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The Role of Histamine in Sleep and Wakefulness
Like hypocretin/orexin neurons, histamine neurons play an important role in promoting and stabilizing wakefulness.1-4
In the CNS, histamine neurons originate only in the hypothalamic tuberomammillary nucleus (TMN) and project to key wake-promoting regions in the brain.2 Studies in animals and humans have shown that histamine neurons help to promote and stabilize wakefulness by:
- Activating the cortex and wake-promoting neurons outside of the hypothalamus5
- Inhibiting non-REM sleep–promoting neurons and REM sleep–promoting neurons2,5-7
Enhance Cortical Activity
- During wakefulness, histamine neurons directly activate cortical neurons, which helps provide the framework for cognitive functions such as attention2,6,8,9
- In animals, cortical EEG is impaired in the absence of histamine, with changes consistent with reduced capacity for attention8
Activate Wake-Promoting Neurons
- Histamine neurons help to promote wakefulness by activating wake-promoting neurons outside of the hypothalamus (e.g., norepinephrine, acetylcholine, serotonin, and dopamine neurons)2,10,11
- Animals lacking histamine have particularly impaired wakefulness at the beginning of their active period, suggesting that these neurons may also play an important role in initiating wakefulness1,8
Inhibit Non-REM Sleep and REM Sleep
During the day, histamine neurons help to stabilize wakefulness by inhibiting non-REM sleep–promoting neurons and REM sleep–promoting neurons.2,4-6
- Histamine neurons in the TMN and non-REM sleep–promoting neurons in the ventrolateral preoptic nucleus (VLPO) inhibit each other, which may play a role in transitions between sleep and wakefulness.12,13 An in vitro study in mice has shown that histamine from the TMN inhibits neuronal activity of the VLPO, which contains neurons that are essential for promoting non-REM sleep.5,6
- Through in vitro animal studies, histamine has been shown to activate wake-promoting neurons known to inhibit REM sleep, specifically norepinephrine and serotonin neurons2,6,10,14
Watch videos
The Importance of Histamine in Stabilizing Wakefulness
Histamine neurons may play an important role in sustaining wakefulness for long periods during the day. Review study results that suggest increased activation of histamine neurons may help stabilize wakefulness in narcolepsy.6,15
Exploring Histamine in Sleep-Wake State Stability
Dr. Thomas Scammell
Thomas Scammell, MD, from Beth Israel Deaconess Medical Center, Boston Children's Hospital, and Harvard Medical School, discusses key data from several animal studies that support why histamine plays an important role in disorders characterized by sleep-wake state instability, such as narcolepsy.1,2
Sleep-Wake State Stability
Brush up on the characteristics of normal sleep and wakefulness.
Review »
- España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
- 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
- Williams RH, Chee MJ, Kroeger D, et al. Optogenetic-mediated release of histamine reveals distal and autoregulatory mechanisms for controlling arousal. J Neurosci. 2014;34(17):6023-6029.
- Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747-765.
- 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.
- Parmentier R, Ohtsu H, Djebbara-Hannas Z, Valatx JL, Watanabe T, Lin JS. Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control. J Neurosci. 2002;22(17):7695-7711.
- Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW. Control of sleep and wakefulness. Physiol Rev. 2012;92(3):1087-1187.
- Korotkova TM, Sergeeva OA, Ponomarenko AA, Haas HL. Histamine excites noradrenergic neurons in locus coeruleus in rats. Neuropharmacology. 2005;49(1):129-134.
- Torrealba F, Riveros ME, Contreras M, Valdes JL. Histamine and motivation. Front Syst Neurosci. 2012;6:51. doi:10.3389/fnsys.2012.00051
- Liu YW, Li J, Y JH. Histamine regulates activities of neurons in the ventrolateral preoptic nucleus. J Physiol. 2010:588(Pt 21):4103-4116.
- Cheng J, Wu F, Zhang M, et al. The interaction between the ventrolateral preoptic nucleus and the tuberomammillary nucleus in regulating the sleep-wakefulness cycle. Front Neurosci. 2020;14:615854.
- Brown RE, Sergeeva OA, Eriksson KS, Haas HL. Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J Neurosci. 2002;22(20):8850-8859.
- Mochizuki T, Arrigonia E, Marcus JN, et al. Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice. Proc Natl Acad Sci. 2011;108(11):4471-4476.
- Shan L, Dauvilliers Y, Siegel JM. Interactions of the histamine and hypocretin systems in CNS disorders. Nat Rev Neurol. 2015;11(7):401-413.
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