Orexin and melanin-concentrating hormone (MCH) neurons innervate each other and have opposite effects for rapid eye movement sleep (REMs) regulation. Narcolepsy patients appear abnormal REMs behaviors such as rapid transitions into REMs. The causal role of orexin neurons in narcolepsy is well established, but that of MCH neurons remains unclear. We hypothesized that in the absence of orexins, the effects of MCH on REMs can be unbalanced, potentially contributing to aspects of abnormal REMs observed in narcolepsy. To test this hypothesis, we generated MCH-Cre::OX-KO mice and characterized sleep-wake behaviors and cataplexy with chemogenetic activation and pharmacological inhibition of MCH signaling.
In mice lacking orexins, activation of the MCH neurons also increased abnormal intrusions of REMs manifest as cataplexy and short latency transitions into REMs (SLREM). Conversely, a MCH receptor 1 antagonist, SNAP 94847, almost completely eliminated SLREM and cataplexy in OX-KO mice. These findings affirm that MCH neurons promote REMs under normal circumstances, and their activity in mice lacking orexins likely triggers abnormal intrusions of REMs into non-REMs and wake, resulting in the SLREM and cataplexy characteristic of narcolepsy.

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