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The Pioneering Experimental Studies on Sleep Deprivation
Abstract
The experimental studies on sleep deprivation were initiated by the Russian physician and scientist, Marie de Manacéine, who studied sleep-deprived puppies kept in constant activity. She reported in 1894 that the complete absence of sleep was fatal in a few days, pointing out that the most severe lesions occurred in the brain. In 1898, the Italian physiologists Lamberto Daddi and Giulio Tarozzi also kept dogs awake by walking them; the animals died after 9-17 days, and their survival was unrelated to food consumption. In the histological study performed by Daddi, degenerative alterations, mainly represented by chromatolytic changes, were observed in neurons of the spinal ganglia, Purkinje cells of the cerebellum, and neurons of the frontal cortex. Daddi ascribed these changes to a state of autointoxication of the brain during insomnia. In 1898, the psychiatrist Cesare Agostini, interested in the psychic phenomena caused by prolonged insomnia in humans, sleep deprived dogs by keeping them in a metallic cage in order to avoid fatigue. The dogs survived about 2 weeks, and degenerative changes were observed in their brains. In these experimental paradigms, the effect of sleep loss was confounded by motor exhaustion and/or intense sensory stimulation. In spite of the absence of adequate controls, the pioneering studies performed at the end of the 19th century represented the first experimental attempts to relate sleep with neural centers and suggested that sleep is a vital function and that the brain may be affected by insomnia.
... Early work in the late 19 th century provided initial evidence that sleep deprivation can cause death. In 1894, Russian physician Marie de Manaceine deprived puppies of sleep by keeping them constantly active and found that it was 100% fatal within a few days 8 ...
... Tarozzi kept adult dogs awake with constant activity and found it was 100% fatal within 17 days 8 . While macabre and poorly controlled, these experiments established that sleep was necessary for life. ...
... One region that is particularly affected by sleep deprivation is the nervous system. In the aforementioned studies in dogs by Manaceine, and by Daddi and Tarozzi, both groups found lesions within the brains of the animals post-mortem 8 . In humans, studies have shown that reduced sleep was associated with reduced brain volume and greater brain atrophy 12,13 . ...
Sleep and is critical for proper memory consolidation. The locus coeruleus (LC) releases norepinephrine throughout the brain except when the LC falls silent throughout rapid eye movement (REM) sleep and prior to each non-REM (NREM) sleep spindle. We hypothesize that these transient LC silences allow the synaptic plasticity necessary to incorporate new information into preexisting memory circuits. We found that spontaneous LC activity within sleep spindles triggers a decrease in sleep spindle power. By optogenetically stimulating norepinephrine-containing LC neurons at 2 Hz during sleep, we reduced sleep spindle occurrence as well as NREM delta power and REM theta power, without causing arousals or changing sleep amounts. Stimulating the LC during sleep following a hippocampus-dependent food location learning task interfered with consolidation of newly learned locations, and reconsolidation of previous locations, disrupting next-day place cell activity. The LC stimulation-induced reduction in NREM sleep spindles, delta, and REM theta, and reduced ripple-spindle coupling all correlated with decreased hippocampus-dependent performance on the task. Thus, periods of LC silence during sleep following learning are essential for normal spindle generation, delta and theta power, and consolidation of spatial memories. Sleep quantity and quality also impact many physiological and neural processes. Sleep is affected by the menstrual cycle; however, few studies have examined the effects of the estrous cycle on sleep in rodents. Thus, studies of disease mechanisms in females lack critical information regarding estrous cycle influences on relevant sleep characteristics. We recorded electroencephalographic (EEG) activity from multiple brain regions to assess sleep states as well as sleep traits such as spectral power and interregional spectral coherence in males and freely cycling females across the estrous cycle. Our findings show that the high hormone phase of proestrus decreases the amount of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep and increases the amount of time spent awake compared with males and other estrous phases. This spontaneous sleep deprivation of proestrus was followed by a sleep rebound in estrus with increased NREM and REM sleep and rebound-like sleep architecture. Spectral power increased in the delta 0.5-4 Hz) and the gamma (30-60 Hz) ranges during NREM sleep of proestrus, and in the theta range (5-9 Hz) during REM sleep of both proestrus and estrus. Slow wave activity and cortical sleep spindle density also increased in NREM sleep of proestrus. Finally, interregional NREM and REM spectral coherence increased during proestrus. This work demonstrates that the estrous cycle affects more facets of sleep than previously thought and reveals further sex differences in feature of the sleep-wake cycle, which are relevant to a myriad of physiological processes influenced by sleep.
... Unfortunately, the literature on the chronic effects of sleep restriction is not comprehensive, partly dated, and intrinsically complicated by the many confounding factors that correlate with sleep restriction. To date, experiments addressing this question have been reported in a handful of species only: dogs [reviewed in (7)], rats [reviewed in (8)], cockroaches (9), pigeons (10), and fruit flies (11). In four of the five tested animal species, sleep deprivation experiments eventually terminated with the premature death of the animals, but the underlying cause of lethality still remains unknown. ...
... In four of the five tested animal species, sleep deprivation experiments eventually terminated with the premature death of the animals, but the underlying cause of lethality still remains unknown. In rats and dog pups, death is associated with a severe systemic syndrome bearing important metabolic changes and clear signs of suffering, making it difficult to ultimately conclude whether lethality is caused by the mere removal of sleep or rather by the very invasive and stressful procedures used to keep the animals awake (7,12,13). In the cockroach Diploptera punctata, sleep deprivation was achieved by continuously startling the animals (9), without, however, accounting for exhaustion-induced stress, a known lethal factor for other species of cockroaches (14)(15)(16). ...
... In our view, they command, instead, for a thorough review of existing sleep deprivation literature. The experiments of chronic sleep deprivation performed in dog pups at the end of the 1800s are universally considered too primitive to be trustworthy and too unethically stressful to be reproducible in modern times (7). The early Drosophila experiments were too preliminary to depict a whole picture (11). ...
Sleep appears to be a universally conserved phenomenon among the animal kingdom, but whether this notable evolutionary conservation underlies a basic vital function is still an open question. Using a machine learning–based video-tracking technology, we conducted a detailed high-throughput analysis of sleep in the fruit fly Drosophila melanogaster , coupled with a lifelong chronic and specific sleep restriction. Our results show that some wild-type flies are virtually sleepless in baseline conditions and that complete, forced sleep restriction is not necessarily a lethal treatment in wild-type D. melanogaster . We also show that circadian drive, and not homeostatic regulation, is the main contributor to sleep pressure in flies. These results offer a new perspective on the biological role of sleep in Drosophila and, potentially, in other species.
... Unfortunately, the literature on the chronic effects of sleep restriction is not comprehensive, partly dated and intrinsically complicated by the many confounding factors that correlate with sleep restriction. To date, experiments addressing this question have been reported in a handful of species only: dogs (reviewed in (6)), rats (reviewed in (7)), cockroaches (8), pigeons (9) and fruit flies (10). In four out of the five tested animal species, sleep deprivation experiments eventually terminated with the premature death of the animals but the underlying cause of lethality still remains unknown. ...
... In four out of the five tested animal species, sleep deprivation experiments eventually terminated with the premature death of the animals but the underlying cause of lethality still remains unknown. In rats and dogs pups, death is associated with a severe systemic syndrome bearing important metabolic changes and clear signs of suffering, making it difficult to ultimately conclude whether lethality is caused by the mere removal of sleep or rather by the very invasive and stressful procedures employed to keep the animals awake (6,11,12). In the cockroach Diploptera punctata, sleep deprivation was achieved by continuously startling the animals (8), without however accounting for exhaustion-induced stress, a known lethal factor for other species of cockroaches (13)(14)(15). ...
