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Summary: Sleep modulates the immune response, and sleep loss can reduce vaccine immunogenicity; vice versa, immune responses impact sleep. We aimed to investigate the influence of mental health and sleep quality on the immunogenicity of COVID‐19 vaccinations and, conversely, of COVID‐19 vaccinations on sleep quality. The prospective CoVacSer study monitored mental health, sleep quality and Anti‐SARS‐CoV‐2‐Spike IgG titres in a cohort of 1082 healthcare workers from 29 September 2021 to 19 December 2022. Questionnaires and blood samples were collected before, 14 days, and 3 months after the third COVID‐19 vaccination, as well as in 154 participants before and 14 days after the fourth COVID‐19 vaccination. Healthcare workers with psychiatric disorders had slightly lower Anti‐SARS‐CoV‐2‐Spike IgG levels before the third COVID‐19 vaccination. However, this effect was mediated by higher median age and body mass index in this subgroup. Antibody titres following the third and fourth COVID‐19 vaccinations ("booster vaccinations") were not significantly different between subgroups with and without psychiatric disorders. Sleep quality did not affect the humoral immunogenicity of the COVID‐19 vaccinations. Moreover, the COVID‐19 vaccinations did not impact self‐reported sleep quality. Our data suggest that in a working population neither mental health nor sleep quality relevantly impact the immunogenicity of COVID‐19 vaccinations, and that COVID‐19 vaccinations do not cause a sustained deterioration of sleep, suggesting that they are not a precipitating factor for insomnia. The findings from this large‐scale real‐life cohort study will inform clinical practice regarding the recommendation of COVID‐19 booster vaccinations for individuals with mental health and sleep problems. [ABSTRACT FROM AUTHOR]

Summary: Adequate sleep is critical for development and facilitates the maturation of the neurophysiological circuitries at the basis of cognitive and behavioural function. Observational research has associated early life sleep problems with worse later cognitive, psychosocial, and somatic health outcomes. Yet, the extent to which day‐to‐day sleep behaviours (e.g., duration, regularity) in early life relate to non‐rapid eye movement (NREM) neurophysiology—acutely and the long‐term—remains to be studied. We measured sleep behaviours in 32 healthy 6‐month‐olds assessed with actimetry and neurophysiology with high‐density electroencephalography (EEG) to investigate the association between NREM sleep and habitual sleep behaviours. Our study revealed four findings: first, daytime sleep behaviours are related to EEG slow‐wave activity (SWA). Second, night‐time movement and awakenings from sleep are connected with spindle density. Third, habitual sleep timing is linked to neurophysiological connectivity quantified as delta coherence. And lastly, delta coherence at 6 months predicts night‐time sleep duration at 12 months. These novel findings widen our understanding that infants' sleep behaviours are closely intertwined with three particular levels of neurophysiology: sleep pressure (determined by SWA), the maturation of the thalamocortical system (spindles), and the maturation of cortical connectivity (coherence). The crucial next step is to extend this concept to clinical groups to objectively characterise infants' sleep behaviours 'at risk' that foster later neurodevelopmental problems. [ABSTRACT FROM AUTHOR]

Jin-Hu Shi,1,&ast; Jian Ding,2,&ast; Hu Cheng,1,&ast; Huang Fang,3 Jian Zhu4 1Department of Cardiology, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, People’s Republic of China; 2Department of Disinfection and Supply, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, People’s Republic of China; 3Department of Neurology, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, Hubei Province, People’s Republic of China; 4Department of Thoracic Cardiovascular Surgery, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huang Fang, Department of Neurology, General Hospital of Central Theater Command of the People’s Liberation Army, 627&num;, Wuluo Road, Wuchang District, Wuhan, Hubei Province, 430070, People’s Republic of China, Email mhdytfine@163.com Jian Zhu, Department of Thoracic Cardiovascular Surgery, General Hospital of Central Theater Command of the People’s Liberation Army, 627&num;, Wuluo Road, Wuchang District, Wuhan, Hubei Province, 430070, People’s Republic of China, Fax +86-27-50772388, Email zhujian0718@163.comObjective: To evaluate the effect of sleep duration on blood pressure in patients with hypertension urgencies combined with SARS-CoV-2 infection in a Fangcang shelter hospital.Methods: From April 10, 2020 to May 20, 2022, we statistically analyzed the blood pressure and sleep conditions of 52 patients with combined hypertension urgencies and SARS-CoV-2 infection admitted in Shanghai National Convention and Exhibition Center Fangcang shelter hospital. They were divided into the short-term (daily sleep duration: < 7 h) and normal sleep group (7– 9 h). We performed a comparison of the control effects of basic antihypertensive drugs. Additionally, patients in the short-term sleep group underwent drug therapy for sleep regulation and continuous monitoring of blood pressure.Results: Among these patients, the blood pressure was higher in the short-term sleep group than that of the normal sleep group, and also more difficult to control (p < 0.05). Furthermore, the blood pressure of the patients in the short-term sleep group was more easily controlled after treatment with drugs for sleep regulation and basic antihypertensive drugs (p < 0.05).Conclusion: The blood pressure level in patients with combined SARS-CoV-2 infection and hypertension urgencies was higher in those with a shorter duration of daily sleep, and also more difficult to control in Fangcang shelter hospital. Drug therapy for sleep regulation should be administered early to obtain sufficient blood pressure control effects.Keywords: hypertension urgencies, shelter hospital, sleep regulation, Fangcang hospital, blood pressure, short-term sleep, SARS-CoV-2, COVID-19

