Serotonin's Role In Rem Sleep: A Complex Relationship

Serotonin, also known as 5-HT, is a neurotransmitter that plays a role in regulating sleep. It is produced by serotonergic neurons in the dorsal raphe nuclei and the pons varolii of the brainstem. During wakefulness, these neurons are highly active, but their activity decreases during slow-wave sleep and ceases entirely during REM sleep. This suggests that serotonin promotes wakefulness and inhibits REM sleep.

The role of serotonin in sleep has been studied through various methods, including pharmacological manipulation, electrophysiology, neuroimaging, and genetic approaches. These studies have provided insights into how serotonin affects sleep architecture and the underlying neural mechanisms.

Pharmacological studies have shown that selective serotonin reuptake inhibitors (SSRIs) can induce or exacerbate REM sleep without atonia, a phenomenon associated with REM sleep behavior disorder. Additionally, SSRIs have been linked to an increased risk of developing REM sleep behavior disorder, particularly in older individuals.

Electrophysiological recordings have revealed that serotonergic neurons in the dorsal raphe nuclei exhibit distinct firing patterns during different sleep stages. These neurons are most active during wakefulness, decrease their firing during slow-wave sleep, and become silent during REM sleep.

Neuroimaging techniques, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), have been used to visualize serotonin transporter availability in the brain. These studies suggest that alterations in serotonin transporter availability may play a role in sleep disorders, although the results have been inconclusive.

Genetic approaches, such as gene knockout studies, have provided further insights into the role of serotonin in sleep regulation. For example, mice lacking the gene for tryptophan hydroxylase-2, an enzyme involved in serotonin synthesis, exhibit altered sleep patterns, including increased wakefulness during the night and reduced slow-wave sleep.

In summary, serotonin is a key neuromodulator that influences sleep and wakefulness. While it promotes wakefulness and inhibits REM sleep, the underlying mechanisms are complex and involve interactions with other neurotransmitter systems and brain regions. Further research is needed to fully understand the role of serotonin in sleep regulation and its potential as a therapeutic target for sleep disorders.

Serotonin promotes wakefulness and inhibits REM sleep

The role of serotonin transmission in the regulation of wakefulness and sleep was first identified by the work of Michel Jouvet and his laboratory in Lyon, France. In these experiments, intracerebral administration of serotonin, or electro-stimulation of the DRN or the median raphe nucleus (MnRN), where most

Serotonin is a true neuromodulator of sleep

Serotonin, also known as 5-HT, is a neurotransmitter that plays a crucial role in regulating sleep and wakefulness. The understanding of its function has evolved over time, with early studies suggesting that serotonin promoted sleep, while more recent evidence indicates that it primarily promotes wakefulness and inhibits REM sleep.

The Honeymoon Phase: Serotonin as a Sleep Promoter

During the 1960s and early 1970s, Michel Jouvet and his team conducted experiments on cats, demonstrating that serotonin injection or electrical stimulation of the dorsal raphe nuclei (DRN) induced sleep. Conversely, reducing serotonin levels through inhibition of synthesis or destruction of DRN neurons resulted in severe insomnia. These findings led to the "serotoninergic hypothesis of sleep," proposing serotonin as the primary sleep neurotransmitter.

The Divorce: Serotonin as a Wakefulness Promoter and REM Sleep Inhibitor

However, subsequent research revealed a more complex role for serotonin. It was discovered that serotonin neurons in the DRN were most active during wakefulness and progressively slowed their activity during the transition to sleep, becoming silent during REM sleep. This finding contradicted the idea that serotonin promoted sleep. Instead, it suggested that serotonin played a role in maintaining calm wakefulness and inhibiting REM sleep.

Further studies using systemic or intraventricular administration of serotonin receptor agonists supported the idea of serotonin as a wakefulness promoter. These agonists stimulated wakefulness and suppressed both NREM and REM sleep. Additionally, selective serotonin reuptake inhibitors (SSRIs) are known to induce or exacerbate REM sleep without atonia, providing further evidence for serotonin's role in inhibiting REM sleep.

The Reconciliation: Serotonin's Diachronistic Role in Sleep

While serotonin release during wakefulness contradicted its role as a sleep promoter, a possible "diachronistic" relationship was proposed. According to the homeostatic regulation of sleep, there is a correlation between the duration of prior wakefulness and the intensity of subsequent sleep. It was hypothesized that serotonin neurons, by firing regularly during wakefulness, might participate in this process by measuring the duration and intensity of waking.

Additionally, the preoptic area, which is involved in sleep mechanisms, was identified as a potential postsynaptic target for serotonin. Microinjections of serotonin or its precursor into this area restored sleep in insomniac cats, suggesting a role for serotonin in sleep onset.

Serotonin's Role in Depression and Sleep Disorders

The link between serotonin and sleep is further highlighted by its involvement in depression and sleep disorders. Lowered levels of serotonin in the brain have been associated with depression, and selective serotonin reuptake inhibitors (SSRIs) are commonly used as antidepressants. Additionally, sleep disturbances, particularly REM sleep disinhibition, are often observed in depressed patients.

In conclusion, serotonin's role in sleep is complex and multifaceted. While early studies suggested it was a sleep promoter, more recent evidence indicates that serotonin primarily promotes wakefulness and inhibits REM sleep. Serotonin's release during wakefulness may initiate a cascade of events that contribute to the homeostatic regulation of sleep. Additionally, serotonin's interaction with specific brain regions, such as the preoptic area, plays a crucial role in sleep onset and maintenance.

