What flips the brain's switch between waking and sleeping?

The leading picture is a switch. A small cluster of neurons in the hypothalamus called the ventrolateral preoptic nucleus (VLPO) is active during sleep and releases the inhibitory messengers GABA and galanin onto the brain's wakefulness-promoting arousal system. The arousal system, in turn, releases norepinephrine and acetylcholine, which inhibit the VLPO. A current theory proposes that the two form a "flip-flop" circuit, a term from electrical engineering: each part, as it turns on, turns the other off, which gives rapid transitions between wake and sleep with minimal time in between.

A second player is orexin, also called hypocretin, a neuropeptide produced by 50,000 to 80,000 neurons in the human lateral hypothalamus that project throughout the brain. Orexin neurons help stabilize the brain in the waking state.

You can see what happens without them in narcolepsy type 1, which is caused by a lack of orexin due to destruction of the cells that make it. The loss destabilizes the wake-sleep switch, resulting in overwhelming sleep episodes during the day and more frequent awakenings at night. Patients also have cataplexy, brief losses of muscle tone, often triggered by strong emotions.

The idea that one hypothalamic area promotes sleep is old. In the early 20th century, Constantin von Economo noticed that people with encephalitis and lesions in the front of the hypothalamus had insomnia, and proposed that this area promotes sleep.