... In our view, they command, instead, for a thorough review of existing sleep deprivation literature. The experiments of chronic sleep deprivation performed in dogs pups at the end of 1800s are universally considered too primitive to be trustworthy and too unethically stressful to be reproducible in modern times (6). The early Drosophila experiments were too preliminary to depict a whole picture, marred by a limited number of animals (12 individuals) and by the adoption of a procedure that is not easily reproducible (human experimenters finger tapping on the tubes) (10). ...
Sleep appears to be a universally conserved phenomenon among the animal kingdom but whether this striking evolutionary conservation underlies a basic vital function is still an open question. Using novel technologies, we conducted an unprecedentedly detailed high-throughput analysis of sleep in the fruit fly Drosophila melanogaster, coupled with a life-long chronic and specific sleep restriction. Our results show that some wild-type flies are virtually sleepless in baseline conditions and that complete, forced sleep restriction is not necessarily a lethal treatment in wild-type Drosophila melanogaster. We also show that circadian drive, and not homeostatic regulation, is the main contributor to sleep pressure in flies. We propose a three-partite model framework of sleep function, according to which, total sleep accounts for three components: a vital component, a useful component, and an accessory component.
... In recent years, a main focus of sleep research has been on the relationship between sleep and synaptic plasticity (Stickgold and Walker, 2013;Dissel et al., 2015a;Dissel and Shaw, 2017;Seibt and Frank, 2019;Tononi and Cirelli, 2020;Frank, 2021). Nevertheless, it is important to note that thermoregulation has been implicated in sleep regulation and function from the earliest days of research in the field (De Manaceine, 1894;Kleitman and Doktorsky, 1933;Bentivoglio and Grassi-Zucconi, 1997). Indeed, decades of research have firmly established that sleep and thermoregulation are inextricably intertwined on many levels (Glotzbach and Heller, 1976;Parmeggiani et al., 1983;Szymusiak and McGinty, 1990). ...
... Historically, sleep deprivation has been used as a powerful tool to evaluate sleep regulation and function (Kleitman, 1963;Rechtschaffen et al., 1989a;Bentivoglio and Grassi-Zucconi, 1997). As mentioned, sleep deprivation was used in the earliest of sleep studies where it was found that sleep loss changed temperature regulation. ...
Despite the fact that sleep deprivation substantially affects the way animals regulate their body temperature, the specific mechanisms behind this phenomenon are not well understood. In both mammals and flies, neural circuits regulating sleep and thermoregulation overlap, suggesting an interdependence that may be relevant for sleep function. To investigate this relationship further, we exposed flies to 12 h of sleep deprivation, or 48 h of sleep fragmentation and evaluated temperature preference in a thermal gradient. Flies exposed to 12 h of sleep deprivation chose warmer temperatures after sleep deprivation. Importantly, sleep fragmentation, which prevents flies from entering deeper stages of sleep, but does not activate sleep homeostatic mechanisms nor induce impairments in short-term memory also resulted in flies choosing warmer temperatures. To identify the underlying neuronal circuits, we used RNAi to knock down the receptor for Pigment dispersing factor, a peptide that influences circadian rhythms, temperature preference and sleep. Expressing UAS-PdfrRNAi in subsets of clock neurons prevented sleep fragmentation from increasing temperature preference. Finally, we evaluated temperature preference after flies had undergone a social jet lag protocol which is known to disrupt clock neurons. In this protocol, flies experience a 3 h light phase delay on Friday followed by a 3 h light advance on Sunday evening. Flies exposed to social jet lag exhibited an increase in temperature preference which persisted for several days. Our findings identify specific clock neurons that are modulated by sleep disruption to increase temperature preference. Moreover, our data indicate that temperature preference may be a more sensitive indicator of sleep disruption than learning and memory.
... In recent years, a main focus of sleep research has been on the relationship between sleep and synaptic plasticity (Stickgold and Walker, 2013;Dissel et al., 2015a;Dissel and Shaw, 2017;Seibt and Frank, 2019;Tononi and Cirelli, 2020;Frank, 2021). Nevertheless, it is important to note that thermoregulation has been implicated in sleep regulation and function from the earliest days of research in the field (De Manaceine, 1894;Kleitman and Doktorsky, 1933;Bentivoglio and Grassi-Zucconi, 1997). Indeed, decades of research have firmly established that sleep and thermoregulation are inextricably intertwined on many levels (Glotzbach and Heller, 1976;Parmeggiani et al., 1983;Szymusiak and McGinty, 1990). ...
... Historically, sleep deprivation has been used as a powerful tool to evaluate sleep regulation and function (Kleitman, 1963;Rechtschaffen et al., 1989a;Bentivoglio and Grassi-Zucconi, 1997). As mentioned, sleep deprivation was used in the earliest of sleep studies where it was found that sleep loss changed temperature regulation. ...
Despite the fact that sleep deprivation substantially affects the way animals regulate their body temperature, the specific mechanisms behind this phenomenon are not well understood. In both mammals and flies, neural circuits regulating sleep and thermoregulation overlap, suggesting an interdependence that may be relevant for sleep function. To investigate this relationship further, we exposed flies to 12 h of sleep deprivation, or 48 h of sleep fragmentation and evaluated temperature preference in a thermal gradient. Flies exposed to 12 h of sleep deprivation chose warmer temperatures after sleep deprivation. Importantly, sleep fragmentation, which prevents flies from entering deeper stages of sleep, but does not activate sleep homeostatic mechanisms nor induce impairments in short-term memory also resulted in flies choosing warmer temperatures. To identify the underlying neuronal circuits, we used RNAi to knock down the receptor for Pigment dispersing factor , a peptide that influences circadian rhythms, temperature preference and sleep. Expressing UAS- Pdfr RNAi in subsets of clock neurons prevented sleep fragmentation from increasing temperature preference. Finally, we evaluated temperature preference after flies had undergone a social jet lag protocol which is known to disrupt clock neurons. In this protocol, flies experience a 3 h light phase delay on Friday followed by a 3 h light advance on Sunday evening. Flies exposed to social jet lag exhibited an increase in temperature preference which persisted for several days. Our findings identify specific clock neurons that are modulated by sleep disruption to increase temperature preference. Moreover, our data indicate that temperature preference may be a more sensitive indicator of sleep disruption than learning and memory.
... She published important contributions to biochemistry, physiology, and sleep deprivation. She discovered that the negative effects of prolonged sleep deprivation originated in the brain and demonstrated that sleep is more important than food for the preservation of life (Bentivoglio and Grassi-Zucconi, 1997). Manasseina published the first comprehensive handbook on sleep in 1889, in Russian. ...
... She countered, also through her research, the pervasive prejudice that women were intellectually inferior to men. In the 1920s, Vogt explicitly stated that her research did not support the hypothesis of a difference between male and female brains (Akkermans, 2018). ...
About half of graduate and postgraduate students and one-third of faculty in the field of neuroscience are women. The proportion of women neuroscientists tend to decrease as they progress through the career ladder. Their responsibilities and their opportunities to secure research funding also tend to be lower compared to men, as in most scientific disciplines and professions. The multiple factors contributing to the under-representation of women in higher-level roles have historical, social, and cultural roots. A process of forgetfulness of pioneer women from the last century prevented the field from having role models in which upcoming generations of women neuroscientists could have identified. Maria Manasseina, Cécile Vogt, Augusta Dejerine Klumpke are only some early pioneers who have recently been rediscovered. The available data show that the profiles of women neuroscientists are overlooked and their remarkable findings receive less recognition. Conscious and unconscious gender biases also affect the evaluation and recruitment process. The presence of cultural and institutional barriers continues to hinder equal opportunities in all aspects of the scientific and academic career. The initiatives launched so far to increase awareness of such barriers and diversity in the workplace have produced a slight improvement but further action should be taken and supported to improve the condition of women in neuroscience.
