Novel concepts in sleep regulation

Wigren, Henna-Kaisa; Porkka‐Heiskanen, Tarja

doi:10.1111/apha.13017

Cited by 15 publications

(7 citation statements)

References 138 publications

(163 reference statements)

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“…ATP can be released from cells by vesicular exocytosis and also through transmembrane channels such as Panx1, which can be activated by effectors that include Ca 2+ transients (107). Extracellular ATP can be converted, by plasma membrane-embedded nucleotidases, to extracellular adenosine, a natural somnogen (18). Extracellular ATP can also increase proteolytic processing and secretion of inflammatory cytokines, including IL-1 and TNFα.…”

Section: Fg Sentinelsmentioning

confidence: 99%

On the cause of sleep: Protein fragments, the concept of sentinels, and links to epilepsy

Varshavsky

2019

Proc. Natl. Acad. Sci. U.S.A.

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The molecular-level cause of sleep is unknown. In 2012, we suggested that the cause of sleep stems from cumulative effects of numerous intracellular and extracellular protein fragments. According to the fragment generation (FG) hypothesis, protein fragments (which are continually produced through nonprocessive cleavages by intracellular, intramembrane, and extracellular proteases) can be beneficial but toxic as well, and some fragments are eliminated slowly during wakefulness. We consider the FG hypothesis and propose that, during wakefulness, the degradation of accumulating fragments is delayed within natural protein aggregates such as postsynaptic densities (PSDs) in excitatory synapses and in other dense protein meshworks, owing to an impeded diffusion of the ∼3,000-kDa 26S proteasome. We also propose that a major function of sleep involves a partial and reversible expansion of PSDs, allowing an accelerated destruction of PSD-localized fragments by the ubiquitin/proteasome system. Expansion of PSDs would alter electrochemistry of synapses, thereby contributing to a decreased neuronal firing during sleep. If so, the loss of consciousness, a feature of sleep, would be the consequence of molecular processes (expansions of protein meshworks) that are required for degradation of protein fragments. We consider the concept of FG sentinels, which signal to sleep-regulating circuits that the levels of fragments are going up. Also discussed is the possibility that protein fragments, which are known to be overproduced during an epileptic seizure, may contribute to postictal sleep and termination of seizures. These and related suggestions, described in the paper, are compatible with current evidence about sleep and lead to testable predictions. fragment | extracellular | intracellular | proteolysis | sleep S leep is universal among mammals and other vertebrates.Animals with much smaller nervous systems, such as insects, also sleep (1-8). Mechanisms that control sleep include circadian circuits, which underlie daily rhythms of sleep and other biological variables (9). However, circadian aspects of sleep do not define it entirely, because sleep has the homeostatic property of becoming longer after sleep deprivation (10, 11). In mammals, birds, and lizards, two alternating modes of sleep have been identified, the non-rapid eye movement (NREM) sleep and the rapid eye movement (REM) sleep (12,13). The depth of NREM sleep is yet another sleep variable. In adult humans, NREM sleep occupies ∼80% of the total sleep time. For recent reviews of sleep, see refs. 14-20.Despite advances in the understanding of neuronal circuits as well as genes, proteins, short peptides, and other compounds that regulate sleep, it is largely unknown why sleep exists and what it is for. Maladaptive aspects of sleep include elevated dangers of predation during sleep, the neglect of territorial defense and foraging for food, and the loss of parental care and mating opportunities. It is unknown what features of sleep did not allow these fitness costs to ca...

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Section: Fg Sentinelsmentioning

confidence: 99%

On the cause of sleep: Protein fragments, the concept of sentinels, and links to epilepsy

Varshavsky

2019

Proc. Natl. Acad. Sci. U.S.A.

