Skin thermal dynamics and hypothalamic thermosensitivity dissociate REM sleep and cataplexy in narcolepsy

Narcolepsy is caused by hypothalamic hypocretin/orexin loss and characterized by cataplexy, a unique brain state triggered by emotion. Cataplexy shares features with rapid eye movement (REM) sleep, including muscle atonia and wake-like electroencephalographic activity. REM sleep is characterized by thermoregulatory suspension and, when the need for thermoregulatory responses is reduced as during ambient thermoneutral warming, melanin-concentrating hormone (MCH) neurons play a critical role in favoring REM sleep expression. However, it remains unknown whether REM sleep and cataplexy share thermomodulatory mechanisms. Here, we demonstrate that reduced skin temperatures and a widening of the distal-to-proximal skin temperature gradient precede cataplexy in both patients with narcolepsy and hypocretin-knockout (Hcrt-KO) narcoleptic mice. To test a causal role for skin temperature in cataplexy modulation, thermoneutral manipulation of skin temperature in Hcrt-KO mice revealed that skin cooling promoted cataplexy, whereas skin warming increased REM sleep. Fiber photometry showed that, at constant ambient temperatures (23°C), cataplexy and REM sleep were associated with increased MCH neuron activity. Skin cooling, however, reduced the MCH calcium imaging dynamics associated with cataplexy. Moreover, MCH optogenetic or chemogenetic manipulation recapitulated these effects, with MCH silencing favoring cataplexy and MCH activation driving REM sleep. Last, using the skin warming condition, we combined cFos staining and retrograde labeling and identified activated monosynaptic inputs from known thermoregulatory hubs such as the median preoptic nucleus, dorsomedial hypothalamus, and the parabrachial nucleus to MCH neurons. These findings unveil an unexplored role for skin thermal dynamics and hypothalamic MCH thermosensitivity in dissociating cataplexy and REM sleep.