Control of Sleep and Wakefulness in Health and Disease - Progress in Molecular Biology and Translational Science - page 144

Under normal circumstances, hypocretin release is elevated during
wake 39,40 and has been hypothesized to be critical in the consolidation of
sleep and wake into single, daily episodes 41 as well as suppression of motor
activity during REMS. 42 Hypocretin is likely involved in the consolidation
of sleep and wake in humans. This consolidation process has been modeled
as the interaction of two distinct, but highly interactive systems—the circa-
dian clock and the sleep/wake homeostat. 43,44 The circadian clock, located
in the SCN (see Chapter 1 ), is a near 24-h oscillator that can be entrained
(synchronized) with the geophysical day. The circadian clock is considered a
predictive mechanism as it modifies endogenous physiology in advance of
changes actually occurring. The human circadian clock has been modeled
as providing two distinct controls of sleep and wake consolidation—a
wake-promoting signal that increases throughout the normal waking day,
peaking just before habitual bedtime, and a sleep-promoting signal that
increases throughout the normal time of the sleep, peaking just before habit-
ual waketime. 44 Hypocretin signaling has been proposed to be a neurolog-
ical correlate of the circadian wake drive, though this remains to be
proven. 40 This circadian drive for sleep and wake interacts with the homeo-
static drive for sleep and wake. Homeostasis, a term popularized by Walter
Cannon in the 1930s, refers to a system that tends toward equilibrium. 45 In
essence, the longer you stay awake, the more tired you get and the longer
you sleep, the less tired you become. It has been hypothesized that extracel-
lular adenosine may be the neurological correlate of the homeostatic drive
for sleep. As wake progresses in duration, the rate of release of adenosine by
neurons in the basal forebrain increases, resulting in elevations of extracel-
lular adenosine. 46 This rate of release of adenosine may be secondary to cel-
lular metabolism of adenosine triphosphate (ATP) or may be specifically
stimulated by prostaglandin D2 (PGD2) via the DP1 receptor. 47 PGD2 is
a naturally occurring somnogenic agent that is produced in the brain by
the meninges and choroid plexus. 47 PGD2 production is also increased in
response to inflammatory stimuli and may be part of the cellular link
between inflammatory processes and the increase in sleepiness that often
accompanies such. 48
Concentrations of adenosine in the basal forebrain rapidly decrease dur-
ing sleep. 46 This extracellular adenosine is hypothesized to inhibit basal fore-
brain cholinergic neurons, decreasing cerebral cholinergic tone, and
decreasing wakefulness. 49 It is likely that this modulation of adenosine is tis-
sue specific as other areas of cortical and subcortical tissue, both in rodent
models and in humans, show little if any increase with increased time