Summary: The orexin 2 receptor‐selective agonist danavorexton (TAK‐925) has been shown to produce wake‐promoting effects in wild‐type mice, narcolepsy‐model mice, and individuals with narcolepsy type 1 and type 2. Here, we report wake‐promoting effects of danavorexton in non‐human primates and healthy men during their sleep phase. Electroencephalogram analyses revealed that subcutaneous administration of danavorexton significantly increased wakefulness in common marmosets (p < 0.05 at 0.1 mg kg−1, and p < 0.001 at 1 mg kg−1 and 10 mg kg−1) and cynomolgus monkeys (p ≤ 0.05 at 1 mg kg−1 and 3 mg kg−1). In a phase 1b crossover, randomized, double‐blind, placebo‐controlled and active‐controlled study in sleep‐deprived healthy participants (ClinicalTrials.gov identifier: NCT03522506), modafinil 300 mg (used to demonstrate assay sensitivity) and continuous infusion of danavorexton 44 mg and danavorexton 112 mg showed statistically superior wake‐promoting effects to placebo (n = 18). Measured using the Maintenance of Wakefulness Test, mean (standard deviation) sleep latencies during infusion of danavorexton 44 mg, danavorexton 112 mg and placebo were 21.4 (8.9), 31.8 (3.2) and 9.2 (6.4) min, respectively. Least‐squares mean difference from placebo in average sleep latency was 16.8 min with danavorexton 44 mg and 30.2 min with danavorexton 112 mg (both p < 0.001). Karolinska Sleepiness Scale scores were statistically significantly lower (indicating decreased sleepiness) for participants receiving danavorexton than for those receiving placebo during infusion (danavorexton 44 mg, p = 0.010; danavorexton 112 mg, p < 0.001). Together, these results indicate that an orexin 2 receptor agonist increases wakefulness in non‐human primates and healthy individuals during their sleep phase. [ABSTRACT FROM AUTHOR]

The sleep–wake cycle is a highly regulated behavior in which a circadian clock times sleep and waking, whereas a homeostatic process controls sleep need. Both the clock and the sleep homeostat interact, but to what extent they influence each other is not understood. There is evidence that clock genes, in particular Period2 (Per2), might be implicated in the sleep homeostatic process. Sleep regulation depends also on the proper functioning of neurons and astroglial cells, two cell-types in the brain that are metabolically dependent on each other. In order to investigate clock-driven contributions to sleep regulation we non-invasively measured sleep of mice that lack the Per2 gene either in astroglia, neurons, or all body cells. We observed that mice lacking Per2 in all body cells (Per2Brdm and TPer2 animals) display earlier onset of sleep after sleep deprivation (SD), whereas neuronal and astroglial Per2 knock-out animals (NPer2 and GPer2, respectively) were normal in that respect. It appears that systemic (whole body) Per2 expression is important for physiological sleep architecture expressed by number and length of sleep bouts, whereas neuronal and astroglial Per2 weakly impacts night-time sleep amount. Our results suggest that Per2 contributes to the timing of the regulatory homeostatic sleep response by delaying sleep onset after SD and attenuating the early night rebound response.

The sleep–wake cycle is a highly regulated behavior in which a circadian clock times sleep and waking, whereas a homeostatic process controls sleep need. Both the clock and the sleep homeostat interact, but to what extent they influence each other is not understood. There is evidence that clock genes, in particular Period2 (Per2), might be implicated in the sleep homeostatic process. Sleep regulation depends also on the proper functioning of neurons and astroglial cells, two cell-types in the brain that are metabolically dependent on each other. In order to investigate clock-driven contributions to sleep regulation we non-invasively measured sleep of mice that lack the Per2 gene either in astroglia, neurons, or all body cells. We observed that mice lacking Per2 in all body cells (Per2Brdm and TPer2 animals) display earlier onset of sleep after sleep deprivation (SD), whereas neuronal and astroglial Per2 knock-out animals (NPer2 and GPer2, respectively) were normal in that respect. It appears that systemic (whole body) Per2 expression is important for physiological sleep architecture expressed by number and length of sleep bouts, whereas neuronal and astroglial Per2 weakly impacts night-time sleep amount. Our results suggest that Per2 contributes to the timing of the regulatory homeostatic sleep response by delaying sleep onset after SD and attenuating the early night rebound response. [ABSTRACT FROM AUTHOR]

