A 45-year-old shift worker complains of daytime somnolence and has a polysomnography showing frequent transitions from NREM stage N3 to wakefulness without REM sleep. Which neurotransmitter system, when dysfunctional, most specifically explains failure to maintain normal sleep architecture with adequate REM sleep?

• A Serotonergic neurons of the raphe nuclei, which initiate REM sleep by depolarising cholinergic neurons
• B Noradrenergic neurons of the locus coeruleus, which are maximally active during REM sleep to generate PGO waves
• C GABAergic neurons of the ventrolateral preoptic (VLPO) nucleus, which exclusively inhibit REM-promoting circuits
• D Orexin (hypocretin) neurons of the lateral hypothalamus, which stabilise state transitions and promote REM–NREM cycling ✓

Explanation

Orexin (hypocretin) neurons stabilise sleep–wake state transitions; deficiency leads to narcolepsy with frequent, abrupt shifts between wakefulness and sleep stages and fragmented REM sleep (cataplexy, sleep-onset REM). Serotonergic raphe neurons are actually maximally active during waking and suppress REM; they do not initiate it. Locus coeruleus noradrenergic neurons are silent during REM sleep (not active), enabling REM-active cholinergic neurons to dominate. VLPO GABAergic neurons inhibit arousal-promoting monoaminergic nuclei to facilitate NREM sleep, but do not specifically explain REM architecture failure.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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Written and medically reviewed by the StethoPrep medical team.