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The Neurobiology of Sleep: Genetics, cellular physiology and subcortical networks

Key Points

  • Over the past decade, technological advances in molecular biology and cellular neurophysiology have allowed us to construct a much more complete picture of the genetic events, cellular mechanisms and subcortical networks that underlie the neurobiology of sleep.

  • An interlocking positive–negative feedback mechanism that controls gene transcription in individual cells of the suprachiasmatic nucleus (SCN) of the hypothalamus is the molecular basis of circadian rhythmicity in mammals. This endogenous periodicity can be entrained to the ambient photoperiod by photons impinging on the circadian photopigment melanopsin in retinal ganglion cells. These cells use the neurotransmitter glutamate to convey this information to the SCN monosynaptically through the retinohypothalamic tract (RHT).

  • SCN cells output their intrinsic circadian rhythmicity by action potentials that impinge on adjacent nuclei of the anterior hypothalamus, including the paraventricular nucleus, the subparaventricular nucleus (SPZ), the dorsomedial nucleus (DMH) and the medial preoptic area, which, in turn, convey circadian rhythmicity to structures that control rhythmic physiological processes, such as sleep, temperature and endocrine output.

  • Feedback to the SCN circadian oscillator can occur by melatonin from the pineal gland, which reliably secretes this sleep-related hormone in response to polysynaptically conveyed signals from the SCN. In addition, other neuromodulatory systems, including the neurotransmitter acetylcholine, modulate the SCN's responsiveness to photic input from the RHT. The sensitivity of the circadian pacemaker to such modulation also shows temporal specificity: the SCN is responsive to particular modulatory signals only at specific times during the circadian day.

  • A key hypothalamic structure that receives circadian output from the SCN through the SPZ and the DMH is the GABA (γ-aminobutyric acid)-containing ventrolateral preoptic area (VLPO), which promotes non-REM (NREM) sleep. The VLPO might initiate sleep onset through its reciprocal inhibition of cholinergic, noradrenergic and serotonergic arousal systems in the brainstem, as well as histaminergic arousal systems of the posterior hypothalamus and cholinergic systems of the basal forebrain, all of which are modulated by the orexinergic arousal system of the lateral hypothalamus. All these arousal systems promote the activated brain states of waking, whereas the cholinergic system acts alone to promote the activated state of rapid eye movement (REM) sleep.

  • The VLPO is triggered to initiate sleep onset by both circadian input from the anterior hypothalamus and sleep–wake homeostatic information from endogenous chemical signals, such as adenosine, which accumulate in proportion to time spent awake. Circadian and homeostatic signals are integrated in diencephalic structures so as to initiate sleep with an adaptive timing.

  • Once sleep is initiated, an ultradian oscillator in the mesopontine junction controls the regular alternation of NREM and REM sleep. The executive control of this oscillator involves a reciprocal interaction between cholinergic REM-on and aminergic REM-off cell groups, whose influence on one another is mediated by interposed excitatory, inhibitory and autoregulatory circuits that involve GABA and glutamate, as well as serotonin, noradrenaline and acetylcholine.

  • Both the sleep–wake and REM–NREM oscillators give rise to regularly recurring changes in neuromodulation of the forebrain structures that mediate behaviour, consciousness and cognitive processes such as memory consolidation. The burgeoning literature detailing molecular-biological, cellular and neuromodulatory mechanisms indicates that sleep research has entered a new era.

Abstract

To appreciate the neural underpinnings of sleep, it is important to view this universal mammalian behaviour at multiple levels of its biological organization. Molecularly, the circadian rhythm of sleep involves interlocking positive- and negative-feedback mechanisms of circadian genes and their protein products in cells of the suprachiasmatic nucleus that are entrained to ambient conditions by light. Circadian information is integrated with information on homeostatic sleep need in nuclei of the anterior hypothalamus. These nuclei interact with arousal systems in the posterior hypothalamus, basal forebrain and brainstem to control sleep onset. During sleep, an ultradian oscillator in the mesopontine junction controls the regular alternation of rapid eye movement (REM) and non-REM sleep. Sleep cycles are accompanied by neuromodulatory influences on forebrain structures that influence behaviour, consciousness and cognition.

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Figure 1: Brain regions and regulatory circuits involved in sleep.
Figure 2: The molecular control of circadian rhythms.
Figure 3: The reciprocal-interaction model of REM–NREM alternation.
Figure 4: Schematic representation of the process of REM sleep generation.
Figure 5: Sleep–wake control systems of the subthalamic diencephalon and their links to input from the circadian clock and to ascending arousal systems of the brainstem.
Figure 6: Transmission of circadian information from the circadian oscillator to hypothalamic systems that control circadian rhythms.

