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Understanding physiology of sleep will help you understand the root causes of your sleep problems, and what to do to fix them. In this post, we cover aspects of sleep physiology that are typically neglected.

You can download our insomnia resource list here.

Summary: How the Brain Controls Sleep

The neural control of sleep is like a seesaw between the sleep and wakefulness state, which is controlled by orexin neurons.

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Mechanisms by which the orexin system maintains consolidated sleep and wakefulness Source: http://pharmrev.aspetjournals.org/content/61/2/162.long

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Primary projections of the VLPO to the main components of the ascending arousal system

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701283/

During sleep, neurons in the hypothalamus (VLPO) in the brain produce sleep neurotransmitters such as GABA and galanin, and inhibit dopamine, histamine, norepinephrine and serotonin neurons (monoaminergic neurons).

During wakefulness, neurons secrete dopamine, histamine, norepinephrine and epinephrine (they inhibit the VLPO neurons).

Sleep and Neurotransmitters

1) Orexin/Hypocretin Promotes Wakefulness and Healthy Sleep/Wake Cycle

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 small cluster of the orexin neurons in the hypothalamus control other neurons that promote wakefulness, including neurons that secrete cholines, dopamine, noradrenaline, and serotonin in the cerebral cortex.

A disruption in this system may lead to disturbed sleep and waking states.

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, R1, R2, R3).

A lack of orexins cause 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). Mice lacking the gene for orexin showed phenotypes similar to humans with narcolepsy (R1, R2) and disruption of the hypocretin receptor 2 (Hcrtr2) caused canine narcolepsy (R).

Both noradrenaline and serotonin can inhibit the activity of orexin neurons (RR2).

Loss of function in the orexin neurons is also involved in altered energy homeostasis (R), which could result in fatigue.

Read this post to learn more about the orexin system and ways to ensure it functions well.

2) Impaired Dopamine Function Causes Sleep Disturbances

Dopamine functions as a neurotransmitter and is crucial for arousal, memory and motor function (R).

Altered brain dopamine leads to several neurological disorders like Parkinson’s, schizophrenia and ADHD (R1, R2).

Individuals with these diseases show dramatic sleep disturbances, including excessive daytime sleepiness, rapid-eye sleep movement disorder, decreased REM sleep and disturbed sleep architecture (R1R2).

These observations show that dopamine function and dopamine receptors may play a role in regulating sleep-wake cycles. Too much or too little dopamine can disrupt sleep. Generally, high dopamine induces wakefulness while blocking dopamine receptors promote sleep.

Activation of the D1 dopamine receptor increases wakefulness, and reduces slow wave sleep and REM sleep (R).

Activation of the D2 dopamine receptor can have different effects at various doses. Low doses reduce wakefulness and increase Slow Wave and REM sleep (predominant activation of the D2 receptors in the neurons that secrete dopamine), whereas large doses induce the opposite effect (predominant facilitation of the D2 postsynaptic receptors on the neurons that receive dopamine) (R).

Compounds that block both D1 and D2 receptors reduce wakefulness and increase deep sleep (R).

Activation of the D3 receptor induces sleepiness and sleep in laboratory animals and man (R).

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).

3) Serotonin is Important for Both Wakefulness and Sleep

Serotonin is an important neurotransmitter for good mood, controlling appetite, and sleep. There are many serotonin (5-HT1-7) receptors, each of which can affect the brain differently. Serotonin is also a precursor to melatonin.

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). It depends on the region of the brain which serotonin is acting on.

Serotonin neurons fire at a steady rate during wakefulness and decrease their firing during slow-wave sleep and virtually stop during REM sleep (R).

Supplementation of 5-HTP (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).

In a study with an individual with a genetic mutation that caused serotonin deficiency, he lacked a circadian rhythm and overate. For this person, supplementation with 5-HTP restored his normal circadian rhythm and food intake (R).

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).

Serotonin Receptors that Affect Sleep

5-HT2A is the bad serotonin receptor because its activation can cause insomnia and reduce deep sleep (R).

5-HT7 receptors play an important role in the circadian rhythm, in addition to mood, pain sensation, and control of body temperature (RR1R2).

5-HT1A (R), 5-HT1B (R), 5-HT2A (R), and 5-HT7 (R) receptors and serotonin transporters (R) control REM sleep (R). The administration of activators for these receptors increases wakefulness and decreases sleep (SWS and REM).

