Advancements in the understanding of narcolepsy are happening. Register for updates »

Advancements in the understanding of narcolepsy are happening. Register for updates »

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

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
Histamine-Hypnogram-Desktop Histamine-Hypnogram-Mobile

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

More

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

Sustained Wakefulness Graph Sustained Wakefulness Graph

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

More

Watch videos

2 Importance of Histamine
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

4 Scammell Exploring Histamine
Exploring Histamine in Sleep-Wake State Stability
Dr. Thomas Scammell
Neurologist and sleep specialist

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

7 Role of Histamine
The Role of Histamine in Sleep and Wakefulness

In the brain, histamine neurons originate only in the hypothalamus and are thought to play an important role in sleep-wake state stability.2,6 Learn how histamine has been shown to help promote and stabilize wakefulness.2,4,6

CA Sleep Stability Icon
Sleep-Wake State Stability

Brush up on the characteristics of normal sleep and wakefulness.

Review »
Etiology Icon
Etiology

Learn about possible causes of hypocretin neuron loss in narcolepsy.

Find out »
  1. España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
  2. Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008;88(3):1183-1241.
  3. Schwartz MD, Kilduff TS. The neurobiology of sleep and wakefulness. Psychiatr Clin North Am. 2015;38(4):615-644.
  4. 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.
  5. 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.
  6. Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747-765.
  7. 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.
  8. 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.
  9. Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW. Control of sleep and wakefulness. Physiol Rev. 2012;92(3):1087-1187.
  10. Korotkova TM, Sergeeva OA, Ponomarenko AA, Haas HL. Histamine excites noradrenergic neurons in locus coeruleus in rats. Neuropharmacology. 2005;49(1):129-134.
  11. Torrealba F, Riveros ME, Contreras M, Valdes JL. Histamine and motivation. Front Syst Neurosci. 2012;6:51. doi: 10.3389/fnsys.2012.00051.
  12. Liu YW, Li J, Y JH. Histamine regulates activities of neurons in the ventrolateral preoptic nucleus. J Physiol. 2010:588(Pt 21):4103-4116.
  13. 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.
  14. 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.
  15. 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.
  16. Shan L, Dauvilliers Y, Siegel JM. Interactions of the histamine and hypocretin systems in CNS disorders. Nat Rev Neurol. 2015;11(7):401-413.

Performance of routine tasks without awareness.

Sudden and brief loss of muscle tone, often triggered by strong emotions or certain situations. Narcolepsy with cataplexy is known as narcolepsy type 1.

Complete collapse to the ground; nearly all skeletal muscles are involved.

Only certain muscle groups are involved.

Biological clock mechanism that regulates the 24-hour cycle in the physiological processes of living beings. It is controlled in part by the SCN in the hypothalamus and is affected by the daily light-dark cycle.

Frequent awakenings and inappropriate transitions between states of sleep and wakefulness during nighttime sleep.

The inability to stay awake and alert during the day.

A neurotransmitter in the brain that supports wakefulness.

Vivid, realistic, and sometimes frightening dream-like events that occur when falling asleep.

Also known as orexin. A neuropeptide that supports wakefulness and helps suppress non-REM sleep and REM sleep.

Primary brain region for regulating the timing of sleep-wake states.

Unintentionally falling asleep due to excessive daytime sleepiness. Also known as “sleep attacks.”

Brief, unintentional lapses into sleep or loss of awareness.

A validated objective measure of the tendency to fall asleep in quiet situations.

People living with narcolepsy type 1 have low levels of hypocretin.

Narcolepsy without cataplexy; the cause of narcolepsy type 2 is unknown.

A state of sleep characterized by slower-frequency, more synchronized neuronal activity and decreased muscle tone. Deep stages help to restore the body.

A multiparameter test that monitors physiologic signals during sleep; used as a diagnostic tool in sleep medicine.

A state of sleep characterized by fast-frequency, desynchronized activity on EEG, vivid dreams, and loss of muscle tone. Normally occurs 60-90 minutes after sleep onset. Also known as “paradoxical sleep.”

Brief loss of control of voluntary muscles with retained awareness at sleep-wake transitions.

Sleep-onset REM period.

The VLPO as well as the median preoptic nucleus (MnPO) are located in the hypothalamus and contain essential neurons for promoting non-REM sleep. These neurons project to all wake-promoting regions to inhibit wakefulness and promote non-REM sleep during the night.8,11 Neurons in the extended VLPO mediate the promotion of REM sleep by inhibiting certain wake-promoting neurons that suppress REM sleep.8