... The noxious consequences of the lack of sleep have been known for a long time and have been used as a form of torture throughout history. However, the first reported experimental studies of sleep deprivation, especially the total absence of sleep, were published at the end the nineteenth century [11]. Conducted on dogs kept awake by constant activity or by using a bespoke cage keeping the animals awake without forced locomotion, they showed that total sleep loss led to 'psychic exhaustion', severe brain degenerations and was lethal after 4-17 days. ...
... Conducted on dogs kept awake by constant activity or by using a bespoke cage keeping the animals awake without forced locomotion, they showed that total sleep loss led to 'psychic exhaustion', severe brain degenerations and was lethal after 4-17 days. The second half of the nineteenth century also saw the emergence of clinical observations revealing the adverse effects of prolonged sleep deprivation and insomnia, provoking severe psychic disturbances such as delirium, hallucinations and emotional disruption [11,12]. Later studies on the effects of extended sleep loss in healthy people documented more detailed sleep-deprivation-induced psychopathological symptoms, including perceptual distortions, mood changes and psychosis [12]. ...
Sleep is highly conserved across evolution, suggesting vital biological functions that are yet to be fully understood. Animals and humans experiencing partial sleep restriction usually exhibit detrimental physiological responses, while total and prolonged sleep loss could lead to death. The perturbation of sleep homeostasis is usually accompanied by an increase in hypothalamic-pituitary-adrenal (HPA) axis activity, leading to a rise in circulating levels of stress hormones (e.g. cortisol in humans, corticosterone in rodents). Such hormones follow a circadian release pattern under undisturbed conditions and participate in the regulation of sleep. The investigation of the consequences of sleep deprivation, from molecular changes to behavioural alterations, has been used to study the fundamental functions of sleep. However, the reciprocal relationship between sleep and the activity of the HPA axis is problematic when investigating sleep using traditional sleep-deprivation protocols that can induce stress per se. This is especially true in studies using rodents in which sleep deprivation is achieved by exogenous, and potentially stressful, sensory-motor stimulations that can undoubtedly confuse their conclusions. While more research is needed to explore the mechanisms underlying sleep loss and health, avoiding stress as a confounding factor in sleep-deprivation studies is therefore crucial. This review examines the evidence of the intricate links between sleep and stress in the context of experimental sleep deprivation, and proposes a more sophisticated research framework for sleep-deprivation procedures that could benefit from recent progress in biotechnological tools for precise neuromodulation, such as chemogenetics and optogenetics, as well as improved automated real-time sleep-scoring algorithms.
... Likewise as Tarchanoff, the first experimental study on sleep deprivation Manasseina presented at the International Congress of Medicine in Rome in 1894, where both scientists traveled together to discuss their data on sleep research. She performed her investigation on 10 puppies (2, 3, or 4 months old), fed by their mothers, by keeping the animals in constant activity [4,6]. ...
... They also found that prolong and continuous insomnia could affect brain histology. The investigators generally supported Manasseina's data on the relation of sleep with cerebral activity and suggested that the function of sleep -yet unknown -is vital [4]. In 1896 two American psychologists, G.T.V. Patrick and J.A. Gilbert, clearly inspired by Manasseina's pioneer work, performed the first study of sleep deprivation in humans [6]. ...
This article is dedicated to two outstanding scientists of the nineteenth century, Ivan Tarchanoff (Ivane Tarkhnishvili) and Maria Manasseina, Russian physiologists worked at the St. Petersburg Medico-Surgical Academy. Among the numerous contributions of Tarchanoff was the discovery of the skin galvanic reflex and of the influence of X-rays on physiological systems and functions, among them the central nervous system and animal behavior, the heart and circulation, and embryonic development. Maria Manasseina, one of the first Russian women-doctor great contributed in biochemistry and both scientists are founders of experimental sleep research by their original discoveries. Tarchanoff and Manasseina presented their interesting findings in experimental studies on sleep at the International Congress of Medicine in Rome in 1894 and published their papers in Archives Italiennes de Biologie in the same year.
... Although not focused on health, Patrick and Gilbert's studies at the University of Iowa around this same time revealed that sleep deprivation impaired human performance (Patrick and Gilbert, 1896). For a more complete historical accounting of early sleep deprivation studies, we refer the interested reader to reviews by Kovalzon (2009) and Bentivoglio and Grassi-Zucconi (1997). ...
This narrative traces the historical discoveries that formed the basis of our current understanding of sleep - immune interactions.
... Sleep is a fundamental biological process that plays a crucial role in many physiological functions. Studies using various model organisms have demonstrated that severe sleep loss or total sleep deprivation can even have fatal effects (Bentivoglio and Grassi-Zucconi, 1997;Rechtschaffen et al., 1983;Shaw et al., 2002). While the exact biological function of sleep is not fully understood, research has suggested that it plays a crucial role in memory consolidation, which is the process of converting newly acquired memories into a permanent form. ...
Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma, and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with optical imaging tools during sleep-wake cycles in mice. We found that the activity of major glutamatergic cell populations in the DG is organized into infraslow oscillations (0.01–0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep, compared to that during wakefulness. Further experiments revealed that the infraslow oscillation in the DG was correlated with rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by Htr1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.
... Epidemiological data and individuals with chronic sleep loss reveal a link between shortened sleep duration and serious health problems [81,82]. Additionally, in several model organisms, sleep restriction can lead to premature death [48,[83][84][85][86]. Lifespan is reduced in Nf1 mutant flies [87], but its relationship to reduced sleep or circadian dysregulation has been unclear. ...
Neural regulation of sleep and metabolic homeostasis are critical in many aspects of human health. Despite extensive epidemiological evidence linking sleep dysregulation with obesity, diabetes, and metabolic syndrome, little is known about the neural and molecular basis for the integration of sleep and metabolic function. The RAS GTPase-activating gene Neurofibromin (Nf1) has been implicated in the regulation of sleep and metabolic rate, raising the possibility that it serves to integrate these processes, but the effects on sleep consolidation and physiology remain poorly understood. A key hallmark of sleep depth in mammals and flies is a reduction in metabolic rate during sleep. Here, we examine multiple measures of sleep quality to determine the effects of Nf1 on sleep-dependent changes in arousal threshold and metabolic rate. Flies lacking Nf1 fail to suppress metabolic rate during sleep, raising the possibility that loss of Nf1 prevents flies from integrating sleep and metabolic state. Sleep of Nf1 mutant flies is fragmented with a reduced arousal threshold in Nf1 mutants, suggesting Nf1 flies fail to enter deep sleep. The effects of Nf1 on sleep can be localized to a subset of neurons expressing the GABAA receptor Rdl. Sleep loss has been associated with changes in gut homeostasis in flies and mammals. Selective knockdown of Nf1 in Rdl-expressing neurons within the nervous system increases gut permeability and reactive oxygen species (ROS) in the gut, raising the possibility that loss of sleep quality contributes to gut dysregulation. Together, these findings suggest Nf1 acts in GABA-sensitive neurons to modulate sleep depth in Drosophila.
... Studies on model organisms have demonstrated that severe sleep loss can even be fatal, emphasizing the importance of sleep (Rechtschaffen, Gilliland et al. 1983, Bentivoglio and Grassi-Zucconi 1997, Shaw, Tononi et al. 2002. While the exact biological function of sleep is not fully understood, research has suggested that it plays a crucial role in memory consolidation, which is the process of converting newly acquired memories into a permanent form. ...
