Circadian and homeostatic influences help regulate sleep and wakefulness over a 24-hour period. Sleep and wake states are produced by the interplay of centers in the brain stem, the hypothalamus, thalamus, and forebrain. Two mutually inhibitory groups of these centers, a wake-promoting group and a sleep-producing group, result in a flip-flop circuit that provides sleep-wake control. Wake-promoting neurocircuitry is under circadian control and is active during the day, while the sleep-producing effect is a homeostatic influence in which the drive to sleep increases the longer one is awake, and abates during sleep. When one system inhibits the other, the result is a switch between wakefulness and sleep. Clearly, external influences can affect this relationship; for example, a person may be able to stay awake all night to care for a sick person, when they would normally be asleep.
Wakefulness results from activity in brain stem and hypothalamic arousal centers (the “ascending reticular activating system” or ARAS) with neurons that project widely to the limbic system and cortex by two routes: a ventral (lower) route through the ventral forebrain and a dorsal (upper) route through the thalamus. These are active during wakefulness but inactive during sleep, especially during rapid eye movement (REM) sleep. In the cortex and other regions they produce excitatory effects and increase neuronal activity. This activation is responsible for electroencephalogram (EEG) desynchronization during wakefulness and REM sleep. (See Figure 1.3.)
Wake-promoting pathways use several types of neurotransmitters involving monoamines (serotonin [5-HT], dopamine [DA], norepinephrine [NE]), acetylcholine (ACh), and histamine clustered in various centers. These include the noradrenergic locus coeruleus, the serotonergic raphe nuclei, the dopaminergic nuclei of the periaqueductal gray and ventral tegmental area, the histaminergic tuberomammillary nucleus of the posterior hypothalamus, and cholinergic nuclei in the laterodorsal and pedunculopontine tegmentum (LDT/PPT) and basal forebrain. During wakefulness, the LDT/PPT neurons release ACh in the thalamus, enabling the thalamus to relay information to and from the cortex. Wake-promoting centers in the basal forebrain involving other ACh-producing neurons project directly to the cortex, exciting cortical neurons. The basal forebrain also contains GABA-producing neurons that create arousal by reducing activity in inhibitory neurons in the cortex, allowing increased cortical activity. (See Figures 1.4 and 1.5.)
Neurons producing orexins are another key element of the wake promoting system. Orexin-A and orexin-B are peptide neurotransmitters only produced by a small cluster of neurons in the lateral hypothalamus. These neurons project to each of the brain stem and hypothalamic arousal centers where they release orexins during the wake state. These act through the OX1 and OX2 receptors to increase activity in target monoaminergic and cholinergic neurons, and thereby promote wakefulness. The orexins produce long-lasting activation of these target neurons, and consequent long, sustained periods of wakefulness and suppression of sleep.
The orexin centers receive input from the suprachiasmatic nucleus (SCN) that provides the circadian regulation of sleep. The SCN, the body’s main biological circadian clock, is located in the hypothalamus immediately above the optic chiasm and receives input from the retina. It is genetically controlled to provide circadian rhythmicity for nearly every physiological system., , , While its direct connections with the orexin neurons in the lateral hypothalamus are sparse, the lateral hypothalamus does receive abundant input from regions (the stria terminalis, supraventricular zone, and dorsomedial hypothalamus) that do receive innervation directly from the SCN. These may mediate the circadian modulation of orexin neurons.
Figure 1.3: The neural circuit of orexin
Of note, in addition to regulating sleep and wake states, the orexin center is involved in other important regulatory systems. It is influenced by leptin, ghrelin, and glucose levels responsive to energy balance and appetite. It receives input from the amygdala and other limbic systems involved in emotions and orexin neurons also stimulate dopaminergic reward systems of the brain. Thus, orexin may provide an important mechanism for integrating the maintenance of sleep/wake states and alertness with other systems that regulate and respond to emotion, reward, and energy homeostasis.
Switching to Sleep
At the end of the day, the circadian waking signal drops, allowing the homeostatic sleep drive to become dominant (see Figure 1.6)., Sleep homeostasis refers to compensatory increases in sleep amount and intensity, including sleep consolidation, that occurs in response to a period of wakefulness. The homeostatic sleep drive (i.e., sleep need) is near zero when a person wakes up spontaneously in the morning, and increases continually the longer he or she is awake.
