![]() To specifically target MCH neurons in narcoleptic mice, orexin knock-out mice ( Hcrt −/−) mice (derived from founders donated by Yanagisawa, Southwestern Medical Center, Dallas, TX) were crossed with MCH-Cre mice (The Jackson Laboratory stock #014099). We want to know whether and how MCH neurons contribute to the generation or propagation of cataplexy.Īll the manipulations done to the mice followed the policies established in the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee (protocol #IACUC-2019-00,723). In this study, we took advantage of the novel genetic Ca 2+ imaging tool to record real-time MCH neuronal activities during spontaneous cataplexy and emotional cataplexy induced by either positive (palatable food: milk) or negative (innate fear: predator odor) emotions. Likewise, further inhibition might be ineffective due to the “floor” effect if MCH neurons are already silent during cataplexy. For instance, if MCH neurons are active during cataplexy, further stimulation/excitation may have no noticeable effects due to the “ceiling” effect. ![]() However, we believe that the instinctive status of MCH neurons during cataplexy is still crucial for understanding the exact involvement of MCH neurons in cataplexy and for designing optimal intervention strategies to block cataplexy. Indeed, a recent study indicated that chemogenetically activating MCH neurons increased cataplexy and abnormal REM sleep in orexin knock-out mice ( Naganuma et al., 2018). The question could be answered by manipulating MCH neurons in narcoleptic animals using optogenetic or chemogenetic tools. However, whether MCH neurons play a role in cataplexy in narcolepsy patients or narcoleptic animals is still unknown. Cataplexy or cataplexy-like behavior has not been reported in MCH or its receptor knock-out mice, suggesting that there is no causal effect between MCH deficiency and cataplexy. Lack of orexin neurons or loss of the orexin gene causes sleep disorder narcolepsy and its signature symptom cataplexy, a sudden skeletal muscle atonia during waking ( Chemelli et al., 1999 Lin et al., 1999 Hungs and Mignot, 2001). Orexin neurons are wake-active, promoting arousal and maintaining wakefulness ( Adamantidis et al., 2007 Alexandre et al., 2013) while MCH neurons are predominantly rapid eye movement (REM) sleep-active and promote REM sleep ( Jego et al., 2013 Konadhode et al., 2013 Blanco-Centurion et al., 2016, 2019 Izawa et al., 2019). Orexin (hypocretin, HCRT) and melanin-concentrating hormone (MCH) are hypothalamic neuropeptides regulating sleep and wakefulness. 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 knock-out mice. Importantly, a pre-cataplexy elevation of Ca 2+ signals from MCH neurons was not a prerequisite for cataplexy initiation. Moreover, MCH neurons displayed significantly lower Ca 2+ signals during cataplexy. Similar to wild-type mice, MCH neurons of the narcoleptic mice displayed significantly higher Ca 2+ transient fluorescent intensity during rapid eye movement (REM) sleep and active waking (AW) episodes compared with non-REM (NREM) sleep. Here we used the live animal deep-brain calcium (Ca 2+) imaging tool to record MCH neuron dynamics during cataplexy by expressing calcium sensor GCaMP6s into genetically defined MCH neurons in orexin knock-out mice, which are a model of human narcolepsy. 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. ![]() Hypothalamic orexin (hypocretin, HCRT) deficiency causes sleep disorder narcolepsy with cataplexy in humans and murine.
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