. Amyotroph Lateral Scler Other Motor Neuron Disord. 2005;6:55–62. doi:10.1080/17434470510045230.

    Article  PubMed  CAS  Google Scholar 

  42. Hamadeh MJ, Rodriguez MC, Kaczor JJ, Tarnopolsky MA. Caloric restriction transiently improves motor performance but hastens clinical onset of disease in the Cu/Zn-superoxide dismutase mutant G93A mouse. Muscle Nerve. 2005;31:214–20. doi:10.1002/mus.20255.

    Article  PubMed  CAS  Google Scholar 

  43. Barneoud P, Curet O. Beneficial effects of lysine acetylsalicylate, a soluble salt of aspirin, on motor performance in a transgenic model of amyotrophic lateral sclerosis. Exp Neurol. 1999;155:243–51. doi:10.1006/exnr.1998.6984.

    Article  PubMed  CAS  Google Scholar 

  44. Weijnen JA. Licking behavior in the rat: measurement and situational control of licking frequency. Neurosci Biobehav Rev. 1998;22:751–60. doi:10.1016/S0149-7634(98)00003-7.

    Article  PubMed  CAS  Google Scholar 

  45. Hiiemae KM, Palmer JB. Food transport and bolus formation during complete feeding sequences on foods of different initial consistency. Dysphagia. 1999;14:31–42. doi:10.1007/PL00009582.

    Article  PubMed  CAS  Google Scholar 

  46. Silani V, Kasarskis EJ, Yanagisawa N. Nutritional management in amyotrophic lateral sclerosis: a worldwide perspective. J Neurol. 1998;245(Suppl 2):S13–9. discussion S29.

    Article  PubMed  Google Scholar 

  47. Hillel A, Dray T, Miller R, Yorkston K, Konikow N, Strande E, et al. Presentation of ALS to the otolaryngologist/head and neck surgeon: getting to the neurologist. Neurology. 1999;53:S22–5. discussion S35–S26.

    PubMed  CAS  Google Scholar 

  48. Haenggeli C, Kato AC. Differential vulnerability of cranial motoneurons in mouse models with motor neuron degeneration. Neurosci Lett. 2002;335:39–43. doi:10.1016/S0304-3940(02)01140-0.

    Article  PubMed  CAS  Google Scholar 

  49. Allen TC. AFIP laboratory methods in histotechnology. Washington, DC: American Registry of Pathology; 1992.

  50. Bucher S, Braunstein KE, Niessen HG, Kaulisch T, Neumaier M, Boeckers TM, et al. Vacuolization correlates with spin-spin relaxation time in motor brainstem nuclei and behavioural tests in the transgenic G93A-SOD1 mouse model of ALS. Eur J Neurosci. 2007;26:1895–901. doi:10.1111/j.1460-9568.2007.05831.x.

    Article  PubMed  Google Scholar 

  51. Paxinos G, Franklin K. The mouse brain in sterotaxic coordinates. 2nd ed. Sydney, Australia: Academic Press; 2001.

    Google Scholar 

  52. Little RJA, Rubin DB. Statistical analysis with missing data. 2nd ed. Hoboken, NJ: John Wiley & Sons, Inc.; 2002.

    Google Scholar 

  53. Singer J. Using SAS PROC MIXED to fit multilevel models, hierarchical models, and individual growth models. J Educ Behav Stat. 1998;24:323–55.

    Google Scholar 

  54. Peugh J, Enders C. Using the SPSS mixed procedure to fit cross-sectional and longitudinal multilevel models. Educ Psychol Meas. 2005;65:717–41. doi:10.1177/0013164405278558.

    Article  Google Scholar 

  55. Littell RC, Milliken GA, Stroup WW, Wolfinger RD. SAS systems for mixed models. Cary, NC: SAS Institute, Inc.; 1996.

    Google Scholar 

  56. Forthofer RN, Lee ES, Hernandez M. Biostatistics: a guide to design, analysis, and discovery. 2nd ed. Burlington, MA: Elsevier; 2007.

