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

Overview

Journal Neurotherapeutics

Specialty Neurology

Date 2019 Mar 28

PMID 30915710

Citations 9

Authors

Magali Cabanas

Cristiana Pistono

Laura Puygrenier

Divyangana Rakesh

Yannick Jeantet

Maurice Garret

Yoon H Cho

Affiliations

Soon will be listed here.

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.

Citing Articles

Sex-dimorphic functions of orexin in neuropsychiatric disorders.

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Sleep Disorders and Circadian Disruption in Huntington's Disease.

Saade-Lemus S, Videnovic A J Huntingtons Dis. 2023; 12(2):121-131.

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Sleep and Circadian Rhythm Dysfunction in Animal Models of Huntington's Disease.

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Sleep Dysfunction in Huntington's Disease: Impacts of Current Medications and Prospects for Treatment.

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References

Fisher S, Schwartz M, Wurts-Black S, Thomas A, Chen T, Miller M . 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. 2015; 39(2):379-91. PMC: 4712407. DOI: 10.5665/sleep.5448. View

Kudo T, Schroeder A, Loh D, Kuljis D, Jordan M, Roos K . Dysfunctions in circadian behavior and physiology in mouse models of Huntington's disease. Exp Neurol. 2010; 228(1):80-90. PMC: 4346330. DOI: 10.1016/j.expneurol.2010.12.011. View

Broberger C, de Lecea L, Sutcliffe J, Hokfelt 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. J Comp Neurol. 1998; 402(4):460-74. View

Morton A . Circadian and sleep disorder in Huntington's disease. Exp Neurol. 2012; 243:34-44. DOI: 10.1016/j.expneurol.2012.10.014. View

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; 463(1):31-4. DOI: 10.1016/j.neulet.2009.07.035. View

Jeantet Y, Cayzac S, Cho Y . β 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. PMC: 3828365. DOI: 10.1371/journal.pone.0079509. View

Sutton E . Profile of suvorexant in the management of insomnia. Drug Des Devel Ther. 2015; 9:6035-42. PMC: 4651361. DOI: 10.2147/DDDT.S73224. View

Ramanathan L, Siegel J . Gender differences between hypocretin/orexin knockout and wild type mice: age, body weight, body composition, metabolic markers, leptin and insulin resistance. J Neurochem. 2014; 131(5):615-24. PMC: 8734533. DOI: 10.1111/jnc.12840. View

Deacon R . Assessing nest building in mice. Nat Protoc. 2007; 1(3):1117-9. DOI: 10.1038/nprot.2006.170. View

10.

Fisher S, Black S, Schwartz M, Wilk A, Chen T, Lincoln W . Longitudinal analysis of the electroencephalogram and sleep phenotype in the R6/2 mouse model of Huntington's disease. Brain. 2013; 136(Pt 7):2159-72. DOI: 10.1093/brain/awt132. View

11.

Cuesta M, Aungier J, Morton A . The methamphetamine-sensitive circadian oscillator is dysfunctional in a transgenic mouse model of Huntington's disease. Neurobiol Dis. 2011; 45(1):145-55. DOI: 10.1016/j.nbd.2011.07.016. View

12.

Pallier P, Maywood E, Zheng Z, Chesham J, Inyushkin A, Dyball R . Pharmacological imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse model of Huntington's disease. J Neurosci. 2007; 27(29):7869-78. PMC: 6672877. DOI: 10.1523/JNEUROSCI.0649-07.2007. View

13.

Meier A, Mollenhauer B, Cohrs S, Rodenbeck A, Jordan W, Meller J . Normal hypocretin-1 (orexin-A) levels in the cerebrospinal fluid of patients with Huntington's disease. Brain Res. 2005; 1063(2):201-3. DOI: 10.1016/j.brainres.2005.09.028. View

14.

Zielonka D, Marinus J, Roos R, De Michele G, Di Donato S, Putter H . The influence of gender on phenotype and disease progression in patients with Huntington's disease. Parkinsonism Relat Disord. 2012; 19(2):192-7. DOI: 10.1016/j.parkreldis.2012.09.012. View

15.

Ma J, Svetnik V, Snyder E, Lines C, Roth T, Herring W . Electroencephalographic power spectral density profile of the orexin receptor antagonist suvorexant in patients with primary insomnia and healthy subjects. Sleep. 2014; 37(10):1609-19. PMC: 4173918. DOI: 10.5665/sleep.4068. View

16.

Elias C, Sita L, Zambon B, Oliveira E, Vasconcelos L, Bittencourt J . Melanin-concentrating hormone projections to areas involved in somatomotor responses. J Chem Neuroanat. 2007; 35(2):188-201. DOI: 10.1016/j.jchemneu.2007.10.002. View

17.

Jeantet Y, Cho Y . Design of a twin tetrode microdrive and headstage for hippocampal single unit recordings in behaving mice. J Neurosci Methods. 2003; 129(2):129-34. DOI: 10.1016/s0165-0270(03)00172-9. View

18.

Hassani O, Henny P, Lee M, Jones B . GABAergic neurons intermingled with orexin and MCH neurons in the lateral hypothalamus discharge maximally during sleep. Eur J Neurosci. 2010; 32(3):448-57. PMC: 2921479. DOI: 10.1111/j.1460-9568.2010.07295.x. View

19.

Loh D, Kudo T, Truong D, Wu Y, Colwell C . The Q175 mouse model of Huntington's disease shows gene dosage- and age-related decline in circadian rhythms of activity and sleep. PLoS One. 2013; 8(7):e69993. PMC: 3728350. DOI: 10.1371/journal.pone.0069993. View

20.

Whittaker D, Wang H, Loh D, Cachope R, Colwell C . Possible use of a H3R antagonist for the management of nonmotor symptoms in the Q175 mouse model of Huntington's disease. Pharmacol Res Perspect. 2017; 5(5). PMC: 5625154. DOI: 10.1002/prp2.344. View