Sleep deprivation (SD) results in profound cellular and molecular changes in the adult mammalian brain. Some of these changes may result in, or aggravate, brain disease. However, little is known about how SD impacts gene expression in developing animals. We examined the transcriptional response in the prefrontal cortex (PFC) to SD across postnatal development in male mice. We used RNA sequencing to identify functional gene categories that were specifically impacted by SD. We find that SD has dramatically different effects on PFC genes depending on developmental age. Gene expression differences after SD fall into 3 categories: present at all ages (conserved), present when mature sleep homeostasis is first emerging, and those unique to certain ages. Developmentally conserved gene expression was limited to a few functional categories, including Wnt-signaling which suggests that this pathway is a core mechanism regulated by sleep. In younger ages, genes primarily related to growth and development are affected while changes in genes related to metabolism are specific to the effect of SD in adults.

Torhild T Pedersen,1 Erlend Sunde,2 Jonathan Wisor,3 Jelena Mrdalj,1 Ståle Pallesen,2,4,5 Janne Grønli1 1Department of Biological and Medical Psychology, Faculty of Psychology, University of Bergen, Bergen, Norway; 2Department of Psychosocial Science, Faculty of Psychology, University of Bergen, Bergen, Norway; 3Sleep and Performance Research Center and Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA; 4Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Bergen, Norway; 5Optentia Research Focus Area, North-West University, Vanderbijlpark, South AfricaCorrespondence: Torhild T Pedersen, Tel +4797007718, Email torhild.pedersen@uib.noPurpose: Millions of people work at times that overlap with the habitual time for sleep. Consequently, sleep often occurs during the day. Daytime sleep is, however, characterized by reduced sleep duration. Despite preserved time spent in deep NREM sleep (stage N3), daytime sleep is subjectively rated as less restorative. Knowledge on how night work influences homeostatic sleep pressure is limited. Therefore, we aimed to explore the effect of three consecutive simulated night shifts on daytime sleep and markers of sleep homeostasis.Patients and Methods: We performed continuous EEG, EMG and EOG recordings in the subjects’ home setting for one nighttime sleep opportunity, and for the daytime sleep opportunities following three consecutive simulated night shifts.Results: For all daytime sleep opportunities, total sleep time was reduced compared to nighttime sleep. While time spent in stage N3 was preserved, sleep pressure at sleep onset, measured by slow wave activity (1– 4 Hz), was higher than nighttime sleep and higher on day 3 than on day 1 and 2. Elevated EEG power during daytime sleep was sustained through 6 h of time in bed. Slow wave energy was not significantly different from nighttime sleep after 6 h, reflecting a less efficient relief of sleep pressure.Conclusion: Adaptation to daytime sleep following three consecutive simulated night shifts is limited. The increased homeostatic response and continuation of sleep pressure relief even after 6 h of sleep, are assumed to reflect a challenge for appropriate homeostatic reduction to occur.Keywords: shift work, daytime sleep, sleep regulation, spectral analysis, sleep homeostasis

The Eph receptor, a prototypically large receptor protein tyrosine kinase, interacts with ephrin ligands, forming a bidirectional signaling system that impacts diverse brain functions. Eph receptors and ephrins mediate forward and reverse signaling, affecting neurogenesis, axon guidance, and synaptic signaling. While mammalian studies have emphasized their roles in neurogenesis and synaptic plasticity, the Drosophila counterparts are less studied, especially in glial cells, despite structural similarities. Using RNAi to modulate Eph / ephrin expression in Drosophila neurons and glia, we studied their roles in brain development and sleep and circadian behavior. Knockdown of neuronal ephrin disrupted mushroom body development, while glial knockdown had minimal impact. Surprisingly, disrupting ephrin in neurons or glial cells altered sleep and circadian rhythms, indicating a direct involvement in these behaviors independent from developmental effects. Further analysis revealed distinct sleep phenotypes between neuronal and glial knockdowns, underscoring the intricate interplay within the neural circuits that govern behavior. Glia-specific knockdowns showed altered sleep patterns and reduced circadian rhythmicity, suggesting an intricate role of glia in sleep regulation. Our findings challenge simplistic models of Eph/ephrin signaling limited to neuron-glia communication and emphasize the complexity of the regulatory networks modulating behavior. Future investigations targeting specific glial subtypes will enhance our understanding of Eph/ephrin signaling's role in sleep regulation across species. • Eph/ephrin signaling in Drosophila impacts brain development & behavior. • Eph/ephrin knockdown in neurons, but not glia, disrupts mushroom body development. • Both neuronal and glial perturbations of Eph/ephrin alter sleep/circadian rhythms. • Glial knockdown reveals intricate glia-specific role in sleep regulation. [ABSTRACT FROM AUTHOR]

