Advertisement

Neurotherapeutics

, Volume 16, Issue 3, pp 784–796 | Cite as

Neurophysiological and Behavioral Effects of Anti-Orexinergic Treatments in a Mouse Model of Huntington’s Disease

  • Magali Cabanas
  • Cristiana Pistono
  • Laura Puygrenier
  • Divyangana Rakesh
  • Yannick Jeantet
  • Maurice Garret
  • Yoon H. ChoEmail author
Original Article

Abstract

Huntington’s disease (HD) is associated with sleep and circadian disturbances in addition to hallmark motor and cognitive impairments. Electrophysiological studies on HD mouse models have revealed an aberrant oscillatory activity at the beta frequency, during sleep, that is associated with HD pathology. Moreover, HD animal models display an abnormal sleep–wake cycle and sleep fragmentation. In this study, we investigated a potential involvement of the orexinergic system dysfunctioning in sleep–wake and circadian disturbances and abnormal network (i.e., beta) activity in the R6/1 mouse model. We found that the age at which orexin activity starts to deviate from normal activity pattern coincides with that of sleep disturbances as well as the beta activity. We also found that acute administration of Suvorexant, an orexin 1 and orexin 2 receptor antagonist, was sufficient to decrease the beta power significantly and to improve sleep in R6/1 mice. In addition, a 5-day treatment paradigm alleviated cognitive deficits and induced a gain of body weight in female HD mice. These results suggest that restoring normal activity of the orexinergic system could be an efficient therapeutic solution for sleep and behavioral disturbances in HD.

Keywords

Orexin 1 and 2 receptor antagonist Sleep Beta activity Cognitive deficits R6/1 mice 

Notes

Acknowledgments

We thank Nicolas Mallet for his valuable help with preliminary experiment and Elodie Poinama and Nathalie Argenta for R6/1 mouse production, and Gill Courtand for help with image processing of immunofluorescence data.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Funding

This work was supported by Hereditary Disease Foundation to YHC.

Compliance with Ethical Standards

All experimental procedures were approved by the Institutional Animal Care and Use Committee, Comité d’Ethique pour l’Expérimentation Animale Bordeaux, and were in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC).

Supplementary material

13311_2019_726_MOESM1_ESM.pdf (516 kb)
ESM 1 (PDF 516 kb)

