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 attention.2,6,8,9
- In animals, cortical EEG is impaired in the absence of histamine, with changes consistent with reduced capacity for attention.8
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 wakefulness.1,8
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 neurons.2,6,10,14
Studies have shown histamine is important for sleep-wake state stability.8,15
Histamine helps stabilize sleep-wake transitions.8
In an in vivo study, histamine-deficient mice had more frequent transitions between sleep-wake states compared with control mice.8
- Significantly shorter episodes of wakefulness and non-REM sleep
- Significantly more bouts of wakefulness, non-REM sleep, and REM sleep
Sleep-wake cycles of histamine-deficient mice and control mice were monitored using cortical EEG. Histamine-deficient mice lacked the histidine decarboxylase (HDC) gene, which encodes the sole enzyme responsible for histamine synthesis. No genetic alterations were made to the hypocretin system in these mice.8
Histamine may be important for sustaining wakefulness for long periods during the day.6,15
In an animal model of narcolepsy, mice with reduced hypocretin activity throughout the brain exhibited fragmented wakefulness. When hypocretin activation was restored to only neurons in the TMN, long bouts of wakefulness were significantly increased.15 This finding suggests increased activation of histamine neurons in the TMN may be sufficient to improve maintenance of wakefulness in narcolepsy.6,15
Hypocretin activity was reduced through disruption of hypocretin receptor type 2 (HCRTR2) signaling, which was achieved by a loxP-flanked transcription disrupter (TD) gene cassette that prevents expression of functional HCRTR2. Local expression of HCRTR2 was induced by microinjection of an adeno-associated viral vector (AAV) coding for Cre recombinase. Wakefulness was scored in 10-s epochs and bouts were characterized during the animals’ normal active period (7:00 pm to 7:00 am).15
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
- 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.