4) Norepinephrine Controls Arousal

Norepinephrine is produced mostly in the locus coeruleus (LC) located in the pons region of the brain.

It is released from the sympathetic nervous system in response to stress. Because the release of norepinephrine affects other organs of the body, it is also referred to as a “stress hormone” (R). This is why stress and anxiety can cause insomnia or reduce sleep quality.

Norepinephrine neurons in the brain (hypothalamus, medial preoptic area)  increase wakefulness and arousal (RR2, R3R4, R5).

LC neurons are highly active during wakefulness, slowly fire during NREM sleep, and are almost completely inactive during REM sleep (R).

Norepinephrine also plays an active role in cataplexy, a condition characterized by transient weakness or paralysis. Blocking the norepinephrine receptor (α1AR) worsens cataplexy, whereas activation of these receptors decreases the number of attacks (R). 

5) Histamine Can Keep You Awake

As a neurotransmitter, histamine promotes wakefulness. In the brain, histamine-releasing neurons are located in the hypothalamus (tuberomammillary nucleus) (R).

Histamine neuron firing ebbs and flows with the circadian rhythm. They are active during the day, stop working during drowsy states before sleep and resume activity at highly vigilant states after waking up (R).

Low brain histamine can cause excessive daytime sleepiness or prolonged nighttime sleep (hypersomnolence) (R).

Evidence for the role of histamine in sleep/wakefulness:

  • Human narcoleptics have decreased brain histamine (R).
  • Inhibitors of the enzyme histamine-N-methyltransferase, which breaks down histamine, increase wakefulness (R).
  • Application of histamine into the hypothalamus increases wakefulness and reduces NREM sleep, in a dose-dependent manner. The highest dose produced maximal wakefulness (R).
  • Antihistamines increase NREM sleep and reduced REM sleep in humans, cats, and dogs (RR2, R3).
  • Inhibitors of histidine decarboxylase (HDC), which is an enzyme that helps produce histamine, increase fatigue (R).

Although histamine promotes wakefulness through the activation of H1R, H2R, and H4R receptors, H3R has an opposite effect. H3R decreases histamine levels and promotes sleep (R,R). Therefore, blocking H3R induces wakefulness (R,R,R).

In Biohacking Insomnia, we discuss managing histamine levels when your histamine is high enough to keep you awake.

6) GABA Helps with Sleep

GABA is the main inhibitory neurotransmitter in the brain. The activation of GABA(A) receptors favors sleep (R). More than 20% of all brain neurons produce GABA (R).

There are mainly two classes of receptors: GABA(A) and GABA(B).

Many drugs that treat sleep loss conditions target these GABA receptors because the activation of these receptors rapidly inhibit the nervous system, thus promoting sleep (R). Drugs blocking the GABA(A) receptors could be used for therapy of disorders such as insomnia, epilepsy, and narcolepsy (R).

The GABA(B) receptor blockers increase active brain states such as when we’re awake or in REM sleep (dreaming stage) (R).

After long periods of supplementation with GABA/5HTP, natural production of GABA receptors increased, which assisted with natural sleep cycles and promotion of healthy sleep (R).

Brain Factors that Promote Sleep

Factors that affect sleep and their time-scale, source: https://www.ncbi.nlm.nih.gov/pubmed/19075717/

Factors that affect sleep and their time-scale, source: https://www.ncbi.nlm.nih.gov/pubmed/19075717/

1) Circadian Rhythm

Human sleep occurs with a circadian periodicity, i.e. we sleep at night and wake during the day. Sleeping at the “wrong circadian time” such as traveling across time zone or shift work confuses our circadian rhythm system (R).

When sleep phase is shifted by sleeping too early or too late, REM sleep readjusts only after several days, while slow wave sleep (SWS), which is less influenced by circadian factors readjusts immediately (R).

The central circadian clock/the circadian pacemaker is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Nerves in the SCN control the pineal gland, which synthesizes and releases melatonin.

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Source: https://www.ncbi.nlm.nih.gov/books/NBK10839/

Predictably, melatonin synthesis increases as light decreases and reaches its maximal level between 2:00 and 4:00 a.m.

In the elderly, the pineal gland calcifies and less melatonin is produced, perhaps explaining why older people sleep fewer hours and are more often afflicted with insomnia (R).