References

  1. 1.
    The Huntington’s disease collaborative research group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes/. Cell. 1993;72(6):971–83.CrossRefGoogle Scholar
  2. 2.
    Raymond LA, André VM, Cepeda C, Gladding CM, Milnerwood AJ, Levine MS. Pathophysiology of Huntington’s disease: time-dependent alterations in synaptic and receptor function. Neuroscience. 2011;198:252–73.CrossRefGoogle Scholar
  3. 3.
    Arnulf I, Nielsen J, Lohmann E, Schiefer J, Wild E, Jennum P, et al. Rapid eye movement sleep disturbances in Huntington disease. Arch Neurol. 2008;65(4):482–8.CrossRefGoogle Scholar
  4. 4.
    Aziz NA, Anguelova GV, Marinus J, Lammers GJ, Roos RA. Sleep and circadian rhythm alterations correlate with depression and cognitive impairment in Huntington’s disease. Parkinsonism Relat Disord. 2010;16(5):345–50.CrossRefGoogle Scholar
  5. 5.
    Goodman AO, Rogers L, Pilsworth S, McAllister CJ, Shneerson JM, Morton AJ, et al. Asymptomatic sleep abnormalities are a common early feature in patients with Huntington’s disease. Curr Neurol Neurosci Rep. 2011;11(2):211–7.CrossRefGoogle Scholar
  6. 6.
    Morton AJ. Circadian and sleep disorder in Huntington’s disease. Exp Neurol. 2013;243:34–44.CrossRefGoogle Scholar
  7. 7.
    Morton AJ, Wood NI, Hastings MH, Hurelbrink C, Barker RA, Maywood ES. Disintegration of the sleep-wake cycle and circadian timing in Huntington’s disease. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2005;25(1):157–63.CrossRefGoogle Scholar
  8. 8.
    Kantor S, Szabo L, Varga J, Cuesta M, Morton AJ. Progressive sleep and electroencephalogram changes in mice carrying the Huntington’s disease mutation. Brain : a journal of neurology. 2013;136(Pt 7):2147–58.CrossRefGoogle Scholar
  9. 9.
    Fisher SP, Black SW, Schwartz MD, Wilk AJ, Chen TM, Lincoln WU, et al. Longitudinal analysis of the electroencephalogram and sleep phenotype in the R6/2 mouse model of Huntington’s disease. Brain : a journal of neurology. 2013;136(Pt 7):2159–72.CrossRefGoogle Scholar
  10. 10.
    Lebreton F, Cayzac S, Pietropaolo S, Jeantet Y, Cho YH. Sleep Physiology Alterations Precede Plethoric Phenotypic Changes in R6/1 Huntington’s Disease Mice. PloS one. 2015;10(5):e0126972.CrossRefGoogle Scholar
  11. 11.
    Kudo T, Schroeder A, Loh DH, Kuljis D, Jordan MC, Roos KP, et al. Dysfunctions in circadian behavior and physiology in mouse models of Huntington’s disease. Exp Neurol. 2011;228(1):80–90.CrossRefGoogle Scholar
  12. 12.
    Fisher SP, Schwartz MD, Wurts-Black S, Thomas AM, Chen TM, Miller MA, et al. Quantitative electroencephalographic analysis provides an early-stage indicator of disease onset and progression in the zQ175 knock-in mouse model of Huntington’s disease. Sleep. 2016;39(2):379–91.CrossRefGoogle Scholar
  13. 13.
    Loh DH, Kudo T, Truong D, Wu Y, Colwell CS. The Q175 mouse model of Huntington’s disease shown gene dosage- and age-related decline in circadian rhythms of activity and sleep. PloS One. 2013;8(7):e69993.CrossRefGoogle Scholar
  14. 14.
    Jeantet Y, Cayzac S, Cho YH. beta oscillation during slow wave sleep and rapid eye movement sleep in the electroencephalogram of a transgenic mouse model of Huntington’s disease. PloS One. 2013;8(11):e79509.CrossRefGoogle Scholar
  15. 15.
    Pietropaolo S, Delage P, Cayzac S, Crusio WE, Cho YH. Sex-dependent changes in social behaviors in motor pre-symptomatic R6/1 mice. PloS one. 2011;6(5):e19965.CrossRefGoogle Scholar
  16. 16.
    Du Z, Chazalon M, Bestaven E, Leste-Lasserre T, Baufreton J, Cazalets JR, et al. Early GABAergic transmission defects in the external globus pallidus and rest/activity rhythm alteration in a mouse model of Huntington’s disease. Neuroscience. 2016;329:363–79.CrossRefGoogle Scholar
  17. 17.
    Pallier PN, Maywood ES, Zheng Z, Chesham JE, Inyushkin AN, Dyball R, et al. Pharmacological imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse model of Huntington’s disease. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2007;27(29):7869–78.CrossRefGoogle Scholar
