“I had no concept that feeling so incredibly tired was not a feeling that others felt.”– Scott
Three Sleep-Wake States Are Defined by Distinct Neurophysiologic Characteristics3,5
Normally, wakefulness is promoted during the day by multiple interconnected neuronal systems, including acetylcholine, dopamine, histamine, norepinephrine, and serotonin neurons.1,2 Wakefulness is characterized by high muscle tone and fast-frequency neuronal activity that is necessary for alertness and higher-order neurocognitive functioning.3,5
Non-REM sleep is a sleep state with slower-frequency neuronal activity and light to deep stages of non-REM sleep. Skeletal muscle tone is lower than during wakefulness.3,5 Nighttime sleep normally begins with an episode of non-REM sleep.3
During REM sleep, which is associated with dreaming and skeletal muscle atonia, neuronal activity is faster and desynchronized, with distinct wave patterns (e.g., sawtooth waves) on electroencephalogram (EEG).3,5,7 Episodes of REM sleep typically occur at night after non-REM sleep and become longer over the course of the night.3
Circadian Timekeeping Coordinates Sleep and Wakefulness With the Daily Light/Dark Cycle3
A normal sleep-wake cycle is generally characterized by consolidated wakefulness during the day and predictable, alternating periods of non-REM and REM sleep at night, with generally infrequent awakenings.2,3,7
The Hypothalamus Is a Critical “Control Center” for Sleep-Wake State Stability3,8-10,∗
Coordinated systems in the brain help to maintain stability between states of sleep and wakefulness.1,3,4,8
The hypothalamus contains several neuronal systems that are responsible for the coordinated timing and appropriate duration of wakefulness, non-REM sleep, and REM sleep.1,3,4,10 Hypocretin and histamine neurons in the brain originate only in the hypothalamus and play similar roles in promoting and stabilizing wakefulness.1,2,11-13
LH (Lateral Hypothalamus)
- Only location in the brain where hypocretin neurons originate2-4
- Hypocretin neurons:
- Promote wakefulness by activating cortical and subcortical neurons, histamine neurons, and wake-promoting neurons outside of the hypothalamus2,3,14
- Stabilize wakefulness by inhibiting non-REM sleep–promoting neurons and REM sleep–promoting neurons1,3
SCN (Suprachiasmatic Nucleus)
- Coordinates circadian timing and other circadian rhythms to align sleep and wakefulness to the daily light-dark cycle3
TMN (Tuberomammillary Nucleus)
- Only neuronal source of histamine in the brain3,11
- Histamine neurons:
- Promote wakefulness by activating cortical and subcortical neurons, and wake-promoting neurons outside of the hypothalamus11
- Stabilize wakefulness by inhibiting non-REM sleep–promoting neurons and REM sleep–promoting neurons3,11,15,16
VLPO (Ventrolateral Preoptic Area)
- The VLPO as well as the median preoptic nucleus (MnPO) contain essential neurons for promoting non-REM sleep1,3
- These neurons project to key wake-promoting regions to inhibit wakefulness1,3
- Neurons in the extended VLPO mediate the promotion of REM sleep by inhibiting certain wake-promoting neurons that suppress REM sleep3
Like hypocretin neurons, histamine neurons play an important role in promoting and stabilizing wakefulness1,11-13 by:
- Activating the cortex and wake-promoting neurons outside of the hypothalamus11
- Inhibiting non-REM sleep–promoting neurons15
- Inhibiting REM sleep–promoting neurons3,11,16
*Based on animal and human studies.
- España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
- Scammell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol. 2003;53(2):154-166.
- Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747-765.
- Schwartz JR, Roth T. Neurophysiology of sleep and wakefulness: basic science and clinical implications. Curr Neuropharmacol. 2008;6(4):367-378.
- Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW. Control of sleep and wakefulness. Physiol Rev. 2012;92(3):1087-1187.
- Broughton R, Valley V, Aguirre M, Roberts J, Suwalski W, Dunham W. Excessive daytime sleepiness and the pathophysiology of narcolepsy-cataplexy: a laboratory perspective. Sleep. 1986;9:205-215.
- Plazzi G, Serra L, Ferri R. Nocturnal aspects of narcolepsy with cataplexy. Sleep Med Rev. 2008;12(2):109-128.
- van der Heide A, Lammers GJ. Narcolepsy. In: Thorpy MJ, Billiard M, eds. Sleepiness: Causes, Consequences and Treatment. Cambridge, UK: Cambridge University Press; 2011:111-125.
- Shan L, Dauvilliers Y, Siegel JM. Interactions of the histamine and hypocretin systems in CNS disorders. Nat Rev Neurol. 2015;11:401-13.
- Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257-1263.
- Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008;88(3):1183-1241.
- Schwartz MD, Kilduff TS. The neurobiology of sleep and wakefulness. Psychiatr Clin North Am. 2015;38(4):615-644.
- Scammell TE, Jackson AC, Franks NP, Wisden W, Dauvilliers Y. Histamine: neural circuits and new medications. Sleep. 2019;42(1): doi: 10.1093/sleep/zsy183.
- Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
- Williams RH, Chee MJ, Kroeger D. Optogenetic-mediated release of histamine reveals distal and autoregulatory mechanisms for controlling arousal. J Neurosci. 2014;34(17):6023-6029.
- Crochet S, Onoe H, Sakai K. A potent non-monoaminergic paradoxical sleep inhibitory system: a reverse microdialysis and single-unit recording study. Eur J Neurosci. 2006;24(5):1404-1412.