“Educating people about just how real this disorder is and how it's not just being tired is crucial.”– Scott
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.9
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.1,9
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
- An in vitro study in mice has shown that histamine inhibits neuronal activity of the ventrolateral preoptic nucleus (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.2,6,10,12
Histamine may be important for sustaining wakefulness for long periods during the day.6,13
Animals with widespread disrupted hypocretin signaling exhibited fragmented wakefulness; however, restoration of hypocretin signaling only in the TMN significantly increased long bouts of wakefulness, suggesting that increased activation of neurons in the TMN is sufficient to improve maintenance of wakefulness.6,13
The Role of Histamine in Sleep and Wakefulness
Watch to learn about the role of histamine in promoting and stabilizing wakefulness.2,4
- 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.
- Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW. Control of sleep and wakefulness. Physiol Rev. 2012;92(3):1087-1187.
- 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.
- 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.
- 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.