“There was this constant, overwhelming exhaustion. It didn't matter how much I slept.” – Scott

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The Role of the Hypothalamus in Sleep and Wakefulness

A coordinated system in the human brain supports the regulation of sleep-wake states.1-4

The hypothalamus is a critical brain region for regulating sleep-wake states1,3-6 and contains several neuronal systems that are responsible for the coordinated timing and appropriate duration of wakefulness, non-REM sleep, and REM sleep.1,3-5

  • Coordinates circadian timing and other circadian rhythms in order to align sleep and wakefulness to the daily light-dark cycle 3

Only location in the brain where hypocretin-producing neurons originate 2-4

Hypocretin neurons:

  • Promote and stabilize wakefulness by activating cortical and subcortical neurons, histamine neurons, and wake-promoting neurons outside of the hypothalamus 1-3,7
  • Inhibit non-REM sleep– and REM sleep–promoting neurons to stabilize wakefulness 1-3

Only source of neuronal histamine in the brain 3,8

Histamine neurons:

  • Promote and stabilize wakefulness by activating cortical and subcortical neurons, and wake-promoting neurons outside of the hypothalamus1,3,8-10
  • Inhibit non-REM sleep– and REM sleep–promoting neurons to help stabilize wakefulness 3,8,10,11
  • The VLPO as well as the median preoptic nucleus (MnPO) contain essential neurons for promoting non-REM sleep 1,3
    • These neurons project to key wake-promoting regions to inhibit wakefulness 1,3
  • Neurons in the extended VLPO mediate the promotion of REM sleep by inhibiting certain wake-promoting neurons that suppress REM sleep 3
Suprachiasmatic Nucleus
  • Coordinates circadian timing and other circadian rhythms in order to align sleep and wakefulness to the daily light-dark cycle 3
Lateral Hypothalamus

Only location in the brain where hypocretin-producing neurons originate 2-4

Hypocretin neurons:

  • Promote and stabilize wakefulness by activating cortical and subcortical neurons, histamine neurons, and wake-promoting neurons outside of the hypothalamus 1-3,7
  • Inhibit non-REM sleep– and REM sleep–promoting neurons to stabilize wakefulness 1-3
Tuberomammillary Nucleus

Only source of neuronal histamine in the brain 3,8

Histamine neurons:

  • Promote and stabilize wakefulness by activating cortical and subcortical neurons, and wake-promoting neurons outside of the hypothalamus1,3,8-10
  • Inhibit non-REM sleep– and REM sleep–promoting neurons to help stabilize wakefulness 3,8,10,11
Ventrolateral Preoptic Area
  • The VLPO as well as the median preoptic nucleus (MnPO) contain essential neurons for promoting non-REM sleep 1,3
    • These neurons project to key wake-promoting regions to inhibit wakefulness 1,3
  • Neurons in the extended VLPO mediate the promotion of REM sleep by inhibiting certain wake-promoting neurons that suppress REM sleep 3
There's More to Know About the Hypothalamus

During the day, hypocretin neurons stabilize wakefulness by:

  • Promoting wakefulness directly by increasing neuronal signaling in cortical and subcortical regions and indirectly by activating other wake-promoting neurons1-3,7
  • Inhibiting non-REM sleep–promoting neurons1,3
  • Inhibiting REM sleep–promoting neurons1-3

Histamine neurons perform similar functions at these same regions.1,3,8-11

Did You Know?

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  1. España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
  2. Scammell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol. 2003;53(2):154-166.
  3. Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747-765.
  4. Schwartz JR, Roth T. Neurophysiology of sleep and wakefulness: basic science and clinical implications. Curr Neuropharmacol. 2008;6(4):367-378.
  5. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257-1263.
  6. Shan L, Dauvilliers Y, Siegel JM. Interactions of the histamine and hypocretin systems in CNS disorders. Nat Rev Neurol. 2015;11:401-13.
  7. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
  8. Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008;88(3):1183-1241.
  9. Torrealba F, Riveros ME, Contreras M, Valdes JL. Histamine and motivation. Front Syst Neurosci. 2012;6(51):1-14.
  10. 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.
  11. 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.

Performance of routine tasks without awareness.

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

Complete collapse to the ground; 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 inappropriate transitions between states of sleep and wakefulness.

The inability to stay awake and alert during the day.

A neurotransmitter that supports wakefulness. The TMN is the only source of histamine in the brain.

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

A neuropeptide that supports wakefulness and helps control 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.

Brief, unintentional lapses into sleep or loss of awareness.

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

A state of sleep when muscle tone is decreased. Deep stages help to restore the body.

Overnight study used to diagnose sleep disorders by monitoring sleep stages and cycles to detect disruptions of a normal sleep pattern.

Normally occurs at night and includes vivid dreams. Also known as “paradoxical sleep.”

Daytime and evening habits and routines to help improve nighttime sleep.

Brief loss of control of voluntary muscles with retained awareness.

Sleep-onset REM period.

People with type 1 narcolepsy have low levels of hypocretin.

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