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 activ