Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex
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 multifacto...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-02-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996119302906 |
| _version_ | 1818646013740580864 |
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| author | Bo Zhang Dongjun Guo Lirong Han Nicholas Rensing Akiko Satoh Michael Wong |
| author_facet | Bo Zhang Dongjun Guo Lirong Han Nicholas Rensing Akiko Satoh Michael Wong |
| author_sort | Bo Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T00:39:53Z |
| format | Article |
| id | doaj.art-e83f4a839ae3460a84d6dc096f3892b9 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T00:39:53Z |
| publishDate | 2020-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-e83f4a839ae3460a84d6dc096f3892b92022-12-21T22:10:03ZengElsevierNeurobiology of Disease1095-953X2020-02-01134Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complexBo Zhang0Dongjun Guo1Lirong Han2Nicholas Rensing3Akiko Satoh4Michael Wong5Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USADepartment of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USADepartment of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USADepartment of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USASleep and Aging Regulation Research Project Team, National Center for Geriatrics and Gerontology, Aichi 474-8511, JapanDepartment of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA; Corresponding author at: Department of Neurology, Box 8111, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.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.http://www.sciencedirect.com/science/article/pii/S0969996119302906SleepSeizureOrexinRapamycinTuberous sclerosisMice |
| spellingShingle | Bo Zhang Dongjun Guo Lirong Han Nicholas Rensing Akiko Satoh Michael Wong Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex Neurobiology of Disease Sleep Seizure Orexin Rapamycin Tuberous sclerosis Mice |
| title | Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex |
| title_full | Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex |
| title_fullStr | Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex |
| title_full_unstemmed | Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex |
| title_short | Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex |
| title_sort | hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex |
| topic | Sleep Seizure Orexin Rapamycin Tuberous sclerosis Mice |
| url | http://www.sciencedirect.com/science/article/pii/S0969996119302906 |
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