Hypocretinergic interactions with the serotonergic system regulate REM sleep and cataplexy

Loss of muscle tone triggered by emotions is called cataplexy and is the pathognomonic symptom of narcolepsy, which is caused by hypocretin deficiency. Cataplexy is classically considered to be an abnormal manifestation of REM sleep and is treated by selective serotonin (5HT) reuptake inhibitors. Here we show that deleting the 5HT transporter in hypocretin knockout mice suppressed cataplexy while dramatically increasing REM sleep. Additionally, double knockout mice showed a significant deficit in the buildup of sleep need. Deleting one allele of the 5HT transporter in hypocretin knockout mice strongly increased EEG theta power during REM sleep and theta and gamma powers during wakefulness. Deleting hypocretin receptors in the dorsal raphe neurons of adult mice did not induce cataplexy but consolidated REM sleep. Our results indicate that cataplexy and REM sleep are regulated by different mechanisms and both states and sleep need are regulated by the hypocretinergic input into 5HT neurons.