The importance of sleep in memory consolidation is well-established, with the hippocampal CA1 and CA3 subregions playing a crucial role in this process. The current working hypothesis postulates that episodic memory traces captured during waking hours are replayed in the hippocampal CA1-CA3 areas and transferred to the cortex for long-term storage during sleep. While the entorhinal cortex provides sensory and spatial information primarily to the hippocampus via the dentate gyrus (DG), the DG has traditionally been regarded as a "silent partner" in memory consolidation. The transfer of captured memory traces from the DG to downstream hippocampal areas remains largely unknown. To investigate this, we used optical imaging tools to record neural activity in the DG during different sleep stages. Strikingly, we found that many of the DG cells are even more active during sleep than wakefulness and the populational activity in the DG slowly oscillates during non-REM (NREM) sleep. The cycles of this oscillatory activity coincided with microarousals and were tightly locked to brief serotonin (5-HT) bursts during NREM sleep. Pharmacological blockade of 5-HT1a receptors abolished the calcium oscillations in the DG. Furthermore, the genetic knockdown of 5-HT1a receptors in the DG lead to memory impairment in spatial and contextual memory tasks. Together, our findings suggest that serotonin-driven infraslow calcium oscillations in the DG during NREM sleep are necessary for memory consolidation.
... glutathione Background Insufficient sleep leads to dysfunction of cognition, immunity, metabolism, and circulatory systems [1][2][3][4]. Numerous studies have linked sleep deprivation to serious health problems [5,6], and sleep restriction can cause premature mortality in model organisms, including rats, flies, and dogs [7,8]. Adequate sleep in early life development is necessary for normal brain function, as the brain maturation of children and adolescents occurs at a critical time after birth [9]. ...
Background
Sleep is crucial for survival. Sleep deprivation causes ROS accumulation and, consequently, oxidative stress. The goal of the study was to evaluate gingival crevicular fluid (GCF) levels of the oxidative stress status hydrogen peroxide (H 2 O 2 ), superoxide glutathione (GSH), and cellular oxidative damage marker malondialdehyde (MDA) in school-aged children and teenagers with insufficient sleep.
Methods
This study investigated sleep duration in 80 participants from two different developmental stages: school-aged children (6–13 years) and teenagers (14–17 years). GCF samples were obtained from all individuals, and samples were investigated to detect H 2 O 2 , GSH, and MDA levels using the micro method.
Results
Results reveal that GCF MDA and H 2 O 2 in school-age children and teenagers with insufficient sleep were significantly higher than in children with sufficient sleep. GCF GSH with insufficient sleep was insignificantly lower than in children with sufficient sleep. There was no significant difference between school-age and teenage populations.
Conclusion
Sleep deprivation causes increased levels of oxidative stress in gingival crevicular fluid, and adequate sleep is essential for maintaining redox balance.
... Accumulating evidence suggests that sleep is essential for survival in invertebrate and vertebrate animals (Rechtschaffen et al., 1989;Bentivoglio and Grassi-Zucconi, 1997;Shaw et al., 2002;Vaccaro et al., 2020). Thus, the core sleep regulatory genes may be essential for survival in mice. ...
Classical forward and reverse mouse genetics require germline mutations and, thus, are unwieldy to study sleep functions of essential genes or redundant pathways. It is also time-consuming to conduct electroencephalogram/electromyogram-based mouse sleep screening owing to labor-intensive surgeries and genetic crosses. Here, we describe a highly accurate SleepV (video) system and adeno-associated virus (AAV)-based adult brain chimeric (ABC)-expression/knockout (KO) platform for somatic genetics analysis of sleep in adult male or female mice. A pilot ABC screen identifies CREB and CRTC1, of which constitutive or inducible expression significantly reduces quantity and/or quality of non-rapid eye movement sleep. Whereas ABC-KO of exon 13 of Sik3 by AAV-Cre injection in Sik3-E13flox/flox adult mice phenocopies Sleepy (Sik3Slp/+) mice, ABC-CRISPR of Slp/Sik3 reverses hypersomnia of Sleepy mice, indicating a direct role of SLP/SIK3 kinase in sleep regulation. Multiplex ABC-CRISPR of both orexin/hypocretin receptors causes narcolepsy episodes, enabling one-step analysis of redundant genes in adult mice. Therefore, this somatic genetics approach should facilitate high-throughput analysis of sleep regulatory genes, especially for essential or redundant genes, in adult mice by skipping mouse development and minimizing genetic crosses.SIGNIFICANCE STATEMENTThe molecular mechanisms of mammalian sleep regulation remain unclear. Classical germline mouse genetics are unwieldy to study sleep functions of essential genes or redundant pathways. The EEG/EMG-based mouse sleep screening is time-consuming owing to labor-intensive surgeries and lengthy genetic crosses. To overcome these "bottlenecks", we developed a highly accurate video-based sleep analysis system and adeno-associated virus-mediated ABC-expression/knockout platform for somatic genetics analysis of sleep in adult mice. These methodologies facilitate rapid identification of sleep regulatory genes, but also efficient mechanistic studies of the molecular pathways of sleep regulation in mice.
... [24] Researchers in the 19th century found that sleep deprivation is lethal in dogs after several days. [25] Also, later studies showed that sleep deprivation in rats leads to death after two to three weeks, furthermore, destruction of the immune system of the host by a systemic bacterial infection is reported. [26][27][28] The idea of sleep deprivation lowering the body's defense system is supported by these studies. ...
Sleep disruption and related disorders are very common among humans. However, this situation is mostly underestimated. Aside from its contribution to daily life functions, sleep quality is also important as a risk factor for a variety of diseases, including neurodegenerative disorders, metabolic diseases, and cardiovascular diseases. The diagnosis and treatment of such diseases may be difficult, but once they are treated, the patients' quality of life will greatly improve. This review aimed to compile and represent information on sleep deprivation, as well as the relationship between sleep and the immune system.
... Henri Pieron and Rene Legendre were convinced that a "hypnotoxin" circulating in the blood of insomniac animals would induce sleep in a non-sleep-deprived one (Legendre & Piéron, 1908). Indeed, they reported that injection of cerebrospinal fluid (CSF) from a sleep-deprived dog into the cisterna magna of a sleep-satiated animal induced sleep in the recipient for 2-6h following the injection (reviewed in (Bentivoglio & Grassi-Zucconi, 1997)). In the 1930s-1950s, neural theories proposed by von Economo, Hess, Moruzzi, Nauta, and others overshadowed the humoral theories of sleep and drew the attention to "regulating centers" (e.g., "waking center" and "sleep center") located in the central nervous system (Hess, 1944;Moruzzi & Magoun, 1949;Nauta, 1993;C. ...
... Traditionally, sleep has been studied as part of psychology and medicine, but the study of sleep from a neuroscience perspective has emerged with advances in technology and the expansion of neuroscience research since the second half of the twentieth century (Bentivoglio and Grassi-Zucconi 1997). The development of improved polysomnographic techniques using fix electrodes to analyze the electrophysiological activity of the brain by electroencephalography (EEG), and also muscles by electromyogram (EMG), heart by electrocardiogram (ECG), and eye by electrooculography (EOG) as a complementary, led scientists to recognize and categorize the stages of sleep. ...
