Chemistry Of Rem Sleep: Brain, Body And Mind

Sleep is a complex process involving many different areas of the brain and a variety of neurotransmitters and hormones. During REM sleep, the eyes continue to move, but the rest of the body's muscles are inactive, potentially to prevent injury. Two powerful brain chemical systems work together to paralyze skeletal muscles during REM sleep: the neurotransmitters gamma-aminobutyric acid (GABA) and glycine. These neurotransmitters cause REM sleep paralysis by switching off the specialized cells in the brain that allow muscles to be active.

GABA is the main inhibitory neurotransmitter involved in switching off the state of wakefulness. It is one of the more prevalent neurotransmitters in the brain and is usually responsible for inhibition. Orexin (or hypocretin) is another neurotransmitter linked to arousal and wakefulness, produced almost exclusively in the hypothalamus. It regulates many different systems involved with sleep and stabilizes both awake and sleep states.

Other neurotransmitters involved in the sleep-wake cycle include acetylcholine, which is often associated with the activation of muscles but is also involved in the cholinergic system, which has inhibitory actions; and serotonin, which is commonly associated with depression but also helps maintain arousal and cortical responsiveness, as well as inhibiting REM sleep.

The role of acetylcholine in REM sleep

Acetylcholine is a neurotransmitter that is at its strongest during REM sleep and wakefulness. It is thought to help the brain retain information gathered while awake, and then consolidate this information during sleep.

Acetylcholine is released from "REM-on" cells in the pons, a region of the brainstem. The activation of these acetylcholine cells creates a particular oscillating pattern of electrical activity, called PGO waves, which pass from the pons through to areas of the brain involved in visual processing and help to create the imaginary world that plays out inside our dreams.

More recent studies have provided evidence that muscarinic acetylcholine receptors are important for REM sleep regulation. Muscarinic receptor agonists and acetylcholinesterase inhibitors increase REM sleep and shorten the REM latency (the time-delay of REM sleep after non-REM sleep). On the other hand, muscarinic receptor antagonists decrease REM sleep and lengthen the REM latency.

A recent study revealed that the Gq protein-coupled muscarinic acetylcholine receptors, Chrm1 and Chrm3, are essential for REM sleep. The almost complete absence of REM sleep in the Chrm1 and Chrm3 double-knockout mice re-emphasised the role of the cholinergic pathway in REM sleep.

The exact mechanism of how acetylcholine contributes to REM sleep is still not fully understood and is the subject of ongoing research.

Norepinephrine and serotonin's impact on REM sleep

Norepinephrine and serotonin are both neurotransmitters that play a role in regulating sleep. Norepinephrine is involved in the ascending arousal system and impacts the efficacy of many wake- and sleep-promoting medications. It is one of the main brain monoamines and has powerful central influences on forebrain neurobiological processes that support the mental activities occurring during the sleep-wake cycle. Norepinephrine neurons are activated during waking, decrease their firing rate during slow-wave sleep, and become silent during REM sleep.

Serotonin is an important chemical in supporting the process of waking up and some wake-promoting serotonin cells are themselves sensitive to light. The role of serotonin in wakefulness can be seen in people who take selective serotonin reuptake inhibitors (SSRIs) and who have problems sleeping. Activation of serotonin cells also leads to the activation of other wake-promoting cells to reinforce the process of staying awake throughout the day. Serotonin is also involved in regulating body temperature and is involved in the mechanisms by which being cold wakes you up.

During REM sleep, norepinephrine cells are inactive. However, there is an important difference between the activity of norepinephrine and histamine cells: only the norepinephrine cells become inactive during cataplexy, which is an episodic loss of muscle tone while awake and occurs in patients with narcolepsy. Neuronal recording studies suggest that the normal cessation of activity of norepinephrine cells during sleep may be related to the loss of muscle tone during sleep, while the normal cessation of activity of histamine cells during sleep may be directly related to the loss of consciousness during sleep. Several studies support the concept that activity in histaminic cell groups is strongly linked to forebrain arousal, whereas norepinephrine and serotonin cell groups are associated with the regulation of muscle tone and perhaps motor activity.

The most caudal neurons in the brain with a major role in sleep control are the serotonin cells, which are located in the raphe nuclei. These serotonin cells, like the histamine and norepinephrine cells, are inactive in sleep (most completely in REM sleep), and they may have a role in maintaining arousal and regulating muscle tone and in regulating some of the phasic events of REM sleep. If these cells are destroyed, these phasic events are released from inhibition. The tonic activity of these serotonin cells during waking would tend to suppress phasic events, and their inactivity during REM sleep allows high-voltage electrical activity to propagate from the pons to the thalamus and cortex, releasing associated eye movements and twitches.

