Sleep onset

Sleep onset is the transition from wakefulness into sleep. Sleep onset usually transmits into non-rapid eye movement sleep (NREM sleep) but under certain circumstances (e.g. narcolepsy) it is possible to transmit from wakefulness directly into rapid eye movement sleep (REM sleep).

History
During the 1920s an obscure disorder that caused encephalitis and attacked the part of the brain that regulates sleep influenced Europe and North America. Although the virus that caused this disorder was never identified, the psychiatrist and neurologist Constantin von Economo decided to study this disease and identified a key component in the sleep-wake regulation. He identified the pathways that regulated wakefulness and sleep onset by studying the parts of the brain that were affected by the disease and the consequences it had on the circadian rhythm. He stated that the pathways that regulated sleep onset are located between the brain stem and the basal forebrain. His discoveries were not appreciated until the last two decades of the 20th century when the pathways of sleep onset were found to reside in the exact place that Constantin von Economo stated.

Physiological overview
Von Economo, in his studies, noticed that lesions in the connection between the midbrain and the diencephalon caused prolonged sleepiness and therefore proposed the idea of an ascending arousal system. During the past few decades major ascending pathways have been discovered with located neurons and respective neurotransmitters. This pathway divides into two branches: one that ascends to the thalamus and activates the thalamus relay neurons, and another one that activates neurons in the lateral part of the hypothalamus and the basal forebrain, and throughout the cerebral cortex. The cell group involved in the first pathway is an acetylcholine-producing cell group called pedunculopontine and laterodorsal tegmental nucleus(PPT/LDT). These neurons play a crucial role in bridging information in between the thalamus and the cerebral cortex. These neurons have high activation during wakefulness and during REM sleep and a low activation during NREM sleep. The second branch originates from monoaminorgenic neurons. These neurons are located in the locus coeruleus, dorsal and median raphe nuclei, ventral periaqueductal grey matter, and tuberomammillary nucleus. Each group produces a different neurotransmitter. The neurons in the locus coeruleus produce noradrenaline, as fore the neurons in the dorsal and median raphe nuclei, ventral periaqueductal grey matter, and tuberomammillary nucleus produce serotonin, dopamine and histamine respectively. They then project onto the hypothalamic peptidergic neurons, which contain melanin-concentrated hormones or orexin, and basal forebrain neurons which contain GABA and acetylcholine. These neurons then project onto the cerebral cortex. It has also been discovered that lesions to this part of the brain cause prolonged sleep or may produce coma.

Sleep onset is induced by sleep-promoting neurons, located in the ventrolateral preoptic nucleus (VLPO). The sleep-promoting neurons are believed to project GABA type A and galanin, two known inhibitory neurotransmitters, to arousal-promoting neurons, such as histaminergic, serotonergic, orexinergic, noradrenergic, and cholinergic neurons (neurons mentioned above). Therefore it is believed that the activation of sleep-promoting neurons causes the inhibition of arousal-promoting neurons, which leads to sleep. Evidence has shown that during the sleep-wake cycle, sleep-promoting neurons and the arousal-promoting neurons have reciprocal discharges, and that during NREM sleep, GABA receptors increase in the arousal-promoting neurons. This had led some to believe that the increase of GABA receptors in the arousal-promoting neurons is another pathway of inducing sleep.

It is also known that the sleep-promoting neurons receive input from the neurons that they inhibit. For example it is known that the monoaminorgic system inhibits VLPO neurons through serotonin and noradrenaline. This suggests that the process of sleep onset is a feedback loop with circuits running in both directions. This is called a flip flop switch.