National Sleep Foundation

Chapter 1: Normal Sleep

Neurobiology of Sleep

Neurobiology of Sleep

Most models of basic sleep regulation are based on understanding the monoaminergic systems (i.e., serotonin, histamine, and noradrenalin) and cholinergic systems (i.e., acetylcholine).

Brainstem monoaminergic activity is highest while awake, is reduced during non-rapid eye movement (NREM) sleep, and is absent in REM sleep. Conversely, brainstem cholinergic activity is highest when awake and during REM sleep, and is minimal (or absent) in NREM sleep.1

Wakefulness is promoted by the activation of the “ascending reticular activating system” (ARAS) by monoaminergic and cholinergic projections from the brainstem, thalamus, hypothalamus, basal forebrain, and cortex. This activation is responsible for electroencephalogram (EEG) desynchronization during wakefulness and rapid eye movement (REM) sleep. (See Figure 1.3.)

Decreasing activity in the ARAS is not enough to induce sleep, however. Rather, sleep is actively induced by stimulation in some hypothalamic regions. Thus, there are both passive and active components in sleep onset. 2, 3, 4

Figure 1.3: Hypothalamic and brainstem sleep-wake regulation system5


 

Key:

  • ARAS: Ascending reticular activating system
  • SCN: Suprachiasmatic nucleus
  • S/W: Sleep- and wake-promoting neurons

The hypothalamus has a significant role promoting wakefulness and sleep, and appears to be a key regulator (or “sleep switch”) of sleep and wakefulness.6  Sleep-promoting GABA/galanininergic (GABA/Gal) neurons are located in the hypocampus’ “ventrolateral preoptic area” (VLPO).  GABA, the most widespread inhibitory neurotransmitters in the central nervous system, regulates sleep and other functions including balance, motor coordination and memory. Galanin is a neurotransmitter that is distributed throughout the brain; it is also involved in functions beyond sleep, including learning and memory.

Wake-promoting hypocretin/orexin neurons are situated in the lateral hypothalamus.

The VLPO and hypocretin systems innervate the ascending arousal system by transmitting inhibitory and stimulatory signals, respectively. The main components of the ascending arousal system include the adrenergic locus coeruleus (LC), serotoninergic dorsal raphe (DR), and histaminergic tuberomammillary nucleus (TMN). Synchronization and desynchronization of these circuits regulate the sleep-wake cycle. (See Figure 1.4.)

Evidence also suggests that other neurotransmitter systems (i.e., dopamine, serotonin, and histamine) influence sleep regulation, as well.

Figure 1.4: Arousal pathways maintaining cortical activation in the waking state7

Key:

  • A10: ventral tegmental area
  • BF: basal forebrain cholinergic nuclei
  • CR: caudal raphe
  • DR: serotoninergic dorsal raphe
  • LC: adrenergic locus coeruleus
  • LDT/PPT: laterodorsal tegmental nuclei/pedunculopontine tegmental nuclei
  • PRF: pontine reticular formation
  • TMN: histaminergic tuberomammillary nucleus
  • VLPO: ventrolateral preoptic area.

 

References

  1. Hess WR. Symptomatik des durch elektrischen Reiz ausgelosten Schlafes und die Topographie des Schlafzentrums. Helv Physiol Pharmacolog. 1:C61:1943.
  2. Nauta WJH. Hypothalamic regulation of sleep in rats. J Neurophysiol. 1946;9:285-316.
  3. Espana, RA, and Scammell, TE, Sleep neurobiology from a clinical perspective, Sleep 34(7):845-858, 2011.
  4. Mignot E, Taheri S, Nishino S. Sleeping with the hypothalamus: emerging targets for sleep disorders. Nat Neurosci. 2002;5:S1071-S1075.
  5. Pace-Schott EF, Hobson JA. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci. 2002;3:591-605.
  6. Pace-Schott EF, Hobson JA. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci. 2002;3:591-605.
  7. Pace-Schott EF, Hobson JA. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci. 2002;3:591-605.