Spices have been added to foods for centuries as flavors, preservatives, and colors and have also been used in traditional medicine in various countries to treat many diseases. Spices play an important role in human health and can be considered as the first functional foods. Although the amount of spices consumed is very low compared to many other foods, the role of spices in the daily diet should not be underestimated due to their health properties. Saffron, ginger, cinnamon, and turmeric are four globally common spices that have been widely used owing to well-known medical benefits in different traditional medicine systems, including Ayurveda, traditional Chinese, and Persian medicine since ancient times. Some general or specific health benefits of these spices include anti-inflammatory, antioxidantAntioxidant, antimicrobial, anti-diabetic, and antihypertensive activities, which have potential protective properties against some ailments such as cancer, type 2 diabetesDiabetes, neurodegenerative and cardiovascular diseases. Recent scientific studies on the therapeutic properties of these common spices have been reviewed in this chapter.
... Traditionally, sleep has been studied as part of psychology and medicine, but the study of sleep from a neuroscience perspective has emerged with advances in technology and the expansion of neuroscience research since the second half of the twentieth century (Bentivoglio and Grassi-Zucconi 1997). The development of improved polysomnographic techniques using fix electrodes to analyze the electrophysiological activity of the brain by electroencephalography (EEG), and also muscles by electromyogram (EMG), heart by electrocardiogram (ECG), and eye by electrooculography (EOG) as a complementary, led scientists to recognize and categorize the stages of sleep. ...
Nowadays, there is an ever-increasing trend in the case of nutraceuticals and superfoods as a result of growing concerns about the effects of diet on health. Nutraceuticals are natural biologically active compounds extractable from various food sources. In contrast, a superfood is any fresh or processed food claimed to have particular health-promoting attributes and/or can decrease the risk of chronic disease further than its basic nutritionalNutritional function. Different studies have shown that the nutraceuticals and superfoods have various beneficial physiological effects, and their consumption can reduce the risk for disease development or can even cure some diseases because they are rich sources of a wide range of bioactiveBioactive molecules and specific nutrients. Some examples of nutraceuticals and superfoods are curcumin, pomegranate, camel milk, bioactive peptides, and walnut, which their potential health benefits and applications for the development of functional foodFunctional food products with health-promoting properties have been studied in the present chapter.
... • People with anteretrograde amnesia are unable to create new memories. • Sleep deprivation results in death [101]. • Dolphins, whales, seals and some birds are capable of putting one hemisphere of their brains to sleep [102]. ...
The design of any artificial intelligence is an interdisciplinary pursuit that requires keeping within perspective, the various properties of matter and life in the known universe, while remaining cautious of biases and misconceptions that arise from the limitations of prior learning, available tools and sensory capabilities. This paper curates a vast collection of human knowledge gathered during the process of exploring and questioning the fundamentals of why the mechanisms that constitute life were built in specific ways, and re-questioning those facts using anomalies that sometimes contradict or expose errors in human assumptions of life and intelligence. A meta-analysis of such knowledge at a single glance also helps identify interesting patterns in various phenomena that can in-time, spur creative solutions, alter the direction of research, assist with intelligent inferences and hopefully result in the identification and creation of artificial intelligence.<br
... Especially in humans, it guides our everyday lives and is one of the key activities that keep us healthy and sane. Both sleep deprivation and the inability to sleep (insomnia) are therefore unpleasant for an individual, have been shown to have harmful physiological effects, 1 and constitute a huge burden on society as a whole. 2 In order to ameliorate insomnia, two ways can be envisioned: one is to make the brain artificially sleepy and the other is to block the signals that mediate wakefulness. While more traditional insomnia medications have tried to do the former, the latter seems like a strategy that should lead to fewer side effects. ...
The orexin receptors are peptide-sensing G protein-coupled receptors that are intimately linked with regulation of the sleep/wake cycle. We used a recently solved X-ray structure of the orexin receptor subtype 2 in computational docking calculations with the aim to identify additional ligands with unprecedented chemotypes. We found validated ligands with a high hit rate of 29% out of those tested, none of them showing selectivity with respect to the orexin receptor subtype 1. Furthermore, of the higher-affinity compounds examined, none showed any agonist activity. While novel chemical structures can thus be found, selectivity is a challenge owing to the largely identical binding pockets.
... A number of pioneering experimental sleep studies were performed in the 19 th century. 1 In 1894, the Russian physician Marie de Manaceine submitted dogs to continuous stimulation to evaluate the effects of sleep deprivation (SD). 2 The results revealed a fascinating discoverysleep absence caused the puppies' deaths. Four years later, Lambert Daddi and Giulio Tarozzi kept dogs awake by walking them until they died, which occurred after 9 to 17 days of SD. 3 Interestingly, both studies revealed that SD provoked alterations in body temperature and blood cells combined with fatigue and small hemorrhages in the brain. ...
... We now know that both cytokines likewise mediate the SWS response to an infectious challenge (353). With respect to the sleep-to-immune directionality, early studies in the late 19th century showed that total sleep deprivation in dogs leads to death after several days (reviewed in Ref. 38). Later studies using more controlled approaches found that sleep deprivation of rats is lethal after~2-3 wk (459), and a breakdown of host defense indicated by a systemic bacterial infection was reported after applying the same method of sleep deprivation (172,175). ...
Sleep and immunity are bidirectionally linked. Immune system activation alters sleep, and sleep in turn affects the innate and adaptive arm of our body's defense system. Stimulation of the immune system by microbial challenges triggers an inflammatory response, which, depending on its magnitude and time course, can induce an increase in sleep duration and intensity, but also a disruption of sleep. Enhancement of sleep during an infection is assumed to feedback to the immune system to promote host defense. Indeed, sleep affects various immune parameters, is associated with a reduced infection risk, and can improve infection outcome and vaccination responses. The induction of a hormonal constellation that supports immune functions is one likely mechanism underlying the immune-supporting effects of sleep. In the absence of an infectious challenge, sleep appears to promote inflammatory homeostasis through effects on several inflammatory mediators, such as cytokines. This notion is supported by findings that prolonged sleep deficiency (e.g., short sleep duration, sleep disturbance) can lead to chronic, systemic low-grade inflammation and is associated with various diseases that have an inflammatory component, like diabetes, atherosclerosis, and neurodegeneration. Here, we review available data on this regulatory sleep-immune crosstalk, point out methodological challenges, and suggest questions open for future research.
... It has been widely recognized a significant reduction of voluntary sleep time over the past decades, especially during the last century (Walsleben et al., 2004). Unfortunately, this leads to significant consequences to health since sleep deprivation (SD) induces several harmful effects to biological systems (Bentivoglio and Grassi-Zucconi, 1997). This is supported by several researchers showing a myriad of pathobiological outcomes induced by sleep loss either in humans or in rodents (Leibowitz et al. 2006). ...
The aim of this study was to evaluate the toll like signaling pathway and atrophy after sleep deprivation (SD) in rat masticatory muscles: masseter and temporal. A total of twenty-four animals was distributed into three groups: Control group (CTL, n = 8), subjected to SD for 96 hours (SD96, n = 8) and subjected to SD for 96 hours more 96 hours of sleep recovery (SD96 + R, n = 8). Histopathological analysis revealed the presence of acute inflammatory cells, congested vessels, fibrosis and high cellularity in the skeletal muscle fibers from masseter and temporal submitted to SD. These morphological alterations were not observed in the control group since neither inflammatory cells nor congested vessels were observed to this group. In the group SD96 + R, the absence of inflammation was noticed to the masseter only. In this group, COX-2 and TNF-alpha downregulation were detected when comparing to control group. MyD88 and pIKK decreased in SD96 and SD96+ R groups being pNFKBp50 downregulatated in SD96 + R. MyD88 expression increased in rats submitted to SD96 and SD96 + R in temporal when compared to control group. On the other hand, pIKK decreased the protein expression in groups SD96 and SD96 + R while pNFKBp50 showed a decreased protein expression in group SD96 only. The activation of atrophy by means of MAFbx upregulation was detected in temporal muscle in SD96 and SD96 + R when compared to control. In summary, our results show that SD is able to induce morphological alterations in rat masticatory muscles. Toll like signaling pathway and atrophy play important roles in ethiopathogenesis induced by SD, being dependent of skeletal muscle type. This article is protected by copyright. All rights reserved
... In today's modern lifestyle, sleep deprivation (SD) is a common phenomenon which can seriously affect the abilities of the subjected individuals (6). The pioneering study on SD was performed on puppies at the end of the 19th century (7) followed by other reports on experimental animal insomnia, mainly in dogs (8) and formal human SD research. In the following years, the dog as animal model for SD was replaced by cat and later by rodents, with the rat being the animal of choice to date (9). ...