What is sleep really, and why is it necessary for the proper functioning of the body? In biological terms, sleep is a state of stillness and the abolition of consciousness, and it can be interrupted at any time. However, despite many studies, not all of its physiological functions have been fully described to date. It is known, however, that sleep disturbances or reductions in sleep impair the functioning of the nervous system. The aim of this study was to attempt to describe the form and function of sleep in mammals and birds. It was noted that although the organization of biological activities in daily cycles is universal in all organisms, it is regulated in different ways in individual taxonomic groups, e.g. the circadian rhythms of birds are regulated by a multiple oscillatory system consisting of the eye retina, pineal gland and nucleus. suprachiasmatic in the hypothalamus, as well as extraocular photoreceptors in the brain, which is completely different from, inter alia, in mammals. [ABSTRACT FROM AUTHOR]

Motivation and its hedonic valence are powerful modulators of sleep/wake behavior, yet its underlying mechanism is still poorly understood. Given the well‐established role of midbrain dopamine (mDA) neurons in encoding motivation and emotional valence, here, neuronal mechanisms mediating sleep/wake regulation are systematically investigated by DA neurotransmission. It is discovered that mDA mediates the strong modulation of sleep/wake states by motivational valence. Surprisingly, this modulation can be uncoupled from the classically employed measures of circadian and homeostatic processes of sleep regulation. These results establish the experimental foundation for an additional new factor of sleep regulation. Furthermore, an electroencephalographic marker during wakefulness at the theta range is identified that can be used to reliably track valence‐related modulation of sleep. Taken together, this study identifies mDA signaling as an important neural substrate mediating sleep modulation by motivational valence. [ABSTRACT FROM AUTHOR]

Summary: The two‐process model serves as a major conceptual framework in sleep science. Although dating back more than four decades, it has not lost its relevance for research today. Retracing its origins, I describe how animal experiments aimed at exploring the oscillators driving the circadian sleep–wake rhythm led to the recognition of gradients of sleep states within the daily sleep period. Advances in signal analysis revealed that the level of slow‐wave activity in non‐rapid eye movement sleep electroencephalogram is high at the beginning of the 12‐light period and then declines. After sleep deprivation, the level of slow‐wave activity is enhanced. By scheduling recovery sleep to the animal's activity period, the conflict between the sleep–wake‐dependent and the circadian influence resulted in a two‐stage recovery pattern. These experiments provided the basis for the first version of the two‐process model. Sleep deprivation experiments in humans showed that the decline of slow‐wave activity during sleep is exponential. The two‐process model posits that a sleep–wake‐dependent homeostatic process (Process S) interacts with a process controlled by the circadian pacemaker (Process C). At present, homeostatic and circadian facets of sleep regulation are being investigated at the synaptic level as well as in the transcriptome and proteome domains. The notion of sleep has been extended from a global phenomenon to local representations, while the master circadian pacemaker has been supplemented by multiple peripheral oscillators. The original interpretation that the emergence of sleep may be viewed as an escape from the rigid control imposed by the circadian pacemaker is still upheld. [ABSTRACT FROM AUTHOR]

Summary: The two‐process model serves as a major conceptual framework in sleep science. Although dating back more than four decades, it has not lost its relevance for research today. Retracing its origins, I describe how animal experiments aimed at exploring the oscillators driving the circadian sleep–wake rhythm led to the recognition of gradients of sleep states within the daily sleep period. Advances in signal analysis revealed that the level of slow‐wave activity in non‐rapid eye movement sleep electroencephalogram is high at the beginning of the 12‐light period and then declines. After sleep deprivation, the level of slow‐wave activity is enhanced. By scheduling recovery sleep to the animal's activity period, the conflict between the sleep–wake‐dependent and the circadian influence resulted in a two‐stage recovery pattern. These experiments provided the basis for the first version of the two‐process model. Sleep deprivation experiments in humans showed that the decline of slow‐wave activity during sleep is exponential. The two‐process model posits that a sleep–wake‐dependent homeostatic process (Process S) interacts with a process controlled by the circadian pacemaker (Process C). At present, homeostatic and circadian facets of sleep regulation are being investigated at the synaptic level as well as in the transcriptome and proteome domains. The notion of sleep has been extended from a global phenomenon to local representations, while the master circadian pacemaker has been supplemented by multiple peripheral oscillators. The original interpretation that the emergence of sleep may be viewed as an escape from the rigid control imposed by the circadian pacemaker is still upheld. [ABSTRACT FROM AUTHOR]

Abstract Motivation and its hedonic valence are powerful modulators of sleep/wake behavior, yet its underlying mechanism is still poorly understood. Given the well‐established role of midbrain dopamine (mDA) neurons in encoding motivation and emotional valence, here, neuronal mechanisms mediating sleep/wake regulation are systematically investigated by DA neurotransmission. It is discovered that mDA mediates the strong modulation of sleep/wake states by motivational valence. Surprisingly, this modulation can be uncoupled from the classically employed measures of circadian and homeostatic processes of sleep regulation. These results establish the experimental foundation for an additional new factor of sleep regulation. Furthermore, an electroencephalographic marker during wakefulness at the theta range is identified that can be used to reliably track valence‐related modulation of sleep. Taken together, this study identifies mDA signaling as an important neural substrate mediating sleep modulation by motivational valence.

