Melanin-concentrating hormone neurons contribute to dysregulation of rapid eye movement sleep in narcolepsy

Neurobiology of Disease
Fumito NaganumaRamalingam Vetrivelan

Abstract

The lateral hypothalamus contains neurons producing orexins that promote wakefulness and suppress REM sleep as well as neurons producing melanin-concentrating hormone (MCH) that likely promote REM sleep. Narcolepsy with cataplexy is caused by selective loss of the orexin neurons, and the MCH neurons appear unaffected. As the orexin and MCH systems exert opposing effects on REM sleep, we hypothesized that imbalance in this REM sleep-regulating system due to activity in the MCH neurons may contribute to the striking REM sleep dysfunction characteristic of narcolepsy. To test this hypothesis, we chemogenetically activated the MCH neurons and pharmacologically blocked MCH signaling in a murine model of narcolepsy and studied the effects on sleep-wake behavior and cataplexy. To chemoactivate MCH neurons, we injected an adeno-associated viral vector containing the hM3Dq stimulatory DREADD into the lateral hypothalamus of orexin null mice that also express Cre recombinase in the MCH neurons (MCH-Cre::OX-KO mice) and into control MCH-Cre mice with normal orexin expression. In both lines of mice, activation of MCH neurons by clozapine-N-oxide (CNO) increased rapid eye movement (REM) sleep without altering other states. In mice lacking o...Continue Reading

Citations

Nov 1, 2018·Molecular Psychiatry·Jun OhLea T Grinberg
Dec 13, 2019·Sleep·Carrie E MahoneyThomas E Scammell
Jan 11, 2020·Sleep·A R AdamantidisThomas E Scammell
Mar 10, 2020·CNS & Neurological Disorders Drug Targets·Andrea RomigiMauro Maccarrone
Oct 3, 2020·Current Neurology and Neuroscience Reports·Sathyajit S BandaruRamalingam Vetrivelan
Feb 11, 2021·Sleep Medicine Reviews·Matteo CataldiLino Nobili
Mar 7, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jean A BoutinKarine Puget
Oct 28, 2021·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Sara Katherine Pintwala, John Peever

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