Sleep deprivation (SD) is known to result in a range of neurological, cognitive and physical consequences in chronically-afflicted subjects. The respiratory nuclei of brain-stem tend to play a pivotal part in the regulating sleep function, hence hypothesized to be affected in various types of sleep-related dysfunctions. The purpose of this methodological report is to explain the techniques of REM sleep deprivation and stereology which can be used to consider changes of the quantitative properties of the respiratory nuclei in sleep-deprived rats.
... These experiments, which were first done in 19th century ( [55]; Tarozzi [88]), demonstrated the fatal outcome of prolonged sleep deprivation in dogs. A review of pioneering studies, which had used the method of sleep deprivation for investigation of sleep function, is given in a special work (Bentivoglio & Grassi-Zucconi [11]). Studies with the same goal, but at a new technical level, continued in the 20th century in dogs (Bikov [12]) and later in rats, in the laboratory of Allan Rechtschaffen, with an elegant disk-over-water method of sleep deprivation (Rechtschaffen et al. [78]; Everson et al. [29]). ...
It was noticed long ago that sleep disorders or interruptions to the normal sleep pattern were associated with various gastrointestinal disorders. We review the studies which established the causal link between these disorders and sleep impairment. However, the mechanism of interactions between the quality of sleep and gastrointestinal pathophysiology remained unclear. Recently, the visceral theory of sleep was formulated. This theory proposes that the same brain structures, and particularly the same cortical sensory areas, which in wakefulness are involved in processing of the exteroceptive information, switch during sleep to the processing of information coming from various visceral systems.We review the studies which demonstrated that neurons of the various cortical areas (occipital, parietal, frontal) during sleep began to fire in response to activation coming from the stomach and small intestine. These data demonstrate that, during sleep, the computational power of the central nervous system, including all cortical areas, is engaged in restoration of visceral systems. Thus, the general mechanism of the interaction between quality of sleep and health became clear.
Sleep loss dysregulates cellular metabolism and energy homeostasis. Highly metabolically active cells, such as neurons, enter a catabolic state during periods of sleep loss, which consequently disrupts physiological functioning. Specific to the central nervous system, sleep loss results in impaired synaptogenesis and long-term memory, effects that are also characteristic of neurodegenerative diseases. In this review, we describe how sleep deprivation increases resting energy expenditure, leading to the development of a negative energy balance—a state with insufficient metabolic resources to support energy expenditure—in highly active cells like neurons. This disruption of energetic homeostasis alters the balance of metabolites, including adenosine, lactate, and lipid peroxides, such that energetically costly processes, such as synapse formation, are attenuated. During sleep loss, metabolically active cells shunt energetic resources away from those processes that are not acutely essential, like memory formation, to support cell survival. Ultimately, these findings characterize sleep loss as a metabolic disorder.
Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with optical imaging tools during sleep-wake cycles. We found that the activity of major glutamatergic cell populations in the DG is organized into infraslow oscillations (0.01 – 0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep. Further experiments revealed that the infraslow oscillation in the DG was correlated with rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by 5-HT1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.
Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with electrophysiological and optical imaging tools during sleep-wake cycles. We found that the activity of major glutamatergic cell populations in the DG is organized into infraslow oscillations (0.01 – 0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep. Further experiments revealed that the infraslow oscillation in the DG is modulated by rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by 5-HT1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.
This chapter explores two decades of research using the model organism Drosophila melanogaster to decipher the genetic underpinnings of sleep. The approaches used to map sleep phenotypes to genomic variants and genes are discussed. Also presented are genetic approaches to localize sleep circuitry in the brain and peripheral tissues. Additionally, the chapter explores the role of physiological and environmental context on sleep, including aging, immune response, metabolism, and sleep deprivation. The chapter concludes with some emerging trends based on the present understanding in the field.
Circadian rhythms are present in almost all cells and play a crucial role in regulating various biological processes. Maintaining a stable circadian rhythm is essential for overall health. Disruption of this rhythm can alter the expression of clock genes and cancer-related genes, and affect many metabolic pathways and factors, thereby affecting the function of the immune system and contributing to the occurrence and progression of tumors. This paper aims to elucidate the regulatory effects of BMAL1, clock and other clock genes on immune cells, and reveal the molecular mechanism of circadian rhythm’s involvement in tumor and its microenvironment regulation. A deeper understanding of circadian rhythms has the potential to provide new strategies for the treatment of cancer and other immune-related diseases.
Insomnia is a prevalent sleep disorder characterized by difficulties in initiating sleep or experiencing non-restorative sleep. It is a multifaceted condition that impacts both the quantity and quality of an individual’s sleep. Recent advancements in machine learning (ML), and deep learning (DL) have enabled automated sleep analysis using physiological signals. This has led to the development of technologies for more accurate detection of various sleep disorders, including insomnia. This paper explores the algorithms and techniques for automatic insomnia detection.
Methods: We followed the recommendations given in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) during our process of content discovery. Our review encompasses research papers published between 2015 and 2023, with a specific emphasis on automating the identification of insomnia. From a se- lection of well-regarded journals, we included more than 30 publications dedicated to insomnia detection. In our analysis, we assessed the performance of various meth- ods for detecting insomnia, considering different datasets and physiological signals. A common thread across all the papers we reviewed was the utilization of artificial intel- ligence (AI) models, trained and tested using annotated physiological signals. Upon closer examination, we identified the utilization of 15 distinct algorithms for this de- tection task.
Results: Result: The major goal of this research is to conduct a thorough study to categorize, compare, and assess the key traits of automated systems for identifying insomnia. Our analysis offers complete and in-depth information. The essential com- ponents under investigation in the automated technique include the data input source, objective, machine learning (ML) and deep learning (DL) network, training framework, and references to databases. We classified pertinent research studies based on ML and DL model perspectives, considering factors like learning structure and input data types.
Conclusion: Based on our review of the studies featured in this paper, we have identi- fied a notable research gap in the current methods for identifying insomnia and oppor- tunities for future advancements in the automation of insomnia detection. While the current techniques have shown promising results, there is still room for improvement in terms of accuracy and reliability. Future developments in technology and machine learning algorithms could help address these limitations and enable more effective and efficient identification of insomnia.
Homeostatic control of sleep is typically addressed through mechanical stimulation-induced forced wakefulness and the measurement of subsequent increases in sleep. A major confound attends this approach: biological responses to deprivation may reflect a direct response to the mechanical insult rather than to the loss of sleep. Similar confounds accompany all forms of sleep deprivation and represent a major challenge to the field. Here we describe a new paradigm for sleep deprivation in Drosophila that fully accounts for sleep-independent effects. Our results reveal that deep sleep states are the primary target of homeostatic control and establish the presence of multi-cycle sleep rebound following deprivation. Furthermore, we establish that specific deprivation of deep sleep state results in state-specific homeostatic rebound. Finally, by accounting for the molecular effects of mechanical stimulation during deprivation experiments, we show that serotonin levels track sleep pressure in the fly's central brain. Our results illustrate the critical need to control for sleep-independent effects of deprivation when examining the molecular correlates of sleep pressure and call for a critical reassessment of work that has not accounted for such non-specific effects.