Sleep-Promoting Substances that Build Up throughout the Day

2) Adenosine Buildup Makes You Sleepy

Adenosine is a part of ATP (the energy molecule). The buildup of adenosine throughout the day create sleepiness, and sufficient levels of adenosine are necessary for good sleep.

Caffeine provokes wakefulness and prevents sleep by blocking adenosine receptors (R).

How Adenosine Makes Us Sleepy

ATP release from astrocytes contributes to the levels of adenosine between cells in the brain. The adenosine reduces synaptic transmission (communication between neurons), thus reduces brain function (R).

Mutant mice that cannot move adenosine into space between brain cells showed a reduced slow wave sleep and a decrease in the recovery sleep following sleep deprivation (R).

There are 4 known adenosine receptors (A1R, A2aR, A2bR and A3R), of which A1R and A2aR play a major role in sleep homeostasis (since both of them are expressed at high levels throughout the brain) (R1, R2).

A2aR has been associated with inflammatory diseases and neurodegenerative disorders (R).

A2AR receptors make us sleepy by:

  • inhibiting of histamine-releasing neurons (R)
  • turning on sleep-active neurons in the VLPO part of the hypothalamus (R)
  • increasing of acetylcholine release in the pontine reticular formation, which result in increased time in SWS and REM sleep (R).

Adenosine receptor activation decreases wakefulness and increases sleep (R). Furthermore, molecules that activate adenosine receptors tend to increase the deeper stages of SWS (R). 

Evidence for the role of adenosine in promoting sleep:

  • A specific adenosine A1Receptor activator called N6-l-methylcyclopentyladenosine has a sleep-promoting effect (R).
  • Deoxycoformycin increases adenosine levels by inhibiting adenosine deaminase. Deoxycoformycin enhanced REM sleep at a lower dose and enhanced deep NREM sleep at a higher dose (R).
  • Administration of adenosine (190 nmol) into the brain puts dogs to sleep (R).

3) Uridine Induces Sleep

Uridine induces sleep through uridine receptors in the central nervous system (R). Uridine binds to the P2Y receptors in areas of the brain which regulate natural sleep.

Uridine, when administered through a systematic route (such as in the stomach), may pass through the blood-brain barrier to balance sleep (R).
Uridine enhances both REM and NREM in mice at a dose of 1 pmol (R).

P2Y2 (P2Y2R) is activated with equal potency by ATP and uridine triphosphate (UTP) (R). The SNP rs1791933 (T allele) in the P2Y2 gene is linked to caffeine-related sleep disturbance (R). Note: SelfDecode has this SNP so you can find out if you have this SNP by uploading your 23andme data.

4) Oxidized Glutathione

Glutathione is an important cellular antioxidant in its reduced form (GSH). The oxidized form of glutathione (GSSG) is a sleep inducer. This might explain why some therapies that increase oxidative stress in the brain like LLLT and hyperbaric oxygen therapy can induce sleepiness. However, I wouldn’t use these therapies at night because they can shift the circadian rhythm and worsen sleep.

GSSG is a hexapeptide (has 6 amino acids) and GSH is a tripeptide (has 3 amino acids). In the mammalian brain, glutathione mainly exists in the form of GSH (R). GSH is easily converted to GSSG by a peroxidase enzyme (R).

GSSG significantly enhances REM sleep at a dose of 25 nmol and non-REM sleep at a dose of 20-50 nmol (R). The higher the GSSG concentration is, the stronger the enhancement.

In rats, infusing the brain with a substance that induces oxidative stress (such as t-butyl hydroperoxide) at a low dose can trigger sleep in rats (R). 

In animal models, t-butyl hydroperoxide causes oxidative stress in the neurons. However, injecting low doses of this peroxide into the preoptic/anterior hypothalamus (POAH) induces the release of the sleep-inducing chemicals such as nitric oxide and adenosine.

Glutathione inhibits oxidative stress and protects POAH neurons. Also, brain glutathione increases the sleep-inducing effects of t-butyl-hydroperoxide through increasing other sleep-inducing substances, nitric oxide, and adenosine.

This data suggests that low levels of oxidation in the brain under the control of an antioxidant system may trigger sleep through the increase of GSSG and other substances in the POAH (R).

5) Inflammatory Cytokines, such as IL-1beta and TNF-alpha

Administration of exogenous IL-1beta or TNF-alpha increased non-rapid eye movement sleep (NREMS). Inhibition of IL-1 or TNF-alpha makes it harder to fall asleep (R). This may explain why I find that taking supplements that reduce inflammation such as curcumin too late in the day will keep me up at night. In addition, people who get inflammation from foods often get tired after eating.