Circadian rhythm is an important biological process for humans as it modulates a wide range of physiological processes, including body temperature, sleep-wake cycle, and cognitive performance. As the most powerful external stimulus of circadian rhythm, light has been studied as a zeitgeber to regulate the circadian phase and sleep. This paper addresses the human alertness optimization problem, by optimizing light exposure and sleep schedules to relieve fatigue and cognitive impairment, in cases of night-shift workers and subjects with certain mission periods based on dynamics of the circadian rhythm system. A three-process hybrid dynamic model is used for simulating the circadian rhythm and predicting subjective alertness and sleepiness. Based on interindividual difference in sleep type and living habits, we propose a tunable sleep schedule in the alertness optimization problem, which allows the appropriate tuning of sleep and wake times based on sleep propensity. Variational calculus is applied to evaluate the impacts of light and sleep schedules on the alertness and a gradient descent algorithm is proposed to determine the optimal solutions to maximize the alertness level in various cases. Numerical simulation results demonstrate that the cognitive performance during certain periods can be significantly improved by optimizing the light input and tuning sleep/wake times compared to empirical data. [ABSTRACT FROM AUTHOR]

Jacqueline MT Henderson,1 Neville M Blampied,1 Karyn G France2 1School of Psychology, Speech and Hearing, Te Kura Mahi ā-Hirikapo, College of Science, University of Canterbury, Te Whare Wānanga o Waitaha, Christchurch, New Zealand; 2School of Health Sciences, University of Canterbury, Te Whare Wānanga o Waitaha, Christchurch, New ZealandCorrespondence: Jacqueline MT HendersonSchool of Psychology, Speech and Hearing, Te Kura Mahi ā-Hirikapo, College of Science, University of Canterbury, Te Whare Wānanga o Waitaha, Private Bag 4800, Christchurch, New ZealandTel +64 33694358Email Jacki.henderson@canterbury.ac.nzBackground: An important developmental task for infants over their first few years of life is to learn to settle to sleep with a reasonably short latency, maintain sleep through the night and coordinate with family sleeping and waking schedules. A child who can reliably do this is exhibiting self-regulated sleep. Otherwise, children’s sleep may have to be other (non-self) regulated to some degree and they may exhibit pediatric sleep disturbances (e.g., extended sleep latency, and/or frequent nightwaking); these are reported by 36– 45% of parents of infants between ages four to 12 months.Purpose: To answer the question: Can infant and parent factors observed at 1 month of infant age predict which infants will have regulated sleep at 6- and 12-months of age? Prediction from 1 month has not previously been investigated.Methods: In a prospective longitudinal study, the mothers of 52 typically developing infants completed 6-day sleep diaries at 1, 3, 6, 9 and 12 months from which a composite sleep score (CSS) was derived for each child at each month. Diary reliability was assessed once (for 54% of families) using all-night videosomnography.Results: At 6 months, CSS scores were distributed bi-modally and thus differentiated into two groups by an empirically observed CSS cutoff score, with a majority (56%) of infants classified as self-sleep regulated (S-R) and the rest as non-self sleep-regulated (NS-R). At 12 months, 72% could similarly be classified as S-R, while 28% exhibited some continuing sleep disturbance. Discriminant function analysis investigated the predictors of S-R vs NS-R group membership at 6 and 12 months from parent and child variables recorded at 1 month. Parent presence at sleep onset and less total infant sleep time predicted group membership at 6 months with 94% classification accuracy, and parental presence at sleep onset and frequency of infant night wakings predicted group membership at 12 months with 85% accuracy. At 1 month, parents of infants later classified as NS-R at 6 and 12 months had higher frequencies of all settling activities than parents of those later classified as S-R.Conclusion: Variables measured at 1 month that predicted sleep status at 6 and 12 months were parental presence at sleep onset, frequency of infant night waking and total infant sleep time. The overall frequency of parent settling activities at 1 month also clearly differentiated the two sleep groups at the older ages. Parenting behaviours are modifiable factors and thus may have the potential for preventing pediatric sleep disturbances in children.Keywords: infant, sleep regulation, predictors, parent behavior

