Abstract Introduction: Cataplexy, a symptom of narcolepsy, is defined as the abrupt and uncontrollable onset of skeletal muscle paralysis during wakefulness. It has been hypothesized that cataplexy results from inappropriate intrusion of REM sleep paralysis into wakefulness. The mechanism of muscle paralysis in cataplexy is unclear, but is thought to result from pathological recruitment of the subcoeruleus nucleus (SubC) that generates REM sleep paralysis. Here, we show that activation of SubC neurons promotes cataplexy in narcoleptic mice, whereas, its inhibition reduces it. Methods: We bilaterally infused 400nL of an AAV harboring a modified G-protein coupled receptor (AAV-HSYN-hm3D(Gq)-mCherry or AAV-HSYN-hm4D(Gi)-mCherry) or an inert fluorophore (AAV-HSYN-GFP) into the SubC region of narcoleptic mice. Animals were instrumented for EEG and EMG recordings. Administration of clozapine-N-oxide (CNO, 0.5mg/kg and/or 5mg/kg) was used to activate/inhibit SubC neurons expressing modified receptors. Sleep/wake data was analyzed for 3 hours following CNO administration. Results: SubC activation in narcoleptic mice triggered a dose dependent increase in the number of cataplexy episodes (0.5mg/kg CNO: hm3D(Gq) x=25 ± 4.1, n=9 vs. control x=2 ± 0.6, n=3, p<0.05; 5mg/kg CNO: hm3D(Gq) x=64 ± 12.4, n=9 vs. control x= 3.3 ± 0.9, n=3, p<0.05) and in overall time spent in cataplexy (0.5mg/kg CNO: hm3D(Gq) x=14.6 ± 2.9% vs. control x= 0.6 ± 0.14%, p<0.05; 5mg/kg CNO: hm3D(Gq) x=33.3 ± 6.9% vs. control x= 0.9 ± 0.34%, p<0.05). Consistent with our hypothesis, inhibition of SubC neurons resulted in a 58% reduction in cataplexy (n=4, p<0.05). Conclusion: These results support our long-standing hypothesis that a REM sleep mechanism modulates muscle paralysis during cataplexy. Support (If Any): This research was funded by the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Ontario Graduate Scholarship (OGS).