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 the Hypothalamus

The hypothalamus is a critical “control center” for sleep-wake state stability.1-4,*

Explore the neuronal systems in the hypothalamus that are responsible for the coordinated timing and appropriate duration of wakefulness, non-REM sleep, and REM sleep.1,4-6

Lateral hypothalamus brain image LH legend

Lateral hypothalamus (LH)

  • Only location in the brain where hypocretin neurons originate1,6,7
  • Hypocretin neurons promote wakefulness by activating cortical and subcortical neurons, histamine neurons, and wake-promoting neurons outside of the hypothalamus1,7,8
  • Histamine and other wake-promoting neurons inhibit non-REM sleep–promoting neurons and REM sleep–promoting neurons.1,5 Hypocretin neurons reinforce this activity to help stabilize wakefulness during the day.5
Tuberomammillary nucleus brain image TMN legend
Tuberomammillary nucleus brain image TMN legend

Tuberomammillary nucleus (TMN)

  • Only neuronal source of histamine in the brain1,9
  • Histamine neurons:
    • Promote wakefulness by activating cortical and subcortical neurons, and wake-promoting neurons outside of the hypothalamus9
    • Stabilize wakefulness by inhibiting non-REM sleep–promoting neurons and REM sleep–promoting neurons1,9-11
Ventrolateral preoptic area brain image VLPO legend

Ventrolateral preoptic area (VLPO)

  • 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
Melanin-concentrating hormone neurons brain image MCH legend

Melanin-concentrating hormone (MCH) neurons

  • Promote and maintain REM sleep at night by inhibiting wake-promoting neurons that suppress REM sleep12-14
  • Evidence suggests MCH neurons are inhibited by hypocretin neurons during the day13,15
Suprachiasmatic nucleus brain image SCN legend

Suprachiasmatic nucleus (SCN)

  • Coordinates circadian timing and other circadian rhythms to align sleep and wakefulness to the daily light-dark cycle1

Like hypocretin neurons, histamine neurons play an important role in promoting and stabilizing wakefulness5,9,11,16 by:

  • Activating the cortex and wake-promoting neurons outside of the hypothalamus9
  • Inhibiting non-REM sleep–promoting neurons10
  • Inhibiting REM sleep–promoting neurons1,9,11
Did You Know?

*Based on animal and human studies.

BF, basal forebrain; DMH, dorsomedial hypothalamic nucleus; GABA, gamma aminobutyric acid; GLU, glutamic acid; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine tegmental nucleus; SLD, sublaterodorsal nucleus; SPZ, subparaventricular zone; vlPAG, ventrolateral periaqueductal gray matter; vPAG, ventral periaqueductal gray matter.

Pathophysiology icon

In most people, narcolepsy is caused
by loss of hypocretin.

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There’s more to know about the role of histamine in regulating wakefulness.

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  1. Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747-765.
  2. van der Heide A, Lammers GJ. Narcolepsy. In: Thorpy MJ, Billiard M, eds. Sleepiness: Causes, Consequences and Treatment. Cambridge: Cambridge University Press; 2011:111-125.
  3. Shan L, Dauvilliers Y, Siegel JM. Interactions of the histamine and hypocretin systems in CNS disorders. Nat Rev Neurol. 2015;11:401-413.
  4. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257-1263.
  5. España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
  6. Schwartz JR, Roth T. Neurophysiology of sleep and wakefulness: basic science and clinical implications. Curr Neuropharmacol. 2008;6(4):367-378.
  7. Scammell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol. 2003;53(2):154-166.
  8. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
  9. Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008;88(3):1183-1241.
  10. 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.
  11. 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
  12. Peyron C, Valentin F, Bayard S, et al. Melanin concentrating hormone in central hypersomnia. Sleep Med. 2011;12(8):768-772.
  13. Naganuma F, Bandaru S, Absi G, Mahoney CE, Scammell TE. Melanin-concentrating hormone neurons contribute to dysregulation of rapid eye movement sleep in narcolepsy. Neurobiol Dis. 2018;120:12-20.
  14. Schrolkamp M, Jennum P, Steen G, Holm A, Kornum BR, Knudsen S. Normal morning melanin-concentrating hormone levels and no association with rapid eye movement or non-rapid eye movement sleep parameters in narcolepsy type 1 and type 2. J Clin Sleep Med. 2017;13(2):235-243.
  15. Apergis-Schoute J, Iordanidou P, Faure C, et al. Optogenetic evidence for inhibitory signaling from orexin to MCH neurons via local microcircuits. J Neurosci. 2015;35(14):5435-5441.
  16. Schwartz MD, Kilduff TS. The neurobiology of sleep and wakefulness. Psychiatr Clin North Am. 2015;38(4):615-644.

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.

An abnormal sleep phenomenon characterized by REM sleep occurrence within 15 minutes of sleep onset; may occur during nighttime sleep or daytime napping.

A group of neurons located in the hypothalamus that are essential for promoting non-REM sleep. These neurons project to all wake-promoting regions to inhibit wakefulness and promote non-REM sleep during the night.