IL-1beta

IL-1beta is a cytokine protein that, in humans, is made from the IL1B gene (R). IL-1beta is one of 11 family members with respective receptors termed the interleukin-1 family (IL1F) (R).

The pro-inflammatory IL1F members, IL-1beta, IL-1 alpha, and IL-18 promote NREM sleep while the IL-1 receptor antagonist/blocker (IL-1RA) reduces NREM sleep (R).

The sleep-promoting effect of IL-1beta was first demonstrated in rabbits, administration of IL-1beta enhanced NREM sleep (R) also an injection of an IL-1beta inhibitor reduced sleep (R).

Injecting IL1-beta increases NREMS in cats (R), monkeys, and humans (R).

In humans, plasma IL1-beta peaks at the onset of slow-wave sleep (R), it enhances the firing rate of hypothalamic sleep-active neurons and inhibits wake-active neurons (R).

TNF-alpha

TNF-alpha is a cytokine involved in systemic inflammation. Sleep-inducing effects of TNF-alpha were also first described in rabbits. Injection of TNF-alpha in the blood or in the brain enhances the duration and intensity of NREMS and decreases REMS (R1, R2).

Circulating TNFα levels increase with sleep propensity (R). In humans, TNFα levels are increased in certain medical conditions associated with altered sleep, such as sleep apnea (R) and insomnia (R).

How Inflammatory Cytokines like IL-1beta and TNF-alpha Make You Sleepy

Sleep regulatory substances activate a number of inflammatory pathways (R), including NF-kB, NO (Nitric oxide), and COX (Cyclooxygenase). These inflammatory pathways induce sleep.

NF-kB exhibits a diurnal rhythm in the cortex (region of the brain). Sleep deprivation activates NF-kB in the cortex part of the brain (R) Furthermore, inhibiting NF-kB reduces spontaneous NREM sleep. Both IL-1beta and TNF-alpha promote sleep by activating nuclear factor kappa-B (NF-kB) (R).

Brain iNOS (inducible Nitric Oxide synthase) has a circadian variation and increases with sleep propensity (R). In rats, iNOS is increased during sleep deprivation. NREM and REM sleep were enhanced after administration of NO precursors, such as L-arginine (R). TNF-alpha mediates many of its actions via iNOS.

Of the two separate COXs (Cyclooxygenases 1 and 2), COX-2 modulates inflammation and sleep (R). Alternatively, IL-1beta and TNF-alpha induce COX-2 production (R).

Inhibiting COX-2 production reduces spontaneous NREM and TNF-alpha-induced sleep (R1, R2).

The figure below shows the various cytokines and their mechanisms as part of a sleep biochemical regulatory network.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692603/

6) BDNF is Important for Quality Sleep

BDNF (Brain-Derived Neurotrophic Factor) is important for the nerve cells to grow. In addition, depressed people have low levels of BDNF, and sleep disturbances are very common among these people (R).

BDNF appears to have a circadian rhythm, being high during the day and lower at night (R).

BDNF production during the day correlates with the amount of slow-wave (deep) sleep during the subsequent night (R), suggesting that BDNF is a measure of sleep pressure (the body’s desire to sleep).

If you have the T allele of the BDNF SNP called rs6265, which lower BDNF levels, you may not sleep as deeply as people with the C allele or the CC genotype. In addition, people with T allele (TT or CT genotype) have worse cognitive decline due to deprivation than people with the CC genotype (R).

In rats, chronic sleep deprivation led to increased IL-1b and TNF and reduced BDNF (R).

Therefore, improving BDNF levels may help with sleep quality.

If you want to overcome insomnia by learning everything about sleep and self-hacking, download our resource list here:

Technical

The Ascending Arousal system

  • The ascending arousal system has two major branches, which include discrete cell populations and neurotransmitters (R).
  • The first branch supplies nerves into the thalamus, activating neurons and nuclei essential for thalamocortical transmission.
  • The second branch of the ascending arousal system projects into the lateral hypothalamus, basal forebrain and cerebral cortex (R1, R2, R3).
  • It comprises a number of cell populations (including noradrenergic, serotoninergic, dopaminergic and histaminergic neurons), lateral hypothalamic peptidergic neurons (orexin/hypocretin) and the basal forebrain (contains acetylcholine or GABA) (R).
  • Neurons in these monoaminergic systems discharge most rapidly during wakefulness, slow down during non-rapid eye movement (NREM) sleep and show a little activity during rapid-eye-movement (REM) sleep (R1, R2, R3). A similar effect is observed with the orexin/hypocretin neurons (R1, R2).
  • In contrast, melatonin-concentrating neurons are strongly active during REM sleep (R).
  • In sum, all these systems together discharge in a specific and coordinated manner to promote cortical arousal (R).