Sleep disturbances are common in patients with stroke, and sleep quality has a critical role in the onset and outcome of stroke. Poor sleep exacerbates neurological injury, impedes nerve regeneration, and elicits serious complications. Thus, exploring a therapy suitable for patients with stroke and sleep disturbances is imperative. As a multi-targeted nonpharmacological intervention, remote ischemic conditioning can reduce the ischemic size of the brain, improve the functional outcome of stroke, and increase sleep duration. Preclinical/clinical evidence showed that this method can inhibit the inflammatory response, mediate the signal transductions of adenosine, activate the efferents of the vagal nerve, and reset the circadian clocks, all of which are involved in sleep regulation. In particular, cytokines tumor necrosis factor α (TNFα) and adenosine are sleep factors, and electrical vagal nerve stimulation can improve insomnia. On the basis of the common mechanisms of remote ischemic conditioning and sleep regulation, a causal relationship was proposed between remote ischemic conditioning and post-stroke sleep quality. [ABSTRACT FROM AUTHOR]

The COVID‐19 confinement has dramatically altered daily routines, causing decreased sleep quality in adults. This necessitates careful observation, as sleep plays a crucial role in brain maturation and poor sleep increases the risk of psychopathology, particularly in the young population. Through an online survey with one baseline (April 2020) and two follow‐up assessments (May and June 2020), we examined the effect of confinement on sleep quality in 452 babies (0–35 months) and 412 preschool children (36–71 months) from several, mainly European, countries. An acute decrease in sleep quality was found in both groups of children. However, at follow‐up assessments, this effect rebounded to the level reported for the period before the confinement. Importantly, caregiver's stress level was identified as a substantial risk factor determining lower sleep quality in both groups of children across assessments. Protective factors conserving children's sleep quality included caregiver's engagement in mindfulness techniques or childcare, and the presence of siblings and pets. In the near future, we may repeatedly experience the circumstances of abruptly enforced confinement. Our findings reveal promising pathways of action to protect young children's sleep, with which to essentially mitigate the long‐term consequences of the pandemic on brain development and mental health. [ABSTRACT FROM AUTHOR]

Circadian rhythm is an important biological process for humans as it modulates a wide range of physiological processes, including body temperature, sleep-wake cycle, and cognitive performance. As the most powerful external stimulus of circadian rhythm, light has been studied as a zeitgeber to regulate the circadian phase and sleep. This paper addresses the human alertness optimization problem, by optimizing light exposure and sleep schedules to relieve fatigue and cognitive impairment, in cases of night-shift workers and subjects with certain mission periods based on dynamics of the circadian rhythm system. A three-process hybrid dynamic model is used for simulating the circadian rhythm and predicting subjective alertness and sleepiness. Based on interindividual difference in sleep type and living habits, we propose a tunable sleep schedule in the alertness optimization problem, which allows the appropriate tuning of sleep and wake times based on sleep propensity. Variational calculus is applied to evaluate the impacts of light and sleep schedules on the alertness and a gradient descent algorithm is proposed to determine the optimal solutions to maximize the alertness level in various cases. Numerical simulation results demonstrate that the cognitive performance during certain periods can be significantly improved by optimizing the light input and tuning sleep/wake times compared to empirical data.

Sleep is a ubiquitous and complex behavior in both its manifestation and regulation. Despite its essential role in maintaining optimal performance, health, and well-being, the genetic mechanisms underlying sleep remain poorly understood. Here, we review the forward genetic approaches undertaken in the last four years to elucidate the genes and gene pathways affecting sleep and its regulation. Despite an increasing number of studies and mining large databases, a coherent picture on “sleep” genes has yet to emerge. We highlight the results achieved by using unbiased genetic screens mainly in humans, mice, and fruit flies with an emphasis on normal sleep and make reference to lessons learned from the circadian field.

Sleep and muscle injury-related pain are in negative relationship, and sleep extension may be a favorable countermeasure. In response to muscle injury, an adaptive sleep response has been described in rats, characterized by an increase in total sleep time (TST) and nonrapid eye movement (NREM) sleep. This study examined the effects of photoperiod lengthening (a model of sleep prolongation in rats) on the sleep characteristics of muscle-injured rats and whether this lengthening could benefit injury-induced mechanical hyperalgesia using the Von Frey test. Switching from the conventional 12:12 light/dark (LD) photoperiod (light on: 08:00-20:00) to LD 16:8 (light extended to 24:00) gives rats an extra window of sleep. Our results show higher TST and NREM sleep times in LD 16:8 versus LD 12:12 injured rats during 4 h of light lengthening for 7 d postinjury, showing the efficiency of photoperiod lengthening to increase sleep time in injured rats. In addition, a cumulative effect with the adaptive sleep response to muscle injury occurred with higher TST and NREM sleep times in LD 16:8 injured versus noninjured rats during the dark period, reflecting the high need for sleep after the injury. Greater stability and higher relative delta power of NREM sleep during the extended light period were also observed in injured rats. Finally, the extended photoperiod limits the muscle injury-induced mechanical hyperalgesia for 13 d and allows faster recovery of the baseline mechanical threshold. This is associated with reduced pro-inflammatory cytokines levels in the hippocampus, a brain structure involved in pain processing., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Vanneau et al.)

