Abstract
Hypothalamic orexin (HCRT) deficiency causes sleep disorder narcolepsy with cataplexy in humans and murine. As another integral group of sleep/wake-regulating neurons in the same brain area, the melanin-concentrating hormone (MCH) neurons’ involvement in cataplexy remains ambiguous. Here we used the live animal deep-brain calcium (Ca2+) imaging tool to record MCH neuron dynamics during cataplexy by expressing calcium sensor GCaMP6s into genetically defined MCH neurons in orexin knockout mice, which are a model of human narcolepsy. Similar to wild type mice, MCH neurons of the narcoleptic mice displayed significantly higher Ca2+ transient fluorescent intensity during rapid eye movement (REM) sleep and active waking episodes compared to non-rapid eye movement (NREM) sleep. Moreover, MCH neurons displayed significantly lower Ca2+ signals during cataplexy. Importantly, a pre-cataplexy elevation of Ca2+ signals from MCH neurons was not a prerequisite for cataplexy initiation. Our results demonstrated the inactivation status of MCH neurons during cataplexy and suggested that MCH neurons are not involved in the initiation and maintenance of cataplexy in orexin knockout mice.
Significance Statement The cataplexy of narcolepsy shares many similarities with normal REM sleep. Thus, REM sleep-promoting MCH neurons are thought to be part of the cataplexy circuitry. Suppressing MCH neurons is assumed to block cataplexy. However, we found that MCH neurons were always inactive during cataplexy in orexin knockout mice. Pre-cataplexy activations of MCH neurons were no different from the activation during regular waking episodes. Importantly, cataplexy could occur in the absence of these pre-cataplexy activations. These results suggest that MCH neurons are not a key component of the cataplexy circuitry in orexin knockout mice.
Footnotes
The authors declare no conflict of interest.
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