A 35-year-old patient with narcolepsy is found to have markedly low CSF hypocretin-1 (orexin-A) levels. The normal physiological role of orexin in sleep-wake regulation is best described as:
- A Orexin promotes NREM sleep by inhibiting the locus coeruleus
- B Orexin drives REM sleep atonia by inhibiting spinal motor neurons
- C Orexin stabilizes wakefulness by simultaneously activating multiple arousal systems (LC, raphe, TMN, basal forebrain) while inhibiting VLPO sleep-promoting neurons ✓
- D Orexin promotes sleep onset by increasing adenosine release in basal forebrain
Explanation
Orexin (hypocretin) neurons in the lateral hypothalamus project broadly to all major arousal-promoting nuclei: locus coeruleus (norepinephrine), dorsal raphe (serotonin), tuberomammillary nucleus (histamine), and basal forebrain cholinergic neurons. Orexin excites these systems while also projecting to the ventrolateral preoptic area (VLPO) where sleep-promoting neurons are found. The VLPO-arousal system interaction is a 'flip-flop' switch; orexin stabilizes the arousal side. Loss of orexin in narcolepsy destabilizes this switch, causing inappropriate transitions into REM sleep (cataplexy, sleep paralysis). REM atonia is mediated by glycinergic/GABAergic neurons in the sublaterodorsal nucleus, not orexin.
Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.
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