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). The second system regulating sleepiness is the homeostatic system, which responds to progressively longer wake periods by increasing the urge to sleep. In humans with narcolepsy, the orexin levels in the brain and spinal fluid are abnormally low.
In experiments with mice, in which the gene for the neurotransmitter orexin was experimentally removed, the animals became narcoleptic. Orexin activation plays a critical role in preventing abnormal transitions into REM sleep during the day, as occurs in narcolepsy. This arousal is mediated by orexin activation of norepinephrine neurons in the locus coeruleus. 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. Orexin provides an excitatory signal to the arousal system, particularly to the norepinephrine neurons. It is these neurons that directly regulate sleep and arousal.
The dorsomedial nucleus then contacts the ventrolateral preoptic nucleus and the orexin neurons in the lateral hypothalamus. 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 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. Researchers first identified these proteins and determined their important roles in sleep by studying the fruit fly Drosophila melanogaster. 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. 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. 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.