Narcolepsy is a sleep disorder caused by selective death of the orexin neurons that often begins in childhood. Orexin neuron loss disinhibits REM sleep during the active period and produces cataplexy, episodes of paralysis during wakefulness. Cataplexy is often worse when narcolepsy develops in children compared to adults, but the reason for this difference remains unknown. We used orexin-tTA; TetO DTA mice to model narcolepsy at different ages. When doxycycline is removed from the diet, the orexin neurons of these mice express diphtheria toxin A and die within 2–3 weeks. We removed doxycycline at 4 weeks (young-onset) or 14 weeks (adult-onset) of age in male and female mice. We implanted electroencephalography (EEG) and electromyography (EMG) electrodes for sleep recordings two weeks later and then recorded EEG/EMG/video for 24 h at 3 and 13 weeks after removal of doxycycline. Age-matched controls had access to doxycycline diet for the entire experiment. Three weeks after doxycycline removal, both young-onset and adult-onset mice developed severe cataplexy and the sleep-wake fragmentation characteristic of narcolepsy. Cataplexy and maintenance of wake were no worse in young-onset compared to adult-onset mice, but female mice had more bouts of cataplexy than males. Orexin neuron loss was similarly rapid in both young- and adult-onset mice. As age of orexin neuron loss does not impact the severity of narcolepsy symptoms in mice, the worse symptoms in children with narcolepsy may be due to more rapid orexin neuron loss than in adults.
People with narcolepsy often experience intrusive episodes of muscle weakness known as cataplexy which are usually triggered by strong, positive emotions. Importantly, cataplexy almost exclusively occurs during social interactions, so we examined whether the prosocial neuropeptide oxytocin promotes cataplexy and mapped the underlying neural circuits. We show in a murine narcolepsy model that social reunification triggers cataplexy, and that an oxytocin antagonist blocks these socially induced episodes of muscle weakness. Chemo- and optogenetic manipulations reveal that cataplexy is driven by oxytocin receptor-expressing neurons of the central amygdala, which inhibit brainstem neurons that suppress muscle atonia. Remarkably, chocolate, a rewarding stimulus associated with strong, positive emotions also engages this oxytocin-amygdala circuit and triggers cataplexy in narcoleptic mice. This oxytocin pathway helps explain the triggering of cataplexy with social and other rewarding stimuli, and may provide a new opportunity to treat cataplexy.
Introduction Narcolepsy is a sleep disorder caused by selective death of the orexin neurons that often begins in childhood. Orexin neuron loss disinhibits REM sleep during the active period and produces cataplexy, an abnormal behavioral state between REM sleep and wakefulness. Cataplexy is often more severe when narcolepsy develops in children compared to adults, but the mechanisms underlying this difference remain unknown. Methods We used orexin-tTA/TetO-DTA mice to model narcolepsy at different ages. When doxycycline is removed from the diet, the orexin neurons of these mice express diphtheria toxin A and die within 2–3 weeks. We removed doxycycline at 4 weeks (young-onset) or 14 weeks (adult-onset) of age in male and female mice. We implanted EEG and EMG electrodes for sleep recordings one week later and then recorded EEG/EMG/video for 24h at 3 and 13 weeks after removal of doxycycline. Age-matched controls had access to doxycycline diet for the entire experiment. Results Three weeks after doxycycline removal, both young-onset and adult-onset mice developed cataplexy and the sleep-wake fragmentation characteristic of narcolepsy. Age of orexin cell loss did not significantly affect cataplexy severity, however, female mice had more cataplexy than male mice overall. Both young- and adult-onset mice showed a 99% loss of orexin neurons at 3 weeks. Conclusion Considered together, our results suggest that the orexin-tTA/TetO-DTA mouse model of narcolepsy does not capture the severe cataplexy that is often seen in the human pediatric population. Support (if any):
Introduction Narcolepsy type 1 is caused by selective loss of orexinergic neurons, resulting in poor maintenance of sleep and wakefulness, and emergence of cataplexy. Orexinergic neurons innervate many brain regions, and specific narcolepsy symptoms likely arise from dysfunction of distinct brain regions. Orexin 2 receptors (OX2R) are expressed in nearly all wake- and REM sleep-regulatory brain regions, and OX2R agonists improve narcolepsy symptoms in mouse models and human patients. However, the key brain regions and pathways through which OX2R signaling stabilizes wake and sleep and suppresses cataplexy are only partially understood. In this study, we restored OX2R expression in specific brain regions of mice lacking orexinergic neurons and OX2R, and assessed if an OX2R-selective agonist improves specific aspects of their narcolepsy symptoms. Methods We produced a murine narcolepsy model with the human diphtheria toxin receptor (DTR) knocked into the endogenous prepro-orexin locus (orexinDTR mice). After injection with diphtheria toxin (DTX), orexinDTR mice have severe and selective loss of orexinergic neurons. We crossed orexinDTR mice with OX2R transcription-disrupted (TD) mice to produce a new narcolepsy model lacking orexinergic neurons and OX2R (OX2R TD::orexinDTR mice). To induce focal expression of OX2R, we microinjected an adeno-associated viral vector coding for Cre recombinase into specific brain regions of OX2R TD::orexinDTR mice. At 6 weeks after DTX injection, we administered an OX2R-selective agonist OX-201 or vehicle orally to OX2R TD::orexinDTR mice expressing OX2R in the specific brain regions and evaluated the effects of OX-201 on narcolepsy symptoms including sleepiness and cataplexy. Results In mice expressing OX2R only in the tuberomammillary nucleus (TMN) or basal forebrain (BF) regions, OX-201 significantly improved maintenance of wakefulness but did not suppress cataplexy. In contrast, in mice expressing OX2R in the ventrolateral periaqueductal grey and lateral pontine tegmentum (vlPAG/LPT) regions, OX-201 significantly suppressed cataplexy without improving maintenance of wakefulness. Conclusion These findings demonstrate that OX2R signaling in the TMN and BF regions can stabilize wake and sleep, and OX2R signaling in the vlPAG/LPT region can suppress cataplexy. Support (if any) This work was funded by Takeda Pharmaceutical Company Limited.
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