The physiology of sleep will help you understand the root causes of sleep problems and how you should approach them. In this post, we cover aspects of sleep physiology, focusing on the roles of neurotransmitters and other brain-derived factors in sleep control.<\/p>\n
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The neural control of sleep is like a seesaw between the sleep and wakefulness state, which is controlled by orexin<\/a> neurons.<\/p>\n During sleep, neurons in the hypothalamus<\/a> produce sleep neurotransmitters such as GABA<\/a> and galanin and inhibit dopamine<\/a>, histamine<\/a>, norepinephrine<\/a> and serotonin<\/a> neurons (monoaminergic neurons).<\/p>\n During wakefulness, neurons secrete dopamine, histamine, norepinephrine, and epinephrine while inhibiting GABA.<\/p>\n Orexin, also called hypocretin, is a neuropeptide that increases arousal, wakefulness, and appetite. Orexin-producing neurons work during active wakefulness and stop during sleep (R<\/a>).<\/p>\n The importance of orexin in the maintenance of sleep\/wake cycle was first demonstrated by the fact that orexin deficiency caused narcolepsy in humans and animals (R<\/a>, R<\/a>, R<\/a>, R<\/a>).<\/p>\n A lack of orexins correlates with narcolepsy. Approximately 90% of patients with narcolepsy (with cataplexy) show decreased orexin-A levels in the cerebrospinal fluid (CSF, the fluid surrounding the brain) (R<\/a>).<\/p>\n Mice lacking the gene for orexin showed phenotypes similar to humans with narcolepsy and disruption of the hypocretin receptor 2 (Hcrtr2) caused canine narcolepsy (R<\/a>, R<\/a>, R<\/a>).<\/p>\n Both noradrenaline and serotonin can inhibit the activity of orexin neurons (R<\/a>, R<\/a>).<\/p>\n Loss of function in the orexin neurons is also involved in altered energy homeostasis, which could result in fatigue (R<\/a>).<\/p>\n Read this post<\/a> to learn more about the orexin system and ways to ensure it functions well.<\/p>\n Dopamine functions as a neurotransmitter and is crucial for arousal, memory and motor function (R<\/a>).<\/p>\n Altered brain dopamine leads to several neurological disorders like Parkinson’s, schizophrenia and ADHD (R<\/a>, R<\/a>).<\/p>\n Individuals with these diseases show dramatic sleep disturbances, including excessive daytime sleepiness, rapid-eye sleep movement disorder, decreased REM sleep and disturbed sleep architecture (R<\/a>, R<\/a>).<\/p>\n These observations show that dopamine function and dopamine receptors may play a role in regulating sleep-wake cycles. <\/strong>Generally, high dopamine induces wakefulness while blocking dopamine receptors promotes sleep.<\/p>\n Activation of the D1 dopamine receptor<\/a> increases wakefulness and reduces slow-wave sleep and REM sleep (R<\/a>).<\/p>\n Activation of the D2 dopamine receptor<\/a> can have different effects at various doses. Low doses reduce wakefulness and increase Slow Wave and REM sleep, whereas large doses induce the opposite effect (predominant facilitation of the D2 postsynaptic receptors on the neurons that receive dopamine) (R<\/a>).<\/p>\n Compounds that block both D1<\/a> and D2<\/a> receptors reduce wakefulness and increase deep sleep (R<\/a>).<\/p>\n Activation of the D3 receptor<\/a> induces sleepiness and sleep in laboratory animals and man (R<\/a>).<\/p>\n During wakefulness, there’s an increase in dopamine neuron activity, and an enhanced release of dopamine in multiple regions of the brain (VTA, the nucleus accumbens, forebrain) (R<\/a>).<\/p>\n Serotonin is an important neurotransmitter for good mood, controlling appetite, and sleep. There are many serotonin (5-HT<\/a>1-7) receptors, each of which can affect the brain differently. Serotonin is also a precursor to melatonin<\/a>, the sleep hormone.