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“…By using GA to activate AANs, the mice will reach the ideal unconsciousness state: a reversed coma state in which they cannot feel or react to pain because related neurons are accurately controlled. Scientists have discovered that some of the AANs in the mice experiment become active during sleep [9]. This illustrates why the mice will be asleep after being anesthetized.…”

Section: Introductionmentioning

confidence: 99%

Does the Sleep-Related Neurons Modulate the Sensation of Pain under the Use of GA?

Fang¹,

Zong²,

Kunes³

2019

ABB

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General anesthetics (GA) has been discovered for centuries and was often used in surgeries. However, many patients are dying from the usage of GA for different reasons. Although scientists are working on to solve the problems, the mechanism of GA is still a mystery. Recently, scientists from Duke University found neurons that are active during sleep can be activated in anesthesia. These neurons are called Anesthetic Activated Neurons (AANs). This is a massive step for us to break the mystery. In this paper, we designed an experiment that aims to reveal one mechanism of GA: the relationship between sleep-related neurons and sensation of pain under the use of GA. The designed experiment involves several control groups that consist of mice with different treatments on their genes and different GA.

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“…The second possibility is the involvement of SIK3(SLP) in non-neural cells, such as astrocytes and microglia (Wigren and Porkka-Heiskanen, 2018). Astrocytes have been shown to modulate sleep need (Halassa et al, 2009;Pelluru et al, 2016;Haydon, 2017).…”

Section: Introductionmentioning

confidence: 99%

Induction of MutantSik3^SleepyAllele in Neurons in Late Infancy Increases Sleep Need

et al. 2021

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Sleep is regulated in a homeostatic manner. Sleep deprivation increases sleep need, which is compensated mainly by increased EEG d power during non-rapid eye movement sleep (NREMS) and, to a lesser extent, by increased sleep amount. Although genetic factors determine the constitutive level of sleep need and sleep amount in mice and humans, the molecular entity behind sleep need remains unknown. Recently, we found that a gain-of-function Sleepy (Slp) mutation in the salt-inducible kinase 3 (Sik3) gene, which produces the mutant SIK3(SLP) protein, leads to an increase in NREMS EEG d power and sleep amount. Since Sik3 Slp mice express SIK3(SLP) in various types of cells in the brain as well as multiple peripheral tissues from the embryonic stage, the cell type and developmental stage responsible for the sleep phenotype in Sik3 Slp mice remain to be elucidated. Here, we generated two mouse lines, synapsin1 CreERT2 and Sik3 ex13flox mice, which enable inducible Cre-mediated, conditional expression of SIK3(SLP) in neurons on tamoxifen administration. Administration of tamoxifen to synapsin1 CreERT2 mice during late infancy resulted in higher recombination efficiency than administration during adolescence. SIK3(SLP) expression after late infancy increased NREMS and NREMS d power in male synapsin1 CreERT2 ; Sik3 ex13flox/1 mice. The expression of SIK3(SLP) after adolescence led to a higher NREMS d power without a significant change in NREMS amounts. Thus, neuron-specific expression of SIK3(SLP) after late infancy is sufficient to increase sleep.

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Novel concepts in sleep regulation

Cited by 15 publications

References 138 publications

On the cause of sleep: Protein fragments, the concept of sentinels, and links to epilepsy

On the cause of sleep: Protein fragments, the concept of sentinels, and links to epilepsy

Does the Sleep-Related Neurons Modulate the Sensation of Pain under the Use of GA?

Induction of MutantSik3^SleepyAllele in Neurons in Late Infancy Increases Sleep Need

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Novel concepts in sleep regulation

Cited by 15 publications

References 138 publications

On the cause of sleep: Protein fragments, the concept of sentinels, and links to epilepsy

On the cause of sleep: Protein fragments, the concept of sentinels, and links to epilepsy

Does the Sleep-Related Neurons Modulate the Sensation of Pain under the Use of GA?

Induction of MutantSik3SleepyAllele in Neurons in Late Infancy Increases Sleep Need

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Induction of MutantSik3^SleepyAllele in Neurons in Late Infancy Increases Sleep Need