Optogenetic Manipulation of Activity and Temporally Controlled Cell-Specific Ablation Reveal a Role for MCH Neurons in Sleep/Wake Regulation

Abstract

Melanin-concentrating hormone (MCH) is a neuropeptide produced in neurons sparsely distributed in the lateral hypothalamic area.Recent studies have reported that MCH neurons are active during rapid eye movement (REM) sleep, but their physiological role in the regulation of sleep/wakefulness is not fully understood. To determine the physiological role of MCH neurons, newly developed transgenic mouse strains that enable manipulation of the activity and fate of MCH neurons in vivo were generated using the recently developed knockin-mediated enhanced gene expression by improved tetracycline-controlled gene induction system. The activity of these cells was controlled by optogenetics by expressing channelrhodopsin2 (E123T/T159C) or archaerhodopsin-T in MCH neurons. Acute optogenetic activation of MCH neurons at 10 Hz induced transitions from non-REM (NREM) to REM sleep and increased REM sleep time in conjunction with decreased NREM sleep. Activation of MCH neurons while mice were in NREM sleep induced REM sleep, but activation during wakefulness was ineffective. Acute optogenetic silencing of MCH neurons using archaerhodopsin-T had no effect on any vigilance states. Temporally controlled ablation of MCH neurons by cell-specific expression of diphtheria toxin A increased wakefulness and decreased NREM sleep duration without affecting REM sleep. Together, these results indicate that acute activation of MCH neurons is sufficient, but not necessary, to trigger the transition from NREM to REM sleep and that MCH neurons also play a role in the initiation and maintenance of NREM sleep.

MCH levels in the CSF, brain preproMCH and MCHR1 gene expression during paradoxical sleep deprivation, sleep rebound and chronic sleep restriction

“…MCHergic neurons increase their firing rate from wakefulness to slow wave sleep (SWS), and from SWS to paradoxical sleep (PS) [8]. Furthermore, the activation of MCHergic neurons by means of the optogenetic technique promotes sleep, mainly PS [9,11,32]. The role of MCH in the modulation of sleep in different brain areas, such as the dorsal raphe nucleus, the preoptic area and the basal forebrain of the rat, as well as in the nucleus pontis oralis of the cat was characterized [4,12,13,29].…”

Alterations of orexinergic and melanin-concentrating hormone neurons in experimental sleeping sickness

“…The MCH neuron population has been implicated in feeding behavior, locomotor activity, autonomic nervous functions, and sleep regulation (Guyon et al, 2009;Peyron et al, 2009;Tsunematsu et al, 2014). In particular, MCH neurons exert an inhibitory influence on OX-A neurons, fine-tuning their final output (Adamantidis et al, 2008;Rao et al, 2008;Burt et al, 2011), and can counteract the wake-promoting activity of arousal neurons (Konadhode et al, 2013), promoting sleep (Jones and Hassani, 2013).…”

Sleep function: Toward elucidating an enigma

“…6 For instance, acute in vivo manipulations of global sleep regulatory neurons by cell type-specific optogenetic activation do not acutely precipitate sleep as one would expect them to do if sleep were a top-down globally-controlled phenomenon, but rather such stimulation increases sleep over longer time scales (hours). 31, 32 …”