Our understanding of the mechanisms and neurophysiology involved in sleep homeostasis is incomplete. Somnogens are sleep-promoting neuroactive chemicals that accumulate during waking and increase the propensity and depth of sleep. Current hypotheses implicate adenosine, cytokines, prostaglandin D, muramyl dipeptides, and tumor necrosis factor-α as sleep promoters. Adenosine, perhaps the most studied, is a simple molecule that rises during wakefulness and falls during sleep in specific brain regions. (Caffeine promotes wakefulness by blocking adenosine receptors.) Less evidence is available on other somnogens, but some may promote sleep during inflammatory conditions. They may act by inhibiting wake promoting neurons or the cortex directly.
As the homeostatic drive increases, neurons in the median and ventrolateral preoptic (VLPO) areas of the anterior hypothalamus become more active. These neurons use the inhibitory neurotransmitters γ-aminobutyric acid (GABA) and galanin. GABA, the most widespread inhibitory neurotransmitter in the central nervous system, regulates sleep and other functions including balance, motor coordination and memory. Galanin is a neurotransmitter that is distributed throughout the brain; it is also involved in functions beyond sleep, including learning and memory. As normal sleep time approaches, the wake promoting circadian signaling decreases and the homeostatic drive becomes dominant. GABA and galanin inhibit all wake-promoting areas in the lateral hypothalamus, posterior hypothalamus, and brain stem arousal centers, leading to the onset of sleep.
During sleep, GABAergic neurons in the hypothalamus inhibit all the wake-promoting brain regions ensuring that all arousal systems are inhibited in a coordinated fashion. Rapid eye movement (REM) sleep and the time of spontaneous awakening from sleep are primarily circadian-driven processes, while slow-wave sleep (SWS, the 3rd stage of NREM sleep) is closely related to the homeostatic sleep drive (i.e., the more sleep deprivation a person experiences, the more SWS happens the next night).
Throughout the brain, most neurons are quiet during NREM sleep, but VLPO neurons remain active, and their activity helps shut down the activity of the wake-promoting systems. During NREM sleep, the decreased activity of cholinergic neurons in LDT/PPT results in less signaling through the thalamus to the cortex. In REM sleep, a subset of cholinergic neurons in the LDT/PPT become active and help produce thalamic and cortical activation. These neurons also trigger a descending pathway that runs through the sublaterodorsal nucleus in the brainstem and down to motor neurons in the spinal cord. This produces the paralysis of REM sleep. REM-promoting circuits are strongly inhibited by the monoamine neurotransmitters, which are released only during wakefulness. , , , , , , , , ,
Figure 1.4: Hypothalamic and brainstem sleep-wake regulation system
ARAS: Ascending reticular activating system
SCN: Suprachiasmatic nucleus
S/W: Sleep- and wake-promoting neurons
Figure 1.5: Arousal pathways maintaining cortical activation in the waking state
A10: ventral tegmental area
BF: basal forebrain cholinergic nuclei
CR: caudal raphe
DR: serotoninergic dorsal raphe
LC: adrenergic locus coeruleus
LDT/PPT: laterodorsal tegmental nuclei/pedunculopontine tegmental nuclei
PRF: pontine reticular formation
TMN: histaminergic tuberomammillary nucleus
VLPO: ventrolateral preoptic area.
Figure 1.6: Sleep-wake cycle: the role of circadian regulation
The circadian rhythm typically emerges two to six months after birth and is entrained by light to Earth’s daily rotation (i.e., adjusted to a 24-hour cycle). The circadian rhythm of people who are “early birds” may be less than 24 hours (i.e., when the external clock is 9:00 PM, an early bird’s internal body time may already be later, like 12:00 AM), while the rhythm of “night owls” rhythm may run longer (i.e., when the external clock is 9:00 PM, a night owl’s internal body time may be earlier, like 5:00 PM).
This rhythm seems to vary over the life cycle: adolescents and young adults are typically night owls, while older people are typically early birds.
Without time cues, individuals maintain a free-running biological rhythm that is usually just slightly longer than 24 hours, although this can vary.
Figure 1.7 (below) shows a 55-day recording of sleep-wake cycles in a normal volunteer. For the first 20 days, the volunteer had a watch and was instructed to go to bed at 12:00 AM and wake up at 8:00 AM. The following 35 days of the study occurred in an environment without any time cues, in which the volunteer turned the light on or off as desired. Over time, the volunteer developed a free-running cycle of 25.3 hours. Thus, over the 35 days, the onset of sleep gradually advanced by a total of 36-37 hours. (Blind people, who lack light clues, have a free-running 25-hour cycle, which causes them unique sleep/wake problems.)
Figure 1.7: Human sleep-wake cycle in a temporal isolation environment
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