Dual orexin and MCH neuron-ablated mice display severe sleep attacks and cataplexy.

Chi Jung Hung,Akihiro Yamanaka,Thomas S Kilduff,Daisuke Ono

doi:10.7554/elife.54275

Abstract

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. Ablation of orexin neurons decreases wakefulness and results in a narcolepsy-like phenotype, whereas ablation of MCH neurons increases wakefulness. 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. Double-ablated mice exhibited increased wakefulness and decreased both rapid eye movement (REM) and non-REM (NREM) sleep. Double-ablated mice showed severe cataplexy compared with orexin neuron-ablated mice, suggesting that MCH neurons normally suppress cataplexy. 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'. 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.

Highlights

The lateral hypothalamus (LH) has long been known to be involved in the regulation of sleep/wakefulness, feeding behavior and metabolism (Theodorides and Vetter, 1972)
We recently reported that rapid eye movement (REM) sleep-active melanin-concentrating hormone-producing (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)
We previously reported that Hcrt-tTA; tetracycline operator (TetO) diphtheria toxin A fragment (DTA) (OX) mice (Tabuchi et al, 2014) or Pmch-tTA; TetO DTA mice (Tsunematsu et al, 2014) enabled us to induce specific ablation of orexin neurons or MCH neurons in a timed-controlled manner, respectively

Summary

Introduction

The lateral hypothalamus (LH) has long been known to be involved in the regulation of sleep/wakefulness, feeding behavior and metabolism (Theodorides and Vetter, 1972). Optogenetic activation of orexin neurons induces wakefulness from sleep while optogenetic inhibition induces sleep from wakefulness (Adamantidis et al, 2007; Tsunematsu et al, 2011; Schone et al, 2012; Williams et al, 2019). Together, these studies indicate that orexin neurons play an important role in the maintenance of wakefulness and prevent cataplexy induced by positive emotions

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Conclusion