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Acknowledgements

This work was supported by grants from the National Institute on Drug Abuse and the National Institutes of Health. We thank R. Stickgold, B. Kocsis, R. Fosse, C. Saper, P.-H. Luppi, R. Lydic, M. Delnero and A. Morgan.

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Correspondence to Edward F. Pace-Schott.

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DATABASES

LocusLink

aryl sulphotransferase

AVP

Bmal1

Clock

CREB

Cry1–2

cytochrome c oxidase

Egr1

galanin

growth hormone

hypocretin

melanopsin

NF-κB

PACAP

parathyroid hormone

Per1–3

prolactin

ryanodine receptors

tau

VIP

OMIM

advanced sleep-phase syndrome

narcolepsy

Parkinson's disease

FURTHER INFORMATION

Encyclopedia of Life Sciences

acetylcholine

adrenaline and noradrenaline

amine neurotransmitters

circadian rhythms

hypothalamus

nitric oxide as a neuronal messenger

serotonin

sleep

sleep disorders

Laboratory of Neurophysiology

Laboratory of Neurophysiology

MIT Encyclopedia of Cognitive Sciences

dreaming

sleep

Glossary

CIRCADIAN RHYTHMS

Biological rhythms of physiology and behaviour that have a 24-h periodicity, which have evolved in response to the 24-h astronomical cycle to which all organisms are exposed.

SUPRACHIASMATIC NUCLEUS

The mammalian circadian pacemaker, or 'master clock', which consists of two tiny, bilaterally symmetrical nuclei in the anterior hypothalamus, located just above the optic chiasm (where the main fibre tracts, or optic nerves, from the two eyes meet). It is therefore ideally situated to receive photic input from the retina through the retinohypothalamic tract, which follows these nerves.

SUBJECTIVE DAY AND SUBJECTIVE NIGHT

The time during which an organism is normally active is referred to as the subjective day. The subjective night describes the period during which an organism is normally inactive and in which its sleep normally occurs. Therefore, a nocturnal animal's subjective day occurs during the astronomical night.

CIRCADIAN TIME

A 24-h period divided into a 12-h activity phase and a 12-h rest phase. In diurnal animals, such as humans, circadian time (CT) 0 designates the start of the activity phase and CT 12 designates the beginning on the rest phase. In nocturnal animals, such as the rat, CT 12 is at the beginning of the activity phase and CT 0 is at the start of the rest phase.

TETRODOTOXIN

A potent marine neurotoxin that blocks voltage-gated sodium channels. Tetrodotoxin was originally isolated from the tetraodon pufferfish, and contains a positively charged guanidinium group and a pyrimidine ring.

LOCUS COERULEUS

A nucleus of the brainstem that is the main supplier of noradrenaline to the brain.

DORSAL RAPHE NUCLEUS

A nucleus of the brainstem that comprises a large cluster of serotonin-containing neurons. An important supplier of serotonin to the forebrain and to other brainstem nuclei.

ULTRADIAN RHYTHMS

Biological rhythms that have a periodicity of less than 24 h, such as the approximately 90-min REM–NREM cycle of the adult human.

TONIC

Physiological events that occur in a sustained manner, unlike phasic events, which occur only transiently with intervening periods of inactivity.

THETA RHYTHM

Rhythmic neural activity with a frequency of 4–8 Hz.

SOMNOGEN

An agent that promotes sleep. Endogenous somnogens accumulate during prolonged waking, tending to produce sleep despite opposing pressures of the circadian cycle. Putative somnogens include adenosine, cytokines, hormones, melatonin, oleomide and prostaglandins

DELTA RHYTHM

Rhythmic neural activity with a frequency of 1–4 Hz that is characteristic of stage III and IV NREM sleep (also known as slow-wave sleep).

SPINDLE RHYTHM

Phasic episodes of 12–14-Hz neural activity that are characteristic of stage II NREM sleep, having a waxing and waning, spindle-like morphology.

ELECTROCULOGRAPHY

The polysomnographic measurement of eye movement by electrodes mounted adjacent to each eye, which detect the electrical dipole produced by the retina.

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Pace-Schott, E., Hobson, J. The Neurobiology of Sleep: Genetics, cellular physiology and subcortical networks. Nat Rev Neurosci 3, 591–605 (2002). https://doi.org/10.1038/nrn895

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