Sleep and immunity have bidirectional relationships. In this chapter, we review the links between sleep and immunity, focusing on immune changes occurring in the insomnia disorder. During physiological sleep, there is a decrease of pro-inflammatory cytokines (IL-1, IL-6 and TNF-α) and a decrease of anti-inflammatory cytokines (IL-4, IL-10). Examinations of ratios of pro-inflammatory and anti-inflammatory cytokines allow to identify rather a pro-inflammatory activity at the beginning of the night and confirm then anti-inflammatory during the second part of the night. Immune cells, as NK-cells, decrease in the blood, due to their migration to secondary lymphoid organs, but their activity increases. Inversely, a short sleep duration appears associated with increased inflammatory processes and increased risk of infection.Only few studies have investigated changes in immunity in patients with insomnia disorder. These studies suggest that insomnia disorder is related to deregulation of the immune system, with an increase in the level of pro-inflammatory cytokines and change in rate of secretion and a decrease in the level of lymphocyte. Insomnia treatments, particularly cognitive behavioral therapy (CBT-I), seems to have a restorative effect not only on sleep, but also on the associated inflammation. Melatonin also seems to reduce inflammation in patients suffering from insomnia disorder.More studies are necessary to better understand the pathophysiology of changes in immune system in patients suffering from insomnia disorders and their clinical implications.KeywordsInsomniaImmunityInflammationSleep immune cross talkSleep disordersSleep deprivationSleep loss
A defining feature of sleep is its homeostatic control, which is most clearly expressed as increased sleep after forced wakefulness. Drosophila has served as a powerful model system for understanding the homeostatic control of sleep and ongoing work continues to be an important complement to studies in mammals and other vertebrate models. Nevertheless, there are significant challenges confronting investigators of sleep regulation in Drosophila. For example, the magnitude of sleep rebound in flies is relatively modest, providing a small dynamic range over which to detect changes in homeostatic responses in experimental subjects. In addition, the perturbation necessary to keep flies awake is associated with physiological and behavioral responses that may obscure homeostatic sleep responses. Furthermore, the analysis of fly sleep as a unitary state, without differentiation between shallow and deep sleep states, clouds our ability to fully characterize homeostatic sleep responses. To address these challenges, we describe the development of a yoked-controlled paradigm for flies that allows us to produce two sets of flies that have experienced identical levels of mechanical perturbation while suffering significantly different amounts of sleep deprivation. Moreover, by differentiating long bouts of sleep from all sleep, we show that flies display significant and lasting homeostatic increases in such long bouts following sleep deprivation, that are only detectable when controlling for the sleep-independent effects of mechanical deprivation. Finally, we illustrate the importance of yoked controls for examining the molecular correlates of sleep pressure. Our work introduces methodological approaches that are likely to support the discovery of new mechanisms of sleep regulation in the fly and calls for the reevaluation of previous work identifying the molecular, physiological, and cellular correlates of sleep pressure.
Although there are still no satisfactory answers to the question of why we need to sleep, a better understanding of its function will help to improve societal attitudes toward sleep. Sleep disorders are very common in neurodegenerative diseases and are a key factor in the quality of life of patients and their families. Alzheimer’s disease (AD) is an insidious and irreversible neurodegenerative disease. Along with progressive cognitive impairment, sleep disorders and disturbances in circadian rhythms play a key role in the progression of AD. Sleep and circadian rhythm disturbances are more common in patients with AD than in the general population and can appear early in the course of the disease. Therefore, this review discusses the bidirectional relationships among circadian rhythm disturbances, sleep disorders, and AD. In addition, pharmacological and non-pharmacological treatment options for patients with AD and sleep disorders are outlined.
Animal models are extremely valuable tools in the study of sleep. The similarities between animal sleep, particularly in higher mammals such as rats, mice, cats, and dogs, and human sleep make it possible to employ complex experimental designs in sleep science and extrapolate the results to humans. By intervening or modulating animal sleep with mechanical devices or drugs, scientists are able to study sleep disorders (e.g., restless legs syndrome, obstructive sleep apnea, narcolepsy, sleep-wake circadian rhythm disorders) to an extent that would not be possible otherwise, thereby helping treat millions of patients worldwide.
Sleep pressure, the driving force of the homeostatic sleep regulation, is accumulated during wakefulness and dissipated during sleep. Sleep deprivation (SD) has been used as a method to acutely increase animal’s sleep pressure for investigating the molecular changes under high sleep pressure. However, SD induces changes not only reflecting increased sleep pressure but also inevitable stresses and prolonged wake state itself. The Sik3Sleepy mutant mice (Sleepy) exhibit constitutively high sleep pressure despite sleeping longer, and have been useful as a model of increased sleep pressure. Here we conducted a cross-comparison of brain metabolomic profiles between SD versus ad lib slept mice, as well as Sleepy mutant versus littermate wild-type mice. Targeted metabolome analyses of whole brains quantified 203 metabolites in total, of which 43 metabolites showed significant changes in SD, whereas three did in Sleepy mutant mice. The large difference in the number of differential metabolites highlighted limitations of SD as methodology. The cross-comparison revealed that a decrease in betaine and an increase in imidazole dipeptides are associated with high sleep pressure in both models. These metabolites may be novel markers of sleep pressure at the whole-brain level. Furthermore, we found that intracerebroventricular injection of imidazole dipeptides increased subsequent NREM sleep time, suggesting the possibility that imidazole dipeptides may participate in the regulation of sleep in mice.
Good quality sleep, which is important for health, is influenced by various chemical compounds such as melatoninMelatoninand adenosineAdenosine produced and released in the body in a 24-h cycle. The production of melatonin, which is made of tryptophanTryptophan in the pineal gland, increases in the evening with the onset of darkness, which tells us that it is time to go to bed. Unlike melatonin, adenosine is produced during the day, and with the beginning of darkness, its amount in the body reaches its maximum, playing an essential role in sleep-inducing sleep. The secretion of chemical sleep stimulants, especially melatonin, is also affected by hormones such as norepinephrine and cortisol. These two hormones, which also play a role in restlessness, anxietyAnxiety and stress, suppressing production of melatonin in the body and deprive a person of good quality sleep. The secretion of hormones such as prolactin and growth hormoneHormone is also dependent on sleep. Sleeping slows down the body activities and reduces body temperature, heart rate, respiration rate and energy expenditure. Sleep also plays an important role in stabilizing and improving memory, effective productivity and high concentration levels, maintaining hormonal balance, regulating temperature and heart rate, removing metabolic wastes from the brainBrain, strengthening the immune systemImmune system, healing wounds and reducing inflammation. Adequate sleep has been also reported to enhance athlete performance and lowers blood pressure, allowing the heart and blood vessels to rest.
Sleep is not considered a pathological state, but it consumes a third of conscious human life. This share is much more than most optimistic life extension forecasts that biotechnologies or experimental and medical interventions can offer. Are there insurmountable physical or biological limitations to reducing the duration of sleep? How far can it be avoided without fatal consequences? What means can reduce the length of sleep? It is widely accepted that sleep is necessary for long-term survival. Here we review the limited yet intriguing evidence that is not consistent with this notion. We concentrate on clinical cases of complete and partial loss of sleep and on human mutations that result in a short sleep phenotype. These observations are supported by new animal studies and are discussed from the perspective of sleep evolution. Two separate hypotheses suggest distinct approaches for remodeling our sleep machinery. If sleep serves an unidentified vital physiological function, this indispensable function has to be identified before “sleep prosthesis” (technical, biological, or chemical) can be developed. If sleep has no vital function, but rather represents a timing mechanism for adaptive inactivity, sleep could be reduced by forging the sleep generation system itself, with no adverse effects.