GABA and glycine's paralysis induction

Sleep is divided into two main phases: non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. During REM sleep, the central nervous system (CNS) is highly active, but the skeletal motor system is forced into a state of muscle paralysis. This state of muscle paralysis is known as REM sleep paralysis.

REM sleep paralysis is caused by the inhibition of somatic motoneuron activity. Motoneurons are switched off during REM sleep due to a powerful drive of the neurotransmitters GABA and glycine, which act on metabotropic GABA(B) and ionotropic GABA(A)/glycine receptors. When motoneurons are cut off from the inhibitory effects of these receptors, REM paralysis is reversed.

GABA is the main inhibitory neurotransmitter involved in switching off the state of wakefulness. It coordinates the process of falling asleep by acting on preoptic cells, which in turn inhibit the activity of wake-promoting brain regions. During NREM sleep, the brain is predominantly associated with the neurotransmitters GABA and the neuropeptide galanin.

Glycine is an inhibitory neurotransmitter that also plays a role in inducing sleep. It blocks the activity of motoneurons during REM sleep, contributing to the state of muscle paralysis.

Orexin/hypocretin's role in REM sleep

Orexin, also known as hypocretin, is a neuropeptide that plays a crucial role in regulating REM sleep. Orexin is produced in the lateral hypothalamus and acts as a neurotransmitter, promoting wakefulness and inhibiting REM sleep. Orexin-producing neurons in the hypothalamus project to several brain regions involved in sleep regulation, such as the brainstem and thalamus.

During wakefulness, orexin neurons are highly active, releasing orexin into their target regions. Orexin promotes arousal, enhances alertness, and helps maintain a state of wakefulness. However, during REM sleep, the activity of orexin neurons decreases, resulting in reduced orexin release. Studies in primates have shown that orexin levels are highest just after the onset of sleep and gradually decrease throughout the night, reaching their lowest levels around wake time. This pattern suggests that orexin primarily inhibits REM sleep rather than solely promoting wakefulness.

Orexin receptor antagonists, which block the action of orexin at its receptors, have been studied as a potential treatment for insomnia. These drugs are believed to inhibit the wake-promoting effects of orexin, leading to increased sleep duration and improved sleep continuity. Interestingly, orexin receptor antagonists have been found to enhance REM sleep regulation, contrary to the traditional notion that orexin solely promotes wakefulness.

The role of orexin in REM sleep is also interconnected with its role in appetite regulation. Orexin neurons project to the lateral hypothalamus, a region involved in appetite control. Orexin helps regulate feeding behaviour and energy balance. During REM sleep, the brain experiences a physiological fasting period, and the abundant REM sleep towards the end of the night acts as an appetite suppressant. This link between orexin, sleep, and appetite has important implications for understanding the complex mechanisms underlying sleep-wake patterns and metabolic control.

Further research is encouraged to fully understand the role of orexin in REM sleep and to explore novel therapeutic approaches for sleep disorders and metabolic conditions associated with orexin dysregulation.

Dopamine's effect on REM sleep

Dopamine is a neurotransmitter that plays a crucial role in the regulation of sleep and wakefulness. It is involved in various brain functions, including reward, motor control, and sleep-wake cycles. While the role of dopamine in promoting arousal and wakefulness is well established, recent studies have also implicated dopaminergic activity in REM sleep.

During REM sleep, the brain systems typically associated with an awake state become active. Dopamine neurons in specific regions of the brain, such as the ventral tegmental area and the dorsal raphe, are active during REM sleep. The release of dopamine in these areas contributes to the generation of REM sleep and its regulatory function in sleep cycles.

Studies on dopamine-deficient mice have provided valuable insights into the effects of dopamine on REM sleep. These mice exhibit reduced time spent in wakefulness and a marked reduction in REM sleep. The results suggest that dopamine plays a critical role in maintaining wakefulness and positively regulating REM sleep.

Additionally, the dopamine transporter (DAT) exhibits circadian fluctuations in expression and function, influencing dopamine levels and release in the brain. These fluctuations may contribute to the relationship between dopamine and sleep across different phases of the circadian cycle.

Abnormalities in dopamine function have been linked to sleep disorders such as restless legs syndrome and narcolepsy. Further research is needed to fully understand the complex role of dopamine in sleep regulation and its potential implications for various psychiatric and neurological disorders.

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