The DR-5HT system was recently proposed to be intimately linked to sleep promotion and sleep pressure in a bidirectional process dependent on 5HT cells’ firing mode 15. 5HTT is the target of major antidepressants called selective serotonin reuptake inhibitors (SSRI), used to treat cataplexy in narcolepsy patients 14. The action of 5HT is terminated by its reuptake from the synaptic cleft into the presynaptic terminals, a process mediated by the serotonin transporter (SERT or 5HTT, encoded by the Slc6A4 gene). These cells project throughout the brain and functions by releasing 5HT, which binds 5HT receptors (up to 14 different 5HT receptors) 13. In contrast to noradrenergic cells of the locus coeruleus, 5HT neurons do not completely cease firing during cataplexy 12. Dorsal raphe (DR) 5HT neurons are active during wakefulness, decrease activity during NREMS, and are mostly silent during REMS 12. Stimulants increase catecholamines (dopamine and noradrenalin) or histamine, while most antidepressants increase serotonin (5-hydroxytryptamine, 5HT). Symptoms of narcolepsy with cataplexy are treated with stimulants and antidepressants 1. Animal studies established that the HCRT system is critical in sustaining the normal waking state and its genetic defects lead to narcolepsy phenotypes in mice and dogs 10, 11.

Wake-promoting nuclei of the brainstem and basal forebrain are major targets of the HCRT system 9. Although confined to the LH, HCRT neurons widely project to the entire central nervous system and signal through two receptors, HCRTR1 and HCRTR2 7. HCRTs (HCRT-1 and -2) are small neuropeptides exclusively produced by a neuronal population of the lateral hypothalamus (LH) 7, 8. The most prevalent hypothesis suggests an autoimmune attack against HCRT neurons 4, 5, 6. REMS regulation is also impaired in narcolepsy patients who experience multiple sleep-onset REM periods during daytime naps, which are rare in normal subjects 2.Ī key wake-promoting system called orexin or hypocretin (hereafter HCRT) is disabled in patients with narcolepsy who presumably lost their HCRT producing neurons 3. The cataplexy and sleep paralysis were interpreted as representing the coexistence of the muscle atonia of REMS with preserved consciousness of wakefulness. Narcolepsy with cataplexy (also called narcolepsy type 1 or NT1) is characterized by excessive daytime sleepiness, cataplexy (sudden loss of muscle tone during wakefulness), hypnogogic hallucinations and sleep paralysis 1. This wake-NREM-REMS cycle is dysregulated in the sleep disorder narcolepsy.

NREMS typically cycles with REMS and wakefulness. Neurotransmitters and neuropeptides released from these nuclei are wake- or sleep-promoting, and their interactions lead to electroencephalographically (EEG) measurable readouts, which are wakefulness, non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS). 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.Ī constellation of cell nuclei located in the brainstem, hypothalamus, basal forebrain, thalamus and cortex communicate with each other to fine-tune the complex behavior sleep. Deleting hypocretin receptors in the dorsal raphe neurons of adult mice did not induce cataplexy but consolidated REM sleep. 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. Additionally, double knockout mice showed a significant deficit in the buildup of sleep need. Here we show that deleting the 5HT transporter in hypocretin knockout mice suppressed cataplexy while dramatically increasing REM sleep.

Cataplexy is classically considered to be an abnormal manifestation of REM sleep and is treated by selective serotonin (5HT) reuptake inhibitors. Loss of muscle tone triggered by emotions is called cataplexy and is the pathognomonic symptom of narcolepsy, which is caused by hypocretin deficiency.