  18. 18.
    Pallier PN, Morton AJ. Management of sleep/wake cycles improves cognitive function in a transgenic mouse model of Huntington’s disease. Brain research. 2009;1279:90–8.CrossRefGoogle Scholar
  19. 19.
    Morton AJ, Hunt MJ, Hodges AK, Lewis PD, Redfern AJ, Dunnett SB, et al. A combination drug therapy improves cognition and reverses gene expression changes in a mouse model of Huntington’s disease. Eur J Neurosci. 2005;21(4):855–70.CrossRefGoogle Scholar
  20. 20.
    Whittaker DS, Wand HB, Loh DH, Cachope R, Colwell CS. Possible use of a H3R antagonist for the management of nonmotor symptoms in the Q175 mouse model of Huntington’s disease. Pharmacological research and perspective. 2017;5(5).Google Scholar
  21. 21.
    Cuesta M, Aungier J, Morton AJ. Behavioral therapy reverses circadian deficits in a transgenic mouse model of Huntington’s disease. Neurobiology of disease. 2014;63:85–91.CrossRefGoogle Scholar
  22. 22.
    Cuesta M, Aungier J, Morton AJ. The methamphetamine-sensitive circadian oscillator is dysfunctional in a transgenic mouse model of Huntington’s disease. Neurobiology of disease. 2012;45(1):145–55.CrossRefGoogle Scholar
  23. 23.
    Wang HB, Loh DH, Whittaker DS, Cutler T, Howland D, Colwell CS. Time-restricted feeding improves circadian dysfunction as well as motor symptoms in the Q175 mouse model of Huntington’s disease. eNeuro. 2017;5(1):ENEURO.0431-17.2017.Google Scholar
  24. 24.
    Wang HB, Whittaker DS, Truong D, Mulji AK, Ghiani CA, Loh DH, et al. Blue light therapy improves circadian dysfunction as well as motor symptoms in two mouse modeld of Huntington’s disease. Neurobiology of sleep and circadian rhythms. 2017;2:39–52.CrossRefGoogle Scholar
  25. 25.
    Hong SL, Cossyleon D, Hussain WA, Walker LJ, Barton SJ, Rebec GV. Dysfunctional behavioral modulation of corticostriatal communication in the R6/2 mouse model of Huntington’s disease. PloS One. 2012;7(10):e47026.CrossRefGoogle Scholar
  26. 26.
    Sakurai T, Amemiya, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998; 92(4), 573–585.CrossRefGoogle Scholar
  27. 27.
    Sakurai T. (2007). The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nature Reviews Neuroscience, 8(3), 171.CrossRefGoogle Scholar
  28. 28.
    Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, De Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature. 2007; 450(7168), 420.CrossRefGoogle Scholar
  29. 29.
    Hassani OK, Henny P, Lee MG, Jones BE. GABAergic neurons intermingled with orexin and MCH neurons in the lateral hypothalamus discharge maximally during sleep. European Journal of Neuroscience. 2010; 32(3), 448–457CrossRefGoogle Scholar
  30. 30.
    Elias CF, Sita LV, Zambon BK, Oliveira ER, Vasconcelos LAP, Bittencourt JC. Melanin-concentrating hormone projections to areas involved in somatomotor responses. Journal of chemical neuroanatomy. 2008; 35(2), 188–201.CrossRefGoogle Scholar
  31. 31.
    Varin C, Luppi PH, Fort P. Melanin-concentrating hormone-expressing neurons adjust slow-wave sleep dynamics to catalyze paradoxical (REM) sleep. Sleep. 2018; 41(6), zsy068.CrossRefGoogle Scholar
  32. 32.
    Petersen A, Gil J, Maat-Schieman ML, Bjorkqvist M, Tanila H, Araujo IM, et al. Orexin loss in Huntington’s disease. Hum Mol Genet. 2005;14(1):39–47.CrossRefGoogle Scholar
  33. 33.
    Roos RA, Aziz NA. Hypocretin-1 and secondary signs in Huntington’s disease. Parkinsonism Relat Disord. 2007;13 Suppl 3:S387–90.CrossRefGoogle Scholar
  34. 34.
    Björkqvist M, Petersén A, Nielsen J, Ecker D, Mulder H, Hayden MR, et al. Cerebrospinal fluid levels of orexin-A are not a clinically useful biomarker for Huntington’s disease. Clinical Genetics. 2006;70(1):78–90.CrossRefGoogle Scholar
  35. 35.
    Meier A, Mollenhauer B, Cohrs S, Rodenbeck A, Jordan W, Meller J, et al. Normal hypocretin-1 (orexin-A) levels in the cerebrospinal fluid of patients with Huntington’s disease. Brain Research. 2005;1063(2):201–3.CrossRefGoogle Scholar
