“There was constant exhaustion. It didn't matter how much I slept.” – Scott
The hypothalamus is a critical “control center” for sleep-wake state stability and contains several neuronal systems that are responsible for the coordinated timing and appropriate duration of wakefulness, non-REM sleep, and REM sleep.1,3-6 Hypocretin and histamine neurons in the brain originate only in the hypothalamus and play similar roles in promoting and stabilizing wakefulness.1,7-10
LH (Lateral Hypothalamus)
- Only location in the brain where hypocretin neurons originate2,3,8
- Hypocretin neurons:
- Promote wakefulness by activating cortical and subcortical neurons, histamine neurons, and wake-promoting neurons outside of the hypothalamus3,8,11
- Stabilize wakefulness by inhibiting non-REM sleep–promoting neurons and REM sleep–promoting neurons1,3
SCN (Suprachiasmatic Nucleus)
- Coordinates circadian timing and other circadian rhythms in order to align sleep and wakefulness to the daily light-dark cycle3
TMN (Tuberomammillary Nucleus)
- Only neuronal source of histamine in the brain3,7
- Histamine neurons:
- Promote wakefulness by activating cortical and subcortical neurons, and wake-promoting neurons outside of the hypothalamus7
- Stabilize wakefulness by inhibiting non-REM sleep–promoting neurons and REM sleep–promoting neurons3,7,12,13
VLPO (Ventrolateral Preoptic Area)
- 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
- España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
- Scammell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol. 2003;53(2):154-166.
- Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747-765.
- Schwartz JR, Roth T. Neurophysiology of sleep and wakefulness: basic science and clinical implications. Curr Neuropharmacol. 2008;6(4):367-378.
- Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257-1263.
- Shan L, Dauvilliers Y, Siegel JM. Interactions of the histamine and hypocretin systems in CNS disorders. Nat Rev Neurol. 2015;11:401-13.
- Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
- Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008;88(3):1183-1241.
- Torrealba F, Riveros ME, Contreras M, Valdes JL. Histamine and motivation. Front Syst Neurosci. 2012;6(51):1-14.
- 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.
- 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.