It is nowadays a common practice to “work without sleep and catch up later.” It is not a good idea to keep up with sleep deficit. In recent years, several reports have shown that the consequences of chronic sleep loss are not reversible. It may cause impairment in neuronal functions and neurodegeneration. The energy expenditure, risk of hypertension, cardiovascular disease increases, and the immune system diffuses into a compromised state during sleep deprivation. Sleep deprivation may cause the deposition of toxic metabolites usually produced during long hours of wakefulness. It may impair neurological functions and cause the death of brain cells. Sleep loss is affecting the health of children, adults, and elderly people. The brain shrinks, and the body becomes vulnerable to diseases. It affects the brain and neural development in children too. It is an irony that though its implications are gradually becoming clear, still it is turning out to be an epidemic in our modern society. Sleep loss can become a liability for the people having unusual lifestyles, working for long hours, in the night shift, and the subjects suffering from chronic sleep disorders. Here, we review some evidence to appraise the understanding of the known changes in our brain and body after prolonged sleep deprivation.
The view that sleep is essential for survival is supported by the ubiquity of this behavior, the apparent existence of sleep-like states in the earliest animals, and the fact that severe sleep loss can be lethal. The cause of this lethality is unknown. Here we show, using flies and mice, that sleep deprivation leads to accumulation of reactive oxygen species (ROS) and consequent oxidative stress, specifically in the gut. ROS are not just correlates of sleep deprivation but drivers of death: their neutralization prevents oxidative stress and allows flies to have a normal lifespan with little to no sleep. The rescue can be achieved with oral antioxidant compounds or with gut-targeted transgenic expression of antioxidant enzymes. We conclude that death upon severe sleep restriction can be caused by oxidative stress, that the gut is central in this process, and that survival without sleep is possible when ROS accumulation is prevented.
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This article addresses the charge that the introduction of the electric light in the late nineteenth century increased disruptions to the human body's biological processes and interfered with the oscillating sleeping-waking cycle. By considering the nineteenth century research into the factors that motivate and disrupt sleep in concert with contemporary discussions of the physiology of street lighting, this article exposes how social and political forces shaped the impact of artificial light on sleep and, more perniciously, on bodily autonomy. As a close reading of artificial light in three influential dystopian novels building on these historical contexts demonstrates, dystopian fiction challenges the commonplace assumption that the advent of the electric light, or of widespread street lighting in public urban spaces, posed an immediate or inherent threat to sleep. Beginning with H. G. Wells's The Sleeper Awakes (1899), in which the eponymous sleeper emerges from a cataleptic trance into a future in which electric light and power are used to control the populace, representations of artificial light in early dystopian fiction of the late nineteenth and early twentieth centuries depict a nightmare of total illumination in which the state exerted its control over the individual. In Aldous Huxley's Brave New World (1932), constant artificial illumination plays a vital role in the chemical and behavioural conditioning undergone by individuals in a post-Fordian world. George Orwell intensifies this relationship between light and individual autonomy in Nineteen Eighty-Four (1949), where access to electric current (and thus light) is limited at certain times of the day, brownouts and electrical rationing occur intermittently, and total illumination is used to torture and reprogram individuals believed to have betrayed Big Brother.
Objective:
Disrupted sleep increases CSF levels of tau and β-amyloid (Aβ) and is associated with an increased risk of Alzheimer disease (AD). Our aim was to determine whether acute sleep loss alters diurnal profiles of plasma-based AD-associated biomarkers.
Methods:
In a 2-condition crossover study, 15 healthy young men participated in 2 standardized sedentary in-laboratory conditions in randomized order: normal sleep vs overnight sleep loss. Plasma levels of total tau (t-tau), Aβ40, Aβ42, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using ultrasensitive single molecule array assays or ELISAs, in the fasted state in the evening prior to, and in the morning after, each intervention.
Results:
In response to sleep loss (+17.2%), compared with normal sleep (+1.8%), the evening to morning ratio was increased for t-tau (p = 0.035). No changes between the sleep conditions were seen for levels of Aβ40, Aβ42, NfL, or GFAP (all p > 0.10). The AD risk genotype rs4420638 did not significantly interact with sleep loss-related diurnal changes in plasma levels of Aβ40 or Aβ42 (p > 0.10). Plasma levels of Aβ42 (-17.1%) and GFAP (-12.1%) exhibited an evening to morning decrease across conditions (p < 0.05).
Conclusions:
Our exploratory study suggests that acute sleep loss results in increased blood levels of t-tau. These changes provide further evidence that sleep loss may have detrimental effects on brain health even in younger individuals. Larger cohorts are warranted to delineate sleep vs circadian mechanisms, implications for long-term recurrent conditions (e.g., in shift workers), as well as interactions with other lifestyle and genetic factors.
We reviewed the ideas of Ivan Pavlov and his Russian forerunners (Ivan Tarkhanov and Maria Manaseina) and followers (Nikolai Rozjanskiy and Konstantin Bykov) on the functional role of sleep. This analysis led to the conclusion that the state of sleep is connected with functional operations that have not been considered in the past and are also not being investigated in present neuroscience. Thus, a real understanding of the function of sleep may only come with a new neurophysiological paradigm.
Sleep deprivation (SD) is known to result in a range of neurological, cognitive and physical consequences in chronically-afflicted subjects. The respiratory nuclei of brain-stem tend to play a pivotal part in the regulating sleep function, hence hypothesized to be affected in various types of sleep-related dysfunctions. The purpose of this methodological report is to explain the techniques of REM sleep deprivation and stereology which can be used to consider changes of the quantitative properties of the respiratory nuclei in sleep-deprived rats.
The results of a series of studies on total and selective sleep deprivation in the rat are integrated and discussed. These studies showed that total sleep deprivation, paradoxical sleep deprivation, and disruption and/or deprivation of non-rapid eye movement (NREM) sleep produced a reliable syndrome that included death, debilitated appearance, skin lesions, increased food intake, weight loss, increased energy expenditure, decreased body temperature during the late stages of deprivation, increased plasma norepinephrine, and decreased plasma thyroxine. The significance of this syndrome for the function of sleep is not entirely clear, but several changes suggested that sleep may be necessary for effective thermoregulation.
Human total sleep deprivation (TSD) findings up to the present show that the organ most affected is the brain, which displays psychological and some neurological decriments. The rest of the body seems to cope surprisingly well, indicating little sign of stress or malfunction. Central nervous system (CNS) effects also include some impairment to homeostatic control, particularly thermoregulation, which in humans seem to be minor, but for small mammals the outcome may be more serious. In humans, only a specific part of the lost sleep is made up, suggesting that a certain portion of a night's sleep ("obligatory" sleep) is essential to the brain, and that the remainder ("facultative" sleep) is more dispensable. Contrasting with the nominal TSD effects on the body (excluding the CNS), there are claims that sleep is necessary for general tissue growth and repair. The underlying evidence is examined, but is shown to have alternative interpretations. Anabolism may not rely so much on sleep, but on food intake and rest.
The issue of whether sleep is physiologically necessary has been unresolved because experiments that reported deleterious effects of sleep deprivation did not control for the stimuli used to prevent sleep. In this experiment, however, experimental and control rats received the same relatively mild physical stimuli, but stimulus presentations were timed to reduce sleep severely in experimental rats but not in controls. Experimental rats suffered severe pathology and death; control rats did not.
Des hallucinations psycho-sensorielles
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