Sleep onset is the transition from wakefulness into sleep. Sleep onset usually transmits into

non-rapid eye movement sleep Non-rapid eye movement sleep (NREM), also known as quiescent sleep, is, collectively, sleep stages 1–3, previously known as stages 1–4. Rapid eye movement sleep (REM) is not included. There are distinct electroencephalographic and other cha ...

(NREM sleep) but under certain circumstances (e.g.

narcolepsy Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affect ...

) it is possible to transit from wakefulness directly into

rapid eye movement sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the sleeper to dream ...

(REM sleep).

History

During the 1920s an obscure disorder that caused

encephalitis Encephalitis is inflammation of the brain. The severity can be variable with symptoms including reduction or alteration in consciousness, headache, fever, confusion, a stiff neck, and vomiting. Complications may include seizures, hallucinations ...

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 Constantin Freiherr von Economo ( gr, Κωνσταντίνος Οικονόμου; 21 August 1876 – 21 October 1931) was an Austrian psychiatrist and neurologist of Greek descent, born in modern-day Romania (then Ottoman Empire). He is mos ...

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 A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...

. He stated that the pathways that regulated sleep onset are located between the brain stem and the

basal forebrain Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal b ...

. His discoveries were not appreciated until the last two decades of the 20th century when the pathways of sleep were found to reside in the exact place that Constantin von Economo stated.

Neural circuit

Sleep electrophysiological measurements can be made by attaching electrodes to the scalp to measure the electroencephalogram (EEG) and to the chin to monitor muscle activity, recorded as the electromyogram (EMG). Electrodes attached around the eyes monitor eye movements, recorded as the electro-oculogram (EOG).

Pathways

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 A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neurot ...

. 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 The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...

and the

, and throughout the

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting o ...

. This refers to the ascending reticular activating system (cf

reticular formation The reticular formation is a set of interconnected nuclei that are located throughout the brainstem. It is not anatomically well defined, because it includes neurons located in different parts of the brain. The neurons of the reticular formatio ...

). The cell group involved in the first pathway is an

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

-producing cell group called pedunculopontine and

laterodorsal tegmental nucleus The laterodorsal tegmental nucleus (or lateroposterior tegmental nucleus) is a nucleus situated in the brainstem, spanning the midbrain tegmentum and the pontine tegmentum. Its location is one-third of the way from the pedunculopontine nucleus ...

. 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 Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the sleeper to dream ...

and a low activation during

NREM sleep Non-rapid eye movement sleep (NREM), also known as quiescent sleep, is, collectively, sleep stages 1–3, previously known as stages 1–4. Rapid eye movement sleep (REM) is not included. There are distinct electroencephalographic and other cha ...

. The second branch originates from monoaminorgenic neurons. These neurons are located in the

locus coeruleus The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system. The locus coer ...

, dorsal and median raphe nuclei, ventral periaqueductal grey matter, and

tuberomammillary nucleus The tuberomammillary nucleus (TMN) is a histaminergic nucleus located within the posterior third of the hypothalamus. It consists of, largely, histaminergic neurons (i.e., histamine-releasing neurons) and is involved with the control of arousal, l ...

. Each group produces a different neurotransmitter. The neurons in the

produce

noradrenaline Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...

, as fore the neurons in the dorsal and median raphe nuclei, ventral periaqueductal grey matter, and

produce serotonin, dopamine and histamine respectively. They then project onto the hypothalamic peptidergic neurons, which contain melanin-concentrated hormones or

orexin Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy) ...

, and basal forebrain neurons which contain GABA and

. These neurons then project onto the

. It has also been discovered that lesions to this part of the brain cause prolonged sleep or may produce coma.

Lesions

Some light was thrown on the mechanisms on sleep onset by the discovery that lesions in the

preoptic area The preoptic area is a region of the hypothalamus. MeSH classifies it as part of the anterior hypothalamus. TA lists four nuclei in this region, (medial, median, lateral, and periventricular). Functions The preoptic area is responsible for ther ...

and anterior

lead to

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

while those in the posterior hypothalamus lead to sleepiness. Further research has shown that the hypothalamic region called ventrolateral preoptic nucleus produces the inhibitory neurotransmitter GABA that inhibits the arousal system during sleep onset.

Direct mechanism

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 Galanin is a neuropeptide encoded by the ''GAL'' gene, that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors. Much of galanin's function ...

, two known inhibitory neurotransmitters, to arousal-promoting neurons, such as histaminergic, serotonergic, orexinergic, noradrenergic, and cholinergic neurons (neurons mentioned above). Levels of acetylcholine, norepinepherine, serotonin, and histamine decrease with the onset of sleep, for they are all wakefulness promoting neurotransmitters. 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

, 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. Adenosine is also known as the sleep promoting nucleoside neuromodulator. Astrocytes maintain a small stock of nutrients in the form of glycogen. In times of increased brain activity, such as during daytime, this glycogen is converted into fuel for neurons; thus, prolonged wakefulness causes a decrease in the level of glycogen in the brain. A fall in the level of glycogen causes an increase in the level of extracellular adenosine, which has an inhibitory effect in neural activity. This accumulation of adenosine serves as a sleep-promoting substance. The majority of sleep neurons are located in the ventrolateral preoptic area (vlPOA). These sleep neurons are silent until an individual shows a transition from waking to sleep. The sleep neurons in the preoptic area receive inhibitory inputs from some of the same regions they inhibit, including the tubermammillary nucleus, raphe nuclei, and locus coeruleus. Thus, they are inhibited by histamine, serotonin, and norepinepherine. This mutual inhibition may provide the basis for establishing periods of sleep and waking. A reciprocal inhibition also characterizes an electronic circuit known as the flip-flop. A flip-flop can assume one of two states, usually referred to as on or off. Thus, either the sleep neurons are active and inhibit the wakefulness neurons, or the wakefulness neurons are active and inhibit the sleep neurons, Because these regions are mutually inhibitory, it is impossible for neurons in both sets of regions to be active at the same time. This flip-flop, switching from one state to another quickly, can be unstable.

Stage 1

The sleep cycle is normally defined in stages. When an individual first begins to sleep, stage 1 is entered, marked by the presence of some theta activity, which indicates that the firing of neurons in the neocortex is becoming more synchronized, as well as alpha wave activity (smooth electrical activity of 8–12 Hz recorded from the brain, generally associated with a state of relaxation). This stage is a transition between sleep and wakefulness. This stage is classified as non-REM sleep.