PMID- 31605778
OWN - NLM
STAT- MEDLINE
DCOM- 20210113
LR  - 20211204
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Print)
IS  - 0969-9961 (Linking)
VI  - 134
DP  - 2020 Feb
TI  - Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep 
      dysfunction in a mouse model of tuberous sclerosis complex.
PG  - 104615
LID - S0969-9961(19)30290-6 [pii]
LID - 10.1016/j.nbd.2019.104615 [doi]
AB  - 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 (Tsc1(GFAP)CKO mice). Sleep studies utilizing EEG, 
      EMG, and behavioral analysis found that Tsc1(GFAP)CKO 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 Tsc1(GFAP)CKO mice. Both the sleep 
      abnormalities and increased orexin expression in Tsc1(GFAP)CKO mice were reversed 
      by rapamycin treatment, indicating their dependence on mTOR activation. An orexin 
      antagonist, suvorexant, also restored normal REM levels in Tsc1(GFAP)CKO 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.
CI  - Copyright (c) 2019 Elsevier Inc. All rights reserved.
FAU - Zhang, Bo
AU  - Zhang B
AD  - Department of Neurology and the Hope Center for Neurological Disorders, 
      Washington University School of Medicine, St. Louis, MO 63110, USA.
FAU - Guo, Dongjun
AU  - Guo D
AD  - Department of Neurology and the Hope Center for Neurological Disorders, 
      Washington University School of Medicine, St. Louis, MO 63110, USA.
FAU - Han, Lirong
AU  - Han L
AD  - Department of Neurology and the Hope Center for Neurological Disorders, 
      Washington University School of Medicine, St. Louis, MO 63110, USA.
FAU - Rensing, Nicholas
AU  - Rensing N
AD  - Department of Neurology and the Hope Center for Neurological Disorders, 
      Washington University School of Medicine, St. Louis, MO 63110, USA.
FAU - Satoh, Akiko
AU  - Satoh A
AD  - Sleep and Aging Regulation Research Project Team, National Center for Geriatrics 
      and Gerontology, Aichi 474-8511, Japan.
FAU - Wong, Michael
AU  - Wong M
AD  - 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.
LA  - eng
GR  - R01 NS056872/NS/NINDS NIH HHS/United States
GR  - R21 NS106356/NS/NINDS NIH HHS/United States
GR  - U54 HD087011/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20191009
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - 0 (Orexins)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - Female
MH  - Hypothalamus/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Neurons/metabolism
MH  - Orexins/*metabolism
MH  - Sleep Wake Disorders/etiology/*metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Tuberous Sclerosis/complications/*metabolism
PMC - PMC6980650
MID - NIHMS1542408
OTO - NOTNLM
OT  - Mice
OT  - Orexin
OT  - Rapamycin
OT  - Seizure
OT  - Sleep
OT  - Tuberous sclerosis
COIS- Conflict of Interest The authors have no conflicts of interest to declare.
EDAT- 2019/10/13 06:00
MHDA- 2021/01/14 06:00
PMCR- 2021/02/01
CRDT- 2019/10/13 06:00
PHST- 2019/04/23 00:00 [received]
PHST- 2019/09/05 00:00 [revised]
PHST- 2019/09/16 00:00 [accepted]
PHST- 2019/10/13 06:00 [pubmed]
PHST- 2021/01/14 06:00 [medline]
PHST- 2019/10/13 06:00 [entrez]
PHST- 2021/02/01 00:00 [pmc-release]
AID - S0969-9961(19)30290-6 [pii]
AID - 10.1016/j.nbd.2019.104615 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2020 Feb;134:104615. doi: 10.1016/j.nbd.2019.104615. Epub 2019 Oct 
      9.