The VLPO and the Sleep State

  • Sherin etal determined that a group of ventrolateral preoptic neurons is specifically activated during sleep (R).
  • The ventrolateral preoptic neuron (VLPO) efferents contain inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and galanin, which play a major role in keeping the ascending arousal system quiet during sleep (R1, R2).
  • Neurons of the extended VLPO are connected with the various sites in the brain that are involved in REM sleep.
  • While the VLPO cluster provides output to the histaminergic neurons. Histaminergic neurons are active during waking, reduce firing during NREM sleep and stop discharge during REM sleep (R1, R2).
  • Afferent neurons of the monoaminergic arousal system also connect with the VLPO (R).
  • Noradrenaline, acetylcholine, and serotonin are all neurotransmitters of wakefulness inhibit VLPO neurons (R). The reciprocal inhibitory interaction of the VLPO neurons with the noradrenergic, serotoninergic and cholinergic waking systems play a key role in regulating sleep (R).
  • Experiments in different animals showed that injury to the VLPO cluster and the extended VLPO decreased NREM and REM sleep (R1, R2).
  • A familial advanced sleep phase syndrome (FASPS) mutation in location 2106 (A-G) of epsilon casein kinase 1 (CK1ε)-binding herp2 gene on chromosome 2 results in translocation of serine in amino-acid 662 with a glycine (56624) (R).
  • Phenotypes are a set of observable characteristics of an individual resulting from the interaction of its genotypes with the environment.
  • De novo synthesis refers to the synthesis of complex molecules from simple molecules such as sugars or amino acids as opposed to recycling after partial degradation.
  • DAT is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into the cytosol, from which other transporters sequester DA into vesicles and storage for later release.
  • Cataplexy is a symptom of narcolepsy in which patients experience abrupt transitions from waking to a state akin to REM sleep, with complete muscle atonia (R).
  • An efferent organ or body part carries impulses from the central nervous system to the effector.
  • Noradrenaline and serotonin inhibit the activity of orexin through the activation of G-protein-regulated inwardly rectifying K+ (GIRK or Kir3) channels via α2-adrenoceptors and 5HT1A-receptors (R).
  • An afferent nerve fiber or organ carries nerve impulses from the sensory organs to the central nervous system (CNS).

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3 COMMENTS

  • Ben Wa

    “How Inflammatory Cytokines like IL-1beta and TNF-alpha Make You Sleepy” how to inhibit those mechanism the best – and fight sleepyness? (NF-kB, NO (Nitric oxide), and COX, COX-2)

  • Tom S

    Great post. My experience with anti inflammatory supplements is definitely a negative impact on sleep and causes fatigue the next day. It’s a frustrating situation. For example, I take small dose of cat’s claw (saventaro) in the morning to get increased mental clarity and wakefulness (probably by reduction in inflammation, perhaps TNF-a suppression). But then have a hard time falling asleep and most certainly get less NREM sleep regardless of how much I sleep, resulting in feeling more tired and fogged the next day. So I use sparingly (2 days/week). Yet, the only days I can accomplish any mentally intensive work is a day with cat’s claw so I still use it. Lately, was diagnosed with Narcolepsy (mild case, no cataplexy, only excessive daytime sleepiness), and thankfully Xyrem (GHB) seems to be helping improve deep sleep (NREM) and improving daytime sleepiness and cognition. But still needing things like cat’s claw to get by.

    1. bob

      I’ve been trying cat’s claw recently and have found about the same…probably too stimulating. I do take some 5HTP before bed and a supplement Natural Sleep sold by Swansons.

      If I wake up middle of the night I take a cap of l-theanine….this usually allows me to get back to sleep. I can’t take it all the time though.

      For long drives and such I drink a strong cup of coffee and eat a bar of 85% dark chocolate…the combo keeps me sharp and aware but without jitters.

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