Journal Article

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

Hobson, J. Allan, Pace-Schott, Edward F.

2002

Overview

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. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animal Genetics and Genomics / Animals / Arousal - genetics / Arousal - physiology / Behavioral Sciences / Biological Clocks - genetics / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Brain / Brain - cytology / Brain - physiology / Circadian rhythm / Circadian Rhythm - genetics / Cognition & reasoning / Eye movements / Genes / Humans / Hypothalamus / Kinases / Nerve Net - cytology / Nerve Net - physiology / Neural Pathways - cytology / Neural Pathways - physiology / Neurobiology / Neurophysiology / Neurosciences / Organisms / Physiology / Proteins / review-article / Sleep / Sleep - genetics / Sleep - physiology / Sleep, REM - genetics / Transcription factors