The Neurobiology of Sleep and Wakefulness

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Key points

  • The monoaminergic systems of the brainstem, the cholinergic neuronal groups found in the brainstem and basal forebrain and the hypocretin/orexin cells of the hypothalamus are critical for the maintenance of wakefulness.

  • Sleep is regulated by GABAergic populations in both the preoptic area and the brainstem; increasing evidence suggests a role for the melanin-concentrating hormone cells of the lateral hypothalamus and the parafacial zone of the brainstem.

  • The pons has historically been viewed as

Cortical activity during sleep and wakefulness

The electrical activity of the cerebral cortex has been used to distinguish sleep versus wakefulness since the earliest electroencephalogram (EEG) studies of sleep.1 The firing rate of cortical neurons generally declines during non–rapid eye movement (NREM) sleep relative to wakefulness and rapid eye movement (REM) sleep,2, 3 although a few studies have reported cortical neurons with the opposite firing pattern.4, 5 EEG activity reflects the aggregate firing of large neuronal ensembles and is

Classic Brainstem Transection Studies

The first investigations relevant to the neurobiology of sleep and wakefulness were conducted in the 1930s. Bremer10 transected the cat brainstem, observing that sleep/wake cycles remained intact after a low medullary level transection (encephale isolé), whereas transection between the pons and midbrain (cerveau isolé) yielded chronic drowsiness. Conversely, electrical stimulation of the midbrain reticular formation caused alerting of the cortex.11 From these observations arose the concept that

Discovery of the Hypocretins and the Orexins

Hypocretins 1 and 2 (Hcrt1 and Hcrt2), also known as orexins A and B, are excitatory hypothalamic neuropeptides that were independently described by 2 groups in 1998.89, 90 Since Sakurai and colleagues91 confirmed the common identity of the Hcrts and the orexins, the authors use the term Hcrt here to refer to this system. Although early studies emphasized the role of the Hcrt system in feeding and energy balance, subsequent research focused on sleep-wake regulation based, in part, on the

Sleep homeostasis and the timing of sleep and wakefulness

Common knowledge, as well as scientific observations, suggests that sleep is a homeostatically regulated physiologic response. The longer one is awake, the more likely one is to sleep or, at least, be sleepy. Sleep deprivation impairs cognition; prolonged sleep deprivation results in impaired physiologic function, ultimately resulting in death.184 This homeostatic property has been incorporated into the 2-process model of sleep regulation,185, 186 which posits that the homeostatic sleep-related

The Suprachiasmatic Nuclei as the Basis for Process C

The hypothalamic suprachiasmatic nuclei (SCN) contain a master circadian pacemaker (or biological clock) in mammals189, 190, 191, 192 and are commonly recognized as the source of process C.193, 194, 195 However, it remains unclear how SCN activity temporally organizes daily sleep-wake rhythms. Early studies relied on SCN lesions to functionally dissect circadian versus homeostatic regulation. The homeostatic response to sleep loss was intact in SCN-lesioned rats with no change in total sleep

Other neurochemicals involved in sleep/wake control

Although functional neuroanatomical approaches, especially when combined with electrophysiology, have led to many fundamental insights into the control of sleep and waking, there is an equally impressive literature on sleep substances and their contributions to behavioral state. These sparks versus soup approaches are highly complementary, and valuable insights into the control of sleep and wakefulness have arisen from both approaches.

Summary

Sleep is a regulated physiologic state with clear implications for cognition, performance, and overall well-being. Although beyond the scope of this review, numerous sleep disorders have been described that negatively impact these functions. Sleep disturbances are also common to a number of psychiatric disorders. The neural substrates of sleep and wakefulness form a highly distributed and, to some extent, redundant network, with hypocretin, monoaminergic and cholinergic systems largely

Acknowledgments

The authors thank Drs Sarah Wurts Black, Stephen Morairty, and Gregory Parks for valuable comments on the article.

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  • Cited by (0)

    This work was supported by NIH R01 HL059658, R01 NS077408, R21 NS087550, R01 NS082876, R21 NS083639 and R21 NS085757.

    Disclosures: Within the last 12 months, Dr T.S. Kilduff has received research support from F. Hoffmann La-Roche and received honoraria from Merck Pharmaceuticals and Pfizer.

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