Sleep onset

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

Contents

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 were found to reside in the exact place that Constantin von Economo stated. [1]

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). [2]

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. 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. This refers to the ascending reticular activating system (cf reticular formation). The cell group involved in the first pathway is an acetylcholine-producing cell group called pedunculopontine and laterodorsal tegmental 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 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. [1] [3] [4] [5]

Lesions

Some light was thrown on the mechanisms on sleep onset by the discovery that lesions in the preoptic area and anterior hypothalamus lead to insomnia while those in the posterior hypothalamus lead to sleepiness. [6] [7] 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. [8]

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, two known inhibitory neurotransmitters, to arousal-promoting neurons, such as histaminergic, serotonergic, orexinergic, noradrenergic, and cholinergic neurons (neurons mentioned above). Levels of acetylcholine, norepinephrine, serotonin, and histamine decrease with the onset of sleep, for they are all wakefulness promoting neurotransmitters. [2] 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. [1] [3] [4] [5]

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. [2]

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. [9] 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. [10] 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. [11]

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. [2]

See also

Related Research Articles

<span class="mw-page-title-main">Neurotransmitter</span> Chemical substance that enables neurotransmission

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

<span class="mw-page-title-main">Hypothalamus</span> Area of the brain below the thalamus

The hypothalamus is a small part of the vertebrate brain that contains a number of 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 is located below the thalamus and is part of the limbic system. It forms the basal part of the diencephalon. All vertebrate brains contain a hypothalamus. In humans, it is about the size of an almond.

<span class="mw-page-title-main">Orexin</span> Neuropeptide that regulates arousal, wakefulness, and appetite.

Orexin, also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone, is caused by a lack of orexin in the brain due to destruction of the cells that produce it.

<span class="mw-page-title-main">Arousal</span> State of being awoken

Arousal is the physiological and psychological state of being awoken or of sense organs stimulated to a point of perception. It involves activation of the ascending reticular activating system (ARAS) in the brain, which mediates wakefulness, the autonomic nervous system, and the endocrine system, leading to increased heart rate and blood pressure and a condition of sensory alertness, desire, mobility, and reactivity.

<span class="mw-page-title-main">Nucleus accumbens</span> Region of the basal forebrain

The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.

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<span class="mw-page-title-main">Arcuate nucleus</span>

The arcuate nucleus of the hypothalamus (ARH), or ARC, is also known as the infundibular nucleus to distinguish it from the arcuate nucleus of the medulla oblongata in the brainstem. The arcuate nucleus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several important and diverse populations of neurons that help mediate different neuroendocrine and physiological functions, including neuroendocrine neurons, centrally projecting neurons, and astrocytes. The populations of neurons found in the arcuate nucleus are based on the hormones they secrete or interact with and are responsible for hypothalamic function, such as regulating hormones released from the pituitary gland or secreting their own hormones. Neurons in this region are also responsible for integrating information and providing inputs to other nuclei in the hypothalamus or inputs to areas outside this region of the brain. These neurons, generated from the ventral part of the periventricular epithelium during embryonic development, locate dorsally in the hypothalamus, becoming part of the ventromedial hypothalamic region. The function of the arcuate nucleus relies on its diversity of neurons, but its central role is involved in homeostasis. The arcuate nucleus provides many physiological roles involved in feeding, metabolism, fertility, and cardiovascular regulation.

<span class="mw-page-title-main">Reticular formation</span> Spinal trigeminal nucleus

The reticular formation is a set of interconnected nuclei that are located in the brainstem, hypothalamus, and other regions. It is not anatomically well defined, because it includes neurons located in different parts of the brain. The neurons of the reticular formation make up a complex set of networks in the core of the brainstem that extend from the upper part of the midbrain to the lower part of the medulla oblongata. The reticular formation includes ascending pathways to the cortex in the ascending reticular activating system (ARAS) and descending pathways to the spinal cord via the reticulospinal tracts.

<span class="mw-page-title-main">Ventrolateral preoptic nucleus</span> Nucleus of the anterior hypothalamus

The ventrolateral preoptic nucleus (VLPO), also known as the intermediate nucleus of the preoptic area (IPA), is a small cluster of neurons situated in the anterior hypothalamus, sitting just above and to the side of the optic chiasm in the brain of humans and other animals. The brain's sleep-promoting nuclei, together with the ascending arousal system which includes components in the brainstem, hypothalamus and basal forebrain, are the interconnected neural systems which control states of arousal, sleep, and transitions between these two states. The VLPO is active during sleep, particularly during non-rapid eye movement sleep, and releases inhibitory neurotransmitters, mainly GABA and galanin, which inhibit neurons of the ascending arousal system that are involved in wakefulness and arousal. The VLPO is in turn innervated by neurons from several components of the ascending arousal system. The VLPO is activated by the endogenous sleep-promoting substances adenosine and prostaglandin D2. The VLPO is inhibited during wakefulness by the arousal-inducing neurotransmitters norepinephrine and acetylcholine. The role of the VLPO in sleep and wakefulness, and its association with sleep disorders – particularly insomnia and narcolepsy – is a growing area of neuroscience research.

