#Sleep cataplexy skin#

Orexin and MCH neurons have also been reported to interact with each other. While the orexin and MCH neurons have different roles in the regulation of sleep/wakefulness ( Konadhode et al., 2014), they have similar projection areas and receptor distributions ( Trivedi et al., 1998 Hervieu et al., 2000 Kilduff and de Lecea, 2001 Marcus et al., 2001 Saito et al., 2001).

We recently reported that REM sleep-active MCH neurons are involved in memory erasure during REM sleep ( Izawa et al., 2019), further supporting the concept that MCH neurons are involved in multiple physiological functions ( Diniz and Bittencourt, 2017 Arrigoni et al., 2019). These observations suggest that MCH neurons are likely involved in the regulation of both NREM and REM sleep. Ablation of MCH neurons promotes wakefulness and decreases time in NREM sleep but has no effect on REM sleep ( Tsunematsu et al., 2014). Optogenetic activation of MCH neurons increases the total time in rapid eye movement (REM) sleep and reduces non-REM (NREM) sleep in mice ( Jego and Adamantidis, 2013 Konadhode et al., 2013 Tsunematsu et al., 2014). In mammals, MCH neurons are mainly distributed in the tuberal hypothalamus within which the orexin neurons are also located.

#Sleep cataplexy skin#

The neuropeptide MCH was originally isolated from fish pituitary as a substance that controls skin pigmentation ( Kawauchi et al., 1983). Together, these studies indicate that orexin neurons play an important role in the maintenance of wakefulness and prevent cataplexy induced by positive emotions. Optogenetic activation of orexin neurons induces wakefulness from sleep while optogenetic inhibition induces sleep from wakefulness ( Adamantidis et al., 2007 Tsunematsu et al., 2011 Schöne et al., 2012 Williams et al., 2019). Narcolepsy patients have characteristic symptoms including excessive daytime sleepiness, hallucinations and cataplexy, a sudden loss of muscle tone triggered by positive emotions such as laughter ( American Sleep Disorders Association, 1990 Burgess and Scammell, 2012). Narcolepsy is a chronic sleep disorder ( Mahoney et al., 2019) caused by the specific degeneration of orexin neurons by the immune system ( Peyron et al., 2000 Latorre et al., 2018). Hcrt ( Chemelli et al., 1999) or Hcrtr2 ( Willie et al., 2003) gene knockout mice and orexin neuron-ablated mice ( Hara et al., 2001 Tabuchi et al., 2014) display a narcolepsy-like phenotype. Orexin and MCH neurons project throughout the brain ( Bittencourt et al., 1992 Peyron et al., 1998 Nambu et al., 1999) and are implicated in feeding and sleep/wakefulness ( Sakurai et al., 1998 Shimada et al., 1998 Chemelli et al., 1999 Verret et al., 2003). Orexin/hypocretin-(encoded by the Hcrt gene) and melanin-concentrating hormone (MCH, encoded by the Pmch gene)-producing neurons are distributed within the LH MCH neurons also extend caudally into the zona incerta. The lateral hypothalamus (LH) has long been known to be involved in the regulation of sleep/wakefulness, feeding behavior and metabolism ( Théodoridès and Vetter, 1972). Together, these results indicate a functional interaction between orexin and MCH neurons in vivo that suggests the synergistic involvement of these neuronal populations in the sleep/wakefulness cycle. Double-ablated mice also showed frequent sleep attacks with elevated spectral power in the delta and theta range, a unique state that we call ‘delta-theta sleep’. Double-ablated mice showed severe cataplexy compared with orexin neuron-ablated mice, suggesting that MCH neurons normally suppress cataplexy. Double-ablated mice exhibited increased wakefulness and decreased both rapid eye movement (REM) and non-REM (NREM) sleep. Since it is unclear how orexin and MCH neurons interact to regulate sleep/wakefulness, we generated transgenic mice in which both orexin and MCH neurons could be ablated. Ablation of orexin neurons decreases wakefulness and results in a narcolepsy-like phenotype, whereas ablation of MCH neurons increases wakefulness. Orexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the hypothalamus and project throughout the brain to regulate sleep/wakefulness.