  36. 36.
    Baumann CR, Hersberger M, Bassetti CL. Hypocretin-1 (orexin A) levels are normal in Huntington’s disease. Journal of neurology. 2006;253(9):1232–3.CrossRefGoogle Scholar
  37. 37.
    Williams RH, Morton AJ, Burdakov D. Paradoxical function of orexin/hypocretin circuits in a mouse model of Huntington’s disease. Neurobiol Dis. 2011;42(3):438–45.CrossRefGoogle Scholar
  38. 38.
    Sutton EL. Profile of suvorexant in the management of insomnia. Drug design, development and therapy. 2015; 9, 6035.CrossRefGoogle Scholar
  39. 39.
    Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996;87(3):493–506.CrossRefGoogle Scholar
  40. 40.
    Jeantet Y, Cho YH. Design of a twin tetrode microdrive and headstage for hippocampal single unit recordings in behaving mice. Journal of Neuroscience Methods. 2003;129(2):129–34.CrossRefGoogle Scholar
  41. 41.
    Gerbrandt LK, Lawrence JC, Eckardt MJ, Lloyd RL. Origin of the neocortically monitored theta rhythm in the curarized rat. Electroencephalography and clinical neurophysiology. 1978;45:454–167.CrossRefGoogle Scholar
  42. 42.
    Deacon RM. Assessing nest building in mice. Nature Protocol. 2006; 1(3):1117–9.CrossRefGoogle Scholar
  43. 43.
    Hassani OK, Lee MG, Jones BE. Melanin-concentrating hormone neurons discharge in a reciprocal manner to orexin neurons across the sleep-wake cycle. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(7):2418–22.CrossRefGoogle Scholar
  44. 44.
    Broberger C, De Lecea L, Sutcliffe JG, Hökfelt T. Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. Journal of Comparative Neurolology. 1998;402(4):460–74.CrossRefGoogle Scholar
  45. 45.
    Cvetkovic V, Brischoux F, Jacquemard C, Fellmann D, Griffond B, Risold PY. Characterization of subpopulations of neurons producing melanin-concentrating hormone in the rat ventral diencephalon. Journal of Neurochemistry. 2004;91(4):911–9.CrossRefGoogle Scholar
  46. 46.
    Verret L, Goutagny R, Fort P, Cagnon L, Salvert D, Leger L, et al. A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep. BMC neuroscience. 2003;4:19.CrossRefGoogle Scholar
  47. 47.
    Naver B, Stub C, Moller M, Fenger K, Hansen AK, Hasholt L, et al. Molecular and behavioral analysis of the R6/1 Huntington’s disease transgenic mouse. Neuroscience. 2003;122(4):1049–57.CrossRefGoogle Scholar
  48. 48.
    Nithianantharajah J, Barkus C, Murphy M, Hannan AJ. Gene-environment interactions modulating cognitive function and molecular correlates of synaptic plasticity in Huntington’s disease transgenic mice. Neurobiol Dis. 2008;29(3):490–504.CrossRefGoogle Scholar
  49. 49.
    Zielonka D, Marinus J, Roos RA, De Michele G, Di Donato S, Putter H, Marcinkowski J, Squitieri F, Bentivoglio AR, Landwehrmeyer GB. The influence of gender on phenotype and disease progression in patients with Huntington’s disease. Parkinsonism Related Disorders. 2013;19(2):192–7.CrossRefGoogle Scholar
  50. 50.
    Kuljis DA, Gad L, Loh DH, MacDowell Kaswan Z, Hitchcock ON, Ghiani CA, Colwell CS. Sex Differences in Circadian Dysfunction in the BACHD Mouse Model of Huntington’s Disease. PLoS One. 2016 ;11(2):e0147583.CrossRefGoogle Scholar
  51. 51.
    Kantor S, Varga J, Morton AJ. A single dose of hypnotic corrects sleep and EEG abnormalities in symptomatic Huntington’s disease mice. Neuropharmacology. 2016;105:298–307.CrossRefGoogle Scholar
  52. 52.
    Kantor S, Varga J, Kulkarni S, Morton AJ. Chronic Paroxetine treatment prevents the emergence of abnormal electroencephalogram oscillations in Huntington’s disease mice. Neurotherapeutics. 2017;14(4):1120–33.CrossRefGoogle Scholar
  53. 53.
    Fox SV, Gotter AL, Tye SJ, Garson SL, Savitz AT, Uslaner JM, et al. Quantitative electroencephalography within sleep/wake states differentiates GABA A modulators eszopiclone and zolpidem from dual orexin receptor antagonists in rats. Neuropsychopharmacology, 2013; 38(12), 2401.CrossRefGoogle Scholar