Serotonin is released during waking and decreased during sleep

Serotonin is a neurotransmitter that plays a role in regulating sleep and wakefulness. It is produced by serotonergic neurons in the brain, particularly in the dorsal raphe nucleus (DRN) and the pons varolii. The release of serotonin is increased during wakefulness and decreased during sleep.

During wakefulness, serotonin promotes alertness and inhibits REM sleep. The serotonergic neurons in the DRN fire at a steady rate, activating specific receptors and inducing a decrease in the firing rate of other neurons. This results in the activation of arousal systems and the inhibition of REM sleep.

However, during sleep, serotonin release is reduced. Serotonergic neurons decrease their firing rate during slow-wave sleep and cease activity during REM sleep. This reduction in serotonin release is thought to be involved in the regulation of sleep and the initiation of REM sleep.

The role of serotonin in sleep has been studied using various approaches, including pharmacological manipulations, genetic modifications, and electrophysiological recordings. These studies have provided insights into the complex ways in which serotonin influences sleep and wakefulness.

Overall, the available evidence suggests that serotonin plays a crucial role in maintaining wakefulness and inhibiting REM sleep. The decrease in serotonin release during sleep is a critical aspect of the regulation of sleep and wakefulness cycles.

Serotonin is involved in the regulation of the sleep-wake cycle

The role of serotonin in sleep regulation was first identified by Michel Jouvet and his team in the 1960s and 1970s. Their experiments showed that increasing serotonin levels induced sleep, while decreasing serotonin levels led to insomnia. However, further studies revealed that the relationship between serotonin and sleep was more complex. Serotonin promotes wakefulness and inhibits REM sleep. During wakefulness, serotonin is released and activates specific receptors, leading to increased alertness and suppression of sleep. On the other hand, during the transition to sleep, serotonin activity gradually decreases, allowing for the onset of NREM and REM sleep.

The function of serotonin in sleep regulation is mediated by its receptors, particularly the 5-HT1A and 5-HT2A/2C receptors. Activation of 5-HT1A receptors promotes sleep, while activation of 5-HT2A/2C receptors promotes wakefulness. The balance between these receptor subtypes helps regulate the sleep-wake cycle.

Additionally, serotonin has been implicated in the pathogenesis of REM sleep behavior disorder (RBD). Antidepressants, especially serotonin reuptake inhibitors (SSRIs), can induce RBD by increasing serotonin levels. However, studies using 123I-FP-CIT-SPECT to assess serotonin transporter (SERT) availability at the brainstem level found no significant difference between individuals with idiopathic RBD and healthy controls, suggesting that the serotonergic system may not be directly involved in RBD pathogenesis.

Furthermore, serotonin has been linked to emotional disorders and depression. The "serotonin hypothesis" of depression proposes that reduced serotonin levels or impaired serotonin transmission contribute to the development of depression. Antidepressant medications, such as selective serotonin reuptake inhibitors (SSRIs), which increase serotonin levels in the brain, are commonly used to treat depression.

In summary, serotonin plays a crucial role in regulating the sleep-wake cycle by promoting wakefulness and inhibiting REM sleep. Its function is mediated by specific receptors, and alterations in serotonin levels or receptor activity can impact sleep and mood.

Serotonin is a sleep neurotransmitter

Serotonin promotes the wake state and inhibits REM sleep. The largest accumulation of serotonergic neurons in the brain is observed in the dorsal raphe nuclei (DRN) and the pons varolii (zones B6 and B7). The total number of such cells in the human brain is relatively small — about one hundred thousand. The serotonergic system has two characteristics: first, the unusually numerous ramifications of its axons (up to a million bifurcations of a single axon). Secondly, the extraordinary variety of types (at least 7) and subtypes (at least 14) of their receptors, among which there are both membrane depolarizing and hyperpolarizing.

Experiments with extracellular registration have shown that most serotonergic neurons are very active in the waking state, and during the transition to sleep and further into deep NREM sleep, they progressively slow down their activity and completely "silence" immediately before the transition to REM sleep. It has also been shown to play an important role in the negative regulation of REM sleep: without turning off serotonin transmission, neither initiation nor maintenance of REM sleep is possible.

In this case, selective shutdown of serotonergic transmission should suppress wakefulness by increasing NREM sleep. Such a methodological opportunity appeared with the introduction of molecular genetic and other newest innovative techniques into neurophysiology. It was found that the brain has its own special isoform of the enzyme tryptophan hydroxylase - Tph2, which converts the amino acid tryptophan, which is supplied to the body with protein food, into 5-hydroxytryptophan, a precursor of serotonin, and encoded by a separate gene. This discovery made it possible to create knockout mice for this gene, in which the content of cerebral serotonin does not exceed 4% of its content in the brain of control mice (that is, practically absent).

Finally, in a recently published study led by renowned Boston somnologist Patrick Fuller using a novel method of highly selective chemogenetic activation of serotonergic neurons in the DRN in combination with polysomnography and behavioral tests, no unambiguous results were obtained either. A "compensatory" restoration of NREM sleep, slightly suppressed by the 5-HT neuron activator injection procedure, was shown to return to baseline levels. This effect can hardly be called somnogenic, but it is definitely not activating. In addition, a change in behavior in the open field was found, which the authors interpret as a decrease in the level of anxiety under the influence of the activation of serotonergic neurons in the DRN.

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