<span class="mw-page-title-main">Slow-wave sleep</span> Period of sleep in humans and other animals

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Melanin-concentrating hormone (MCH), also known as pro-melanin stimulating hormone (PMCH), is a cyclic 19-amino acid orexigenic hypothalamic peptide originally isolated from the pituitary gland of teleost fish, where it controls skin pigmentation. In mammals it is involved in the regulation of feeding behavior, mood, sleep-wake cycle and energy balance.

The zona incerta (ZI) is a horizontally elongated region of gray matter in the subthalamus below the thalamus. Its connections project extensively over the brain from the cerebral cortex down into the spinal cord.

<span class="mw-page-title-main">Galanin</span>

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<span class="mw-page-title-main">Dorsomedial hypothalamic nucleus</span>

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<span class="mw-page-title-main">Lateral hypothalamus</span>

The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognitive and physical processes, such as promoting feeding behavior and arousal, reducing pain perception, and regulating body temperature, digestive functions, and blood pressure, among many others. Clinically significant disorders that involve dysfunctions of the orexinergic projection system include narcolepsy, motility disorders or functional gastrointestinal disorders involving visceral hypersensitivity, and eating disorders.

<span class="mw-page-title-main">Median preoptic nucleus</span> Nucleus in the anterior hypothalamus

The median preoptic nucleus is located dorsal to the other three nuclei of the preoptic area of the anterior hypothalamus. The hypothalamus is located just beneath the thalamus, the main sensory relay station of the nervous system, and is considered part of the limbic system, which also includes structures such as the hippocampus and the amygdala. The hypothalamus is highly involved in maintaining homeostasis of the body, and the median preoptic nucleus is no exception, contributing to regulation of blood composition, body temperature, and non-REM sleep.

Ponto-geniculo-occipital waves or PGO waves are distinctive wave forms of propagating activity between three key brain regions: the pons, lateral geniculate nucleus, and occipital lobe; specifically, they are phasic field potentials. These waves can be recorded from any of these three structures during and immediately before REM sleep. The waves begin as electrical pulses from the pons, then move to the lateral geniculate nucleus residing in the thalamus, and end in the primary visual cortex of the occipital lobe. The appearances of these waves are most prominent in the period right before REM sleep, albeit they have been recorded during wakefulness as well. They are theorized to be intricately involved with eye movement of both wake and sleep cycles in many different animals.

<span class="mw-page-title-main">Neuroscience of sleep</span> Study of the neuroscientific and physiological basis of the nature of sleep

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<span class="mw-page-title-main">Parabrachial nuclei</span>

The parabrachial nuclei, also known as the parabrachial complex, are a group of nuclei in the dorsolateral pons that surrounds the superior cerebellar peduncle as it enters the brainstem from the cerebellum. They are named from the Latin term for the superior cerebellar peduncle, the brachium conjunctivum. In the human brain, the expansion of the superior cerebellar peduncle expands the parabrachial nuclei, which form a thin strip of grey matter over most of the peduncle. The parabrachial nuclei are typically divided along the lines suggested by Baxter and Olszewski in humans, into a medial parabrachial nucleus and lateral parabrachial nucleus. These have in turn been subdivided into a dozen subnuclei: the superior, dorsal, ventral, internal, external and extreme lateral subnuclei; the lateral crescent and subparabrachial nucleus along the ventrolateral margin of the lateral parabrachial complex; and the medial and external medial subnuclei

The parafacial zone (PZ) is a brain structure located in the brainstem within the medulla oblongata believed to be heavily responsible for non-rapid eye movement (non-REM) sleep regulation, specifically for inducing slow-wave sleep.

References

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  6. ↑ Sallanon M, Denoyer M, Kitahama K, Aubert C, Gay N, Jouvet M (1989). "Long-lasting insomnia induced by preoptic neuron lesions and its transient reversal by muscimol injection into the posterior hypothalamus in the cat". Neuroscience. 32 (3): 669–83. doi:10.1016/0306-4522(89)90289-3. PMID   2601839.
  7. ↑ Swett CP, Hobson JA (September 1968). "The effects of posterior hypothalamic lesions on behavioral and electrographic manifestations of sleep and waking in cats". Archives Italiennes de Biologie. 106 (3): 283–93. PMID   5724423.
  8. ↑ Saper CB, Chou TC, Scammell TE (December 2001). "The sleep switch: hypothalamic control of sleep and wakefulness". Trends in Neurosciences. 24 (12): 726–31. doi:10.1016/S0166-2236(00)02002-6. PMID   11718878.
  9. ↑ Takahashi, K; JS Lin; K Sakai (June 16, 2009). "Characterization and mapping of sleep-waking specific neurons in the basal forebrain and preoptic hypothalamus in mice". Neuroscience. 161 (1): 269–292. doi:10.1016/j.neuroscience.2009.02.075. PMID   19285545.
  10. ↑ Chou, TC; AA Bjorkum; SE Gaus; J Lu (2002). "Afferents to the Ventrolateral Preoptic Nucleus". The Journal of Neuroscience. 22 (3): 977–990. doi:10.1523/JNEUROSCI.22-03-00977.2002. PMC   6758527 . PMID   11826126.
  11. ↑ Saper, CB; TC Chou; TE Scammell (2001). "The sleep twitch: Hypothalamic control of sleep and wakefulness". Trends in Neurosciences. 24 (12): 726–731. doi:10.1016/s0166-2236(00)02002-6. PMID   11718878.
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