  54. 54.
    Ma J, Svetnik V, Snyder E, Lines C, Roth T, Herring WJ. Electroencephalographic power spectral density profile of the orexin receptor antagonist suvorexant in patients with primary insomnia and healthy subjects. Sleep, 2014; 37(10), 1609–1619.CrossRefGoogle Scholar
  55. 55.
    Morton AJ, Wood NI, Hastings MH, Hurelbrink C, Barker RA, Maywood ES. Disintegration of the sleep-wake cycle and circadian timing in Huntington’s disease. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2005;25(1):157–63.CrossRefGoogle Scholar
  56. 56.
    Kuljis D, Kudo T, Tahara Y, Ghiani CA, Colwell CS. Pathophysiology in the suprachiasmatic nucleus in mouse models of Huntington’s disease. J Neurosci Res. 2018;96(12):1862–1875.CrossRefGoogle Scholar
  57. 57.
    Sakurai T, Mieda M. Connectomics of orexin-producing neurons: interface of systems of emotion, energy homeostatis and arousal. Trends in Pharmacological sciences. 2011;32(8):451–62.CrossRefGoogle Scholar
  58. 58.
    Sakurai, T. (2014). The role of orexin in motivated behaviours. Nature Reviews Neuroscience, 15(11), 719.CrossRefGoogle Scholar
  59. 59.
    Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron. 2001 May;30(2):345–54.CrossRefGoogle Scholar
  60. 60.
    Ramanathan L, Siegel JM. Gender differences between hypocretin/orexin knockout and wild type mice: age, body weight, body composition, metabolic markers, leptin and insulin resistance. J Neurochem. 2014 Dec;131(5):615–24.CrossRefGoogle Scholar
  61. 61.
    Jöhren O, Neidert SJ, Kummer M, Dendorfer A, Dominiak P. Prepro-orexin and orexin receptor mRNAs are differentially expressed in peripheral tissues of male and female rats. Endocrinology. 2001 Aug;142(8):3324–31.CrossRefGoogle Scholar
  62. 62.
    Funabashi T, Hagiwara H, Mogi K, Mitsushima D, Shinohara K, Kimura F. Sex differences in the responses of orexin neurons in the lateral hypothalamic area and feeding behavior to fasting. Neurosci Lett. 2009 Sep 29;463(1):31–4.CrossRefGoogle Scholar
  63. 63.
    Pirnik Z, Bundzikova J, Mikkelsen JD, Zelezna B, Maletinska L, Kiss A. Fos expression in hypocretinergic neurons in C57B1/6 male and female mice after long-term consumption of high fat diet. Endocr Regul. 2008 Sep;42(4):137–46.PubMedGoogle Scholar
  64. 64.
    Roos RA, Vegter-van der Vlis M, Hermans J, Elshove HM, Moll AC, van de Kamp JJ, et al. Age at onset in Huntington’s disease: effect of line of inheritance and patients’s sex. Journal of medical genetics. 1991;28(8):515–9.CrossRefGoogle Scholar
  65. 65.
    Rebec GV, Barton SJ, Ennis MD. Dysregulation of ascorbate release in the striatum of behaving mice expressing the Huntington’s disease gene. Journal of neuroscience. 2002;22(2):RC202.CrossRefGoogle Scholar
  66. 66.
    Simpkins, J. W., Yi, K. D., Yang, S. H., & Dykens, J. A. (2010). Mitochondrial mechanisms of estrogen neuroprotection. Biochimica et Biophysica Acta (BBA)-General Subjects, 1800(10), 1113–1120.CrossRefGoogle Scholar
  67. 67.
    Iwasa T, Matsuzaki T, Munkhzaya M, Tungalagsuvd A, Kuwahara A, Yasui T, et al. Developmental changes in the hypothalamic mRNA levels of prepro-orexin and orexin receptors and their sensitivity to fasting in male and female rats. Int J Dev Neurosci. 2015;46:51–4.CrossRefGoogle Scholar
  68. 68.
    Johren O, Neidert SJ, Kummer M, Dominiak P. Sexually dimorphic expression of prepro-orexin mRNA in the rat hypothalamus. Peptides. 2002;23(6):1177–80CrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  • Magali Cabanas
    • 1
    • 2
  • Cristiana Pistono
    • 1
    • 2
  • Laura Puygrenier
    • 1
    • 2
  • Divyangana Rakesh
    • 1
    • 2
  • Yannick Jeantet
    • 1
    • 2
  • Maurice Garret
    • 1
    • 2
  • Yoon H. Cho
    • 1
    • 2
    Email author
  1. 1.Institute of Cognitive and Integrative Neuroscience of AquitainePessac CedexFrance
  2. 2.Institute of Cognitive and Integrative Neuroscience of AquitaineUniversity of BordeauxBordeauxFrance

Personalised recommendations