This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making.

Orexins/hypocretins are involved in mechanisms of emotional arousal and short-term regulation of feeding. The dense projection of orexin neurons from the lateral hypothalamus to mesocorticolimbic dopaminergic neurons in the ventral tegmental area (VTA) is likely to be important in both of these processes. We used single-unit extracellular and whole-cell patch-clamp recordings to examine the effects of orexins (A and B) and melanin-concentrating hormone (MCH) on neurons in this region. Orexins caused an increase in firing frequency (EC₅₀ 78 nm), burst firing, or no change in firing in different groups of A10 dopamine neurons. Neurons showing oscillatory firing in response to orexins had smaller afterhyperpolarizations than the other groups of dopamine neurons. Orexins (100 nm) also increased the firing frequency of nondopaminergic neurons in the VTA. In the presence of tetrodotoxin (0.5 μm), orexins depolarized both dopaminergic and nondopaminergic neurons, indicating a direct postsynaptic effect. Unlike the orexins, MCH did not affect the firing of either group of neurons. Single-cell PCR experiments showed that orexin receptors were expressed in both dopaminergic and nondopaminergic neurons and that the calcium binding protein calbindin was only expressed in neurons, which also expressed orexin receptors. In narcolepsy, in which the orexin system is disrupted, dysfunction of the orexin modulation of VTA neurons may be important in triggering attacks of cataplexy.

The hypothalamic orexin (hypocretin) neuropeptides are associated with the regulation of sleep and feeding, and disturbances in orexinergic neurotransmission lead to a narcoleptic phenotype. Histamine has also been shown to play a role in the regulation of sleep and feeding. Therefore, we studied the relationship between the orexin and histamine systems of the CNS using electrophysiology, immunocytochemistry, and the reverse transcriptase (RT)-PCR method. Both orexin-A and orexin-B depolarized the histaminergic tuberomammillary neurons and increased their firing rate via an action on postsynaptic receptors. The depolarization was associated with a small decrease in input resistance and was likely caused by activation of both the electrogenic Na⁺/Ca²⁺exchanger and a Ca²⁺ current. In a single-cell RT-PCR study using primers for the two orexin receptors, we found that most tuberomammillary neurons express both receptors and that the expression of the orexin-2 receptor is stronger than that of the orexin-1 receptor. Immunocytochemical studies show that the histamine and orexin neurons are often located very close to each other. The contacts between these two types of neurons seem to be reciprocal, because the orexin neurons are heavily innervated by histaminergic axons. These results suggest a functional connection between the two populations of hypothalamic neurons and that they may cooperate in the regulation of rapid-eye-movement sleep and feeding.

Significance: When we are awake, purposeful thinking and behavior require the synchronization of brain cells involved in different aspects of the same task. Cerebral cortex electrical oscillations in the gamma (30–80 Hz) range are particularly important in such synchronization. In this report we identify a particular subcortical cell type which has increased activity during waking and is involved in activating the cerebral cortex and generating gamma oscillations, enabling active cortical processing. Abnormalities of the brain mechanisms controlling gamma oscillations are involved in the disordered thinking typical of neuropsychiatric disorders such as schizophrenia. Thus, these findings may pave the way for targeted therapies to treat schizophrenia and other disorders involving abnormal cortical gamma oscillations.

During sleep, cortical and subcortical structures within the brain engage in highly structured oscillatory dynamics that can be observed in the electroencephalogram (EEG). The ability to accurately describe changes in sleep state from these oscillations has thus been a major goal of sleep medicine. While numerous studies over the past 50 years have shown sleep to be a continuous, multifocal, dynamic process, long-standing clinical practice categorizes sleep EEG into discrete stages through visual inspection of 30-s epochs. By representing sleep as a coarsely discretized progression of stages, vital neurophysiological information on the dynamic interplay between sleep and arousal is lost. However, by using principled time-frequency spectral analysis methods, the rich dynamics of the sleep EEG are immediately visible—elegantly depicted and quantified at time scales ranging from a full night down to individual microevents. In this paper, we review the neurophysiology of sleep through this lens of dynamic spectral analysis. We begin by reviewing spectral estimation techniques traditionally used in sleep EEG analysis and introduce multitaper spectral analysis, a method that makes EEG spectral estimates clearer and more accurate than traditional approaches. Through the lens of the multitaper spectrogram, we review the oscillations and mechanisms underlying the traditional sleep stages. In doing so, we will demonstrate how multitaper spectral analysis makes the oscillatory structure of traditional sleep states instantaneously visible, closely paralleling the traditional hypnogram, but with a richness of information that suggests novel insights into the neural mechanisms of sleep, as well as novel clinical and research applications.