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

Abstract

Orexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the tuberal hypothalamus and project throughout the brain to regulate sleep/wakefulness. Ablation of orexin neurons in mice 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 conditional 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. The total time in cataplexy and the mean cataplexy bout duration increased significantly in double-ablated mice compared with orexin neuron-ablated mice, suggesting that MCH neurons normally suppress cataplexy and that compromised MCH neurons may exacerbate symptoms in some narcoleptic patients. Double-ablated mice also showed frequent sleep attacks with elevated spectral power in the delta and theta range during wakefulness, a state with EEG characteristics indistinguishable from the transition from NREM into REM 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.