This study investigates the complex interplay between the cardiac and respiratory systems in 268 healthy neonates born between 35 and 40 weeks of gestation. The aim is to provide a comprehensive description of the developing cardiorespiratory information transfer mechanisms as a function of gestational age (GA). This report proposes an extension of the traditional Transfer Entropy measure (TE), which employs multiple lagged versions of the time series of the intervals between two successive R waves of the QRS signal on the electrocardiogram (RR series) and respiration time series (RESP). The method aims to quantify the instantaneous and delayed effects between the two processes within a fine-grained time scale. Firstly, lagged TE was validated on a simulated dataset. Subsequently, lagged TE was employed on newborn cardiorespiratory data. Results indicate a progressive increase in information transfer as a function of gestational age, as well as significant differences in terms of instantaneous and delayed interactions between the cardiac and the respiratory system when comparing the two TE directionalities (RR→RESP vs. RESP→RR). The proposed investigation addresses the role of the different autonomic nervous system (ANS) branches involved in the cardiorespiratory system, since the sympathetic and parasympathetic branches operate at different time scales. Our results allow to infer that the two TE directionalities are uniquely and differently modulated by both branches of the ANS. TE adds an original quantitative tool to understanding cardiorespiratory imbalance in early infancy.

Abstract Sleep disorders are comorbid with most psychiatric disorders, but the link between these is not well understood. Neuroligin-2 (NLGN2) is a cell adhesion molecule that plays roles in synapse formation and neurotransmission. Moreover, NLGN2 has been associated with psychiatric disorders, but its implication in sleep remains underexplored. In the present study, the effect of Nlgn2 knockout (Nlgn2 −/− ) on sleep architecture and electroencephalographic (EEG) activity in mice has been investigated. The EEG and electromyogram (EMG) were recorded in Nlgn2 −/− mice and littermates for 24 h from which three vigilance states (i.e., wakefulness, rapid eye movement [REM] sleep, non-REM [NREM] sleep) were visually identified. Spectral analysis of the EEG was performed for the three states. Nlgn2 −/− mice showed more wakefulness and less NREM and REM sleep compared to wild-type (Nlgn2 +/+ ) mice, especially during the dark period. This was accompanied by changes in the number and duration of individual episodes of wakefulness and sleep, indexing changes in state consolidation, as well as widespread changes in EEG spectral activity in all states. Abnormal ‘hypersynchronized’ EEG events have also been observed predominantly in Nlgn2 −/− mice. These events were mainly observed during wakefulness and REM sleep. In addition, Nlgn2 −/− mice showed alterations in the daily time course of NREM sleep delta (1–4 Hz) activity, pointing to modifications in the dynamics of sleep homeostasis. These data suggest that NLGN2 participates in the regulation of sleep duration as well as EEG activity during wakefulness and sleep.

Sleep disturbances are prevalent in both patients with pituitary insufficiency and with depression. The role of corticotropin releasing hormone (CRH), involved in sleep regulation, has not been fully clarified. Pituitary insufficiency is an ideal model for studying sleep-endocrine effects since no consecutive hormone releases and feedback effects occur after hormone administration. 11 male patients with a chronic insufficiency of the anterior pituitary gland (PI) and under stable hormonal substitution were studied during three consecutive nights in the sleep laboratory. The first night served for adapting to laboratory setting, during the second night placebo was administered and during the third night 4 × 50 μg CRH were injected in pulsatile fashion. Sleep parameters were additionally compared with those of 15 healthy male controls (C) and 15 male patients with depression (D). CRH administration was associated with a numerical increase of wake time (115 ± 15 to 131 ± 13 min) and a decrease of REM sleep (89 ± 8 to 80 ± 8 min), REM latency (69 ± 14 to 55 ± 9 min) and slow wave sleep (66 ± 16 to 57 ± 15 min). Yet, none of these changes reached statistical significance. PI showed a worse sleep profile as compared to both control groups, e.g. indicated by a significantly lower sleep efficiency index (PI:0.80 ± 0.03 vs. C:0.94 ± 0.01 vs. D:0.87 ± 0.03). In conclusion sleep-EEG changes after CRH in PI patients resemble those found in in part in patients with depression. Sleep in anterior pituitary insufficiency was impaired despite full hormonal substitution possibly suggesting an alteration of the receptor organisation of brain structures involved in sleep regulation. [ABSTRACT FROM AUTHOR]