<\/p>\n Early studies indicate that serotonin was associated with the initiation and maintenance of sleep, while later studies indicate that serotonin neurons also play a role in inhibiting sleep (R<\/a>).<\/p>\n Serotonin neurons fire at a steady rate during wakefulness and decrease their firing during slow-wave sleep and virtually stop during REM sleep (R<\/a>).<\/p>\n Supplementation of 5-HTP<\/a> (a precursor of melatonin and serotonin, at a dose of 2 mg\/kg) every night before bed could reduce the arousal level in children (aged 3 – 10) and induce a long-term improvement against nightmares with an effective reduction rate of 93.5% (R<\/a>).<\/p>\n In a study with an individual with a genetic mutation that caused serotonin deficiency<\/a>, he lacked a circadian rhythm<\/a> and overate. For this person, supplementation with 5-HTP restored his normal circadian<\/a> rhythm and food intake (R<\/a>).<\/p>\n A small clinical trial demonstrated that the use of 5-HTP in combination with GABA significantly improves sleep quality in 9 subjects with sleep disorders, in comparison to placebo (R<\/a>).<\/p>\n 5-HT2A<\/a> is the bad serotonin receptor because its activation can cause insomnia and reduce deep sleep (R<\/a>).<\/p>\n 5-HT7 receptors<\/a> play an important role in the circadian rhythm, in addition to mood, pain<\/a> sensation, and control of body temperature (R<\/a>, R<\/a>, R<\/a>).<\/p>\n 5-HT1A<\/a>, 5-HT1B<\/a>, 5-HT2A, and 5-HT7 receptors and serotonin transporters control REM sleep. The administration of activators for these receptors increases wakefulness and decreases sleep (SWS and REM) (R<\/a>, R<\/a>, R<\/a>, R<\/a>).<\/p>\n Norepinephrine<\/a> (noradrenaline) is produced mostly in the locus coeruleus (LC) located in the pons region of the brain.<\/p>\n It is released from the sympathetic nervous system in response to stress<\/a>. Because the release of norepinephrine affects other organs of the body, it is also referred to as a <\/strong>“stress hormone<\/strong>” (R<\/a>).<\/p>\n This is why stress and anxiety<\/a> can cause insomnia or reduce sleep quality.<\/p>\n Norepinephrine neurons in the brain (hypothalamus, medial preoptic area) increase wakefulness and arousal (R<\/a>, R<\/a>, R<\/a>, R<\/a>, R<\/a>).<\/p>\n LC neurons are highly active during wakefulness, slow fire during NREM sleep, and are almost completely inactive during REM sleep (R<\/a>).<\/p>\n Norepinephrine also plays an active role in cataplexy, a condition characterized by transient weakness or paralysis. Blocking the norepinephrine receptor (\u03b11AR) worsens cataplexy, whereas activation of these receptors decreases the number of attacks (R<\/a>).<\/p>\n As a neurotransmitter, histamine promotes wakefulness. In the brain, histamine-releasing neurons are located in the hypothalamus (tuberomammillary nucleus) (R<\/a>).<\/p>\n Histamine neuron firing ebbs and flows with the circadian rhythm. They are active during the day, stop working during drowsy states before sleep<\/a> and resume activity at highly vigilant states after waking up (R<\/a>).<\/p>\n Low brain histamine can contribute to excessive daytime sleepiness or prolonged nighttime sleep (hypersomnolence) (R<\/a>).<\/p>\n Evidence for the role of histamine in sleep\/wakefulness:<\/p>\n Although histamine promotes wakefulness through the activation of H1R, H2R<\/a>, and H4R<\/a> receptors, H3R<\/a> has an opposite effect. H3R decreases histamine levels and promotes sleep (R<\/a>, R<\/a>).<\/p>\n<\/a>1) Orexin\/Hypocretin<\/strong><\/span><\/h3>\n
<\/a>2) Dopamine<\/strong><\/span><\/h3>\n
<\/a>3) Serotonin<\/strong><\/span><\/h3>\n
<\/a>Serotonin Receptors that Affect Sleep<\/strong><\/h4>\n
<\/a>4) Norepinephrine<\/strong><\/span><\/h3>\n
<\/a>5) Histamine <\/strong><\/span><\/h3>\n
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