    Google Scholar 

  57. Veldink JH, Bar PR, Joosten EA, Otten M, Wokke JH, van den Berg LH. Sexual differences in onset of disease and response to exercise in a transgenic model of ALS. Neuromuscul Disord. 2003;13:737–43. doi:10.1016/S0960-8966(03)00104-4.

    Article  PubMed  CAS  Google Scholar 

  58. Lowry KS, Murray SS, McLean CA, Talman P, Mathers S, Lopes EC, et al. A potential role for the p75 low-affinity neurotrophin receptor in spinal motor neuron degeneration in murine and human amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2001;2:127–34. doi:10.1080/146608201753275463.

    Article  PubMed  CAS  Google Scholar 

  59. Azari MF, Lopes EC, Stubna C, Turner BJ, Zang D, Nicola NA, et al. Behavioural and anatomical effects of systemically administered leukemia inhibitory factor in the SOD1(G93A G1H) mouse model of familial amyotrophic lateral sclerosis. Brain Res. 2003;982:92–7. doi:10.1016/S0006-8993(03)02989-5.

    Article  PubMed  CAS  Google Scholar 

  60. Turner BJ, Cheah IK, Macfarlane KJ, Lopes EC, Petratos S, Langford SJ, et al. Antisense peptide nucleic acid-mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice. J Neurochem. 2003;87:752–63. doi:10.1046/j.1471-4159.2003.02053.x.

    Article  PubMed  CAS  Google Scholar 

  61. Druzinsky RE. The time allometry of mammalian chewing movements: chewing frequency scales with body mass in mammals. J Theor Biol. 1993;160:427–40. doi:10.1006/jtbi.1993.1028.

    Article  PubMed  CAS  Google Scholar 

  62. Kasarskis EJ, Berryman S, Vanderleest JG, Schneider AR, McClain CJ. Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death. Am J Clin Nutr. 1996;63:130–7.

    PubMed  CAS  Google Scholar 

  63. Dal Canto MC, Gurney ME. Neuropathological changes in two lines of mice carrying a transgene for mutant human Cu, Zn SOD, and in mice overexpressing wild type human SOD: a model of familial amyotrophic lateral sclerosis (FALS). Brain Res. 1995;676:25–40. doi:10.1016/0006-8993(95)00063-V.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge Elena Pak, Tiepha Renee Cooper, Cory Morris, Sameer Dongre, Emmanuelle Simon, Waseem Ahmed, Emily Barrett, Vladim Bobrovnikov, Mohamed Raafat, and Di Wu for their invaluable assistance with data collection. We also express our gratitude to Ms. Joani Zary and Dr. Hubert Burden from the Department of Anatomy and Cell Biology at East Carolina University for their expert guidance in histologic methods. We also are grateful to the veterinarians and animal technicians in the Department of Comparative Medicine at East Carolina University who kindly maintained the mouse colony for this investigation.

Author information

Authors and Affiliations

  1. Department of Communication Sciences and Disorders, College of Allied Health Sciences, East Carolina University, 600 Moye Blvd., Suite 3310, Greenville, NC, 27858, USA

    Teresa E. Lever, Ambre Gorsek, Kathleen T. Cox & Monica S. Hough

  2. Department of Biostatistics, College of Allied Health Sciences, East Carolina University, Greenville, NC, 27858, USA

    Kevin F. O’Brien

  3. Department of Biomedical Sciences, Baltimore College of Dental Surgery, University of Maryland Dental School, Baltimore, MD, 21201, USA

    Norman F. Capra

  4. Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, 27858, USA

    Alexander K. Murashov

Authors
  1. Teresa E. Lever
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ambre Gorsek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kathleen T. Cox
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kevin F. O’Brien
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Norman F. Capra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Monica S. Hough
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alexander K. Murashov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Teresa E. Lever.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lever, T.E., Gorsek, A., Cox, K.T. et al. An Animal Model of Oral Dysphagia in Amyotrophic Lateral Sclerosis. Dysphagia 24, 180–195 (2009). https://doi.org/10.1007/s00455-008-9190-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00455-008-9190-z

Keywords

Search

Navigation