Tags

Type your tag names separated by a space and hit enter

Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex.
Neurobiol Dis 2019; 134:104615ND

Abstract

Tuberous sclerosis complex (TSC) is a genetic disease related to hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and manifested by neurological symptoms, such as epilepsy and sleep disorders. The pathophysiology of sleep dysfunction is poorly understood and is likely multifactorial, but may involve intrinsic biological regulators in the brain. Here, we characterized a mouse model of sleep disorders in TSC and investigated mechanisms of sleep dysfunction in this conditional knockout model involving inactivation of the Tsc1 gene in neurons and astrocytes (Tsc1GFAPCKO mice). Sleep studies utilizing EEG, EMG, and behavioral analysis found that Tsc1GFAPCKO mice have decreased REM sleep and impaired sleep-wake differentiation between light and dark phases. mTOR activity and orexin expression were increased in hypothalamic sections and cultured hypothalamic neurons from Tsc1GFAPCKO mice. Both the sleep abnormalities and increased orexin expression in Tsc1GFAPCKO mice were reversed by rapamycin treatment, indicating their dependence on mTOR activation. An orexin antagonist, suvorexant, also restored normal REM levels in Tsc1GFAPCKO mice. These results identify a novel mechanistic link between mTOR and orexin in the hypothalamus related to sleep dysfunction and suggest a targeted therapeutic approach to sleep disorders in TSC.

Authors+Show Affiliations

Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.Sleep and Aging Regulation Research Project Team, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan.Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: wong_m@wustl.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31605778

Citation

Zhang, Bo, et al. "Hypothalamic Orexin and Mechanistic Target of Rapamycin Activation Mediate Sleep Dysfunction in a Mouse Model of Tuberous Sclerosis Complex." Neurobiology of Disease, vol. 134, 2019, p. 104615.
Zhang B, Guo D, Han L, et al. Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex. Neurobiol Dis. 2019;134:104615.
Zhang, B., Guo, D., Han, L., Rensing, N., Satoh, A., & Wong, M. (2019). Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex. Neurobiology of Disease, 134, p. 104615. doi:10.1016/j.nbd.2019.104615.
Zhang B, et al. Hypothalamic Orexin and Mechanistic Target of Rapamycin Activation Mediate Sleep Dysfunction in a Mouse Model of Tuberous Sclerosis Complex. Neurobiol Dis. 2019 Oct 9;134:104615. PubMed PMID: 31605778.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex. AU - Zhang,Bo, AU - Guo,Dongjun, AU - Han,Lirong, AU - Rensing,Nicholas, AU - Satoh,Akiko, AU - Wong,Michael, Y1 - 2019/10/09/ PY - 2019/04/23/received PY - 2019/09/05/revised PY - 2019/09/16/accepted PY - 2019/10/13/pubmed PY - 2019/10/13/medline PY - 2019/10/13/entrez KW - Mice KW - Orexin KW - Rapamycin KW - Seizure KW - Sleep KW - Tuberous sclerosis SP - 104615 EP - 104615 JF - Neurobiology of disease JO - Neurobiol. Dis. VL - 134 N2 - Tuberous sclerosis complex (TSC) is a genetic disease related to hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and manifested by neurological symptoms, such as epilepsy and sleep disorders. The pathophysiology of sleep dysfunction is poorly understood and is likely multifactorial, but may involve intrinsic biological regulators in the brain. Here, we characterized a mouse model of sleep disorders in TSC and investigated mechanisms of sleep dysfunction in this conditional knockout model involving inactivation of the Tsc1 gene in neurons and astrocytes (Tsc1GFAPCKO mice). Sleep studies utilizing EEG, EMG, and behavioral analysis found that Tsc1GFAPCKO mice have decreased REM sleep and impaired sleep-wake differentiation between light and dark phases. mTOR activity and orexin expression were increased in hypothalamic sections and cultured hypothalamic neurons from Tsc1GFAPCKO mice. Both the sleep abnormalities and increased orexin expression in Tsc1GFAPCKO mice were reversed by rapamycin treatment, indicating their dependence on mTOR activation. An orexin antagonist, suvorexant, also restored normal REM levels in Tsc1GFAPCKO mice. These results identify a novel mechanistic link between mTOR and orexin in the hypothalamus related to sleep dysfunction and suggest a targeted therapeutic approach to sleep disorders in TSC. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/31605778/Hypothalamic_orexin_and_mechanistic_target_of_rapamycin_activation_mediate_sleep_dysfunction_in_a_mouse_model_of_tuberous_sclerosis_complex L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(19)30290-6 DB - PRIME DP - Unbound Medicine ER -