The Sleep-Wakefulness Cycle

Why do we get sleepy? There are two main determining factors: the circadian system (time of day or night) and how long we have been awake.

The circadian timing system is regulated by the suprachiasmatic nucleus, a small group of nerve cells in the hypothalamus that acts as a master clock. These cells express clock proteins, which go through a biochemical cycle of about 24 hours, setting the pace for daily cycles of activity, sleep, hormone release, and other bodily functions.

Researchers first identified these proteins and determined their important roles in sleep by studying the fruit fly Drosophila melanogaster. The suprachiasmatic nucleus also receives input directly from the retina, and the clock can be reset by light so that it remains linked to the outside world’s day-night cycle. In addition, the suprachiasmatic nucleus provides signals to an adjacent brain area, called the subparaventricular nucleus, which in turn contacts the dorsomedial nucleus of the hypothalamus. The dorsomedial nucleus then contacts the ventrolateral preoptic nucleus and the orexin neurons in the lateral hypothalamus. It is these neurons that directly regulate sleep and arousal.

Orexin provides an excitatory signal to the arousal system, particularly to the norepinephrine neurons. Indeed, recent work using selective stimulation of orexin neurons by artificially inserted receptors sensitive to fiberoptic light pulses — a process referred to as optogenetic stimulation — produces arousal. This arousal is mediated by orexin activation of norepinephrine neurons in the locus coeruleus. Orexin activation plays a critical role in preventing abnormal transitions into REM sleep during the day, as occurs in narcolepsy. In experiments with mice, in which the gene for the neurotransmitter orexin was experimentally removed, the animals became narcoleptic. In humans with narcolepsy, the orexin levels in the brain and spinal fluid are abnormally low.

The second system regulating sleepiness is the homeostatic system, which responds to progressively longer wake periods by increasing the urge to sleep. The subjective sense of the increasing need to sleep coinciding with increasing wakefulness suggests that there might be a brain physiological parallel; that is, the longer a person is awake, the greater the likelihood of an increase in sleep-inducing factor(s). Evidence now suggests that one important sleep factor is the inhibitory neurochemical adenosine. With prolonged wakefulness, increasing levels of adenosine are evident in the brain, initially in the basal forebrain and then throughout the cortex. The increased levels of adenosine serve the purpose of slowing down cellular activity and diminishing arousal. Adenosine levels then decrease during sleep.

These studies of adenosine prompted examination of the compound adenosine triphosphate (ATP), the cellular energy source that powers nerve cells in the brain. Brain adenosine may be produced by ATP breakdown in the course of the high brain activity that takes place during wakefulness. Since nerve cell activity decreases and adenosine levels decline in non-REM sleep, the logical assumption is that ATP increases during sleep. Indeed, studies in animals found that brain ATP levels soared during the initial hours of non-REM sleep. Because ATP is needed to produce adenosine, which is essential for wakefulness, it makes sense that ATP is produced during sleep. This finding also supports the commonly held notion that sleep is necessary for providing restorative energy.