This study investigates the complex interplay between the cardiac and respiratory systems in 268 healthy neonates born between 35 and 40 weeks of gestation. The aim is to provide a comprehensive description of the developing cardiorespiratory information transfer mechanisms as a function of gestational age (GA). This report proposes an extension of the traditional Transfer Entropy measure (TE), which employs multiple lagged versions of the time series of the intervals between two successive R waves of the QRS signal on the electrocardiogram (RR series) and respiration time series (RESP). The method aims to quantify the instantaneous and delayed effects between the two processes within a fine-grained time scale. Firstly, lagged TE was validated on a simulated dataset. Subsequently, lagged TE was employed on newborn cardiorespiratory data. Results indicate a progressive increase in information transfer as a function of gestational age, as well as significant differences in terms of instantaneous and delayed interactions between the cardiac and the respiratory system when comparing the two TE directionalities (RR→RESP vs. RESP→RR). The proposed investigation addresses the role of the different autonomic nervous system (ANS) branches involved in the cardiorespiratory system, since the sympathetic and parasympathetic branches operate at different time scales. Our results allow to infer that the two TE directionalities are uniquely and differently modulated by both branches of the ANS. TE adds an original quantitative tool to understanding cardiorespiratory imbalance in early infancy. [ABSTRACT FROM AUTHOR]

Sleep spindles are burstlike signals in the electroencephalogram (EEG) of the sleeping mammalian brain and electrical surface correlates of neuronal oscillations in thalamus. As one of the most inheritable sleep EEG signatures, sleep spindles probably reflect the strength and malleability of thalamocortical circuits that underlie individual cognitive profiles. We review the characteristics, organization, regulation, and origins of sleep spindles and their implication in non-rapid-eye-movement sleep (NREMS) and its functions, focusing on human and rodent. Spatially, sleep spindle-related neuronal activity appears on scales ranging from small thalamic circuits to functional cortical areas, and generates a cortical state favoring intracortical plasticity while limiting cortical output. Temporally, sleep spindles are discrete events, part of a continuous power band, and elements grouped on an infraslow time scale over which NREMS alternates between continuity and fragility. We synthesize diverse and seemingly unlinked functions of sleep spindles for sleep architecture, sensory processing, synaptic plasticity, memory formation, and cognitive abilities into a unifying sleep spindle concept, according to which sleep spindles 1) generate neural conditions of large-scale functional connectivity and plasticity that outlast their appearance as discrete EEG events, 2) appear preferentially in thalamic circuits engaged in learning and attention-based experience during wakefulness, and 3) enable a selective reactivation and routing of wake-instated neuronal traces between brain areas such as hippocampus and cortex. Their fine spatiotemporal organization reflects NREMS as a physiological state coordinated over brain and body and may indicate, if not anticipate and ultimately differentiate, pathologies in sleep and neurodevelopmental, -degenerative, and -psychiatric conditions. [ABSTRACT FROM AUTHOR]

Studies over the last 40 years have mainly investigated sleep structure changes as a result of wake duration, in the frame of the classical sleep regulation theories. However, wake intervals of the same duration can profoundly differ in their intensity, which actually reflects the degree of cognitive and physical activity. Data on how sleep can be modified by wake intensity changes (initially sparse and of little consistence) have become much more substantial, especially in the frame of the intense research debate on sleep-memory relationships. Our aim is to examine the vast repertoire of sleep modifications that depend on waking cognitive manipulations, highlighting the sleep features that appear most affected. By systematically addressing this issue, we want to set the basis for future research exploring both the specific nature of the mechanisms involved and the applicative psychosocial and clinical fall-outs, in terms of possible behavioural interventions for sleep quality improvement. [ABSTRACT FROM AUTHOR]

Origin and functions of intermittent transitions among sleep stages, including brief awakenings and arousals, constitute a challenge to the current homeostatic framework for sleep regulation, focusing on factors modulating sleep over large time scales. Here we propose that the complex micro-architecture characterizing sleep on scales of seconds and minutes results from intrinsic non-equilibrium critical dynamics. We investigate θ- and δ-wave dynamics in control rats and in rats where the sleep-promoting ventrolateral preoptic nucleus (VLPO) is lesioned (male Sprague-Dawley rats). We demonstrate that bursts in θ and δ cortical rhythms exhibit complex temporal organization, with long-range correlations and robust duality of power-law (θ-bursts, active phase) and exponential-like (δ-bursts, quiescent phase) duration distributions, features typical of non-equilibrium systems self-organizing at criticality. We show that such non-equilibrium behavior relates to anti-correlated coupling between θ- and δ-bursts, persists across a range of time scales, and is independent of the dominant physiologic state; indications of a basic principle in sleep regulation. Further, we find that VLPO lesions lead to a modulation of cortical dynamics resulting in altered dynamical parameters of θ- and δ-bursts and significant reduction in θ-δ coupling. Our empirical findings and model simulations demonstrate that θ-δ coupling is essential for the emerging non-equilibrium critical dynamics observed across the sleep-wake cycle, and indicate that VLPO neurons may have dual role for both sleep and arousal/brief wake activation. The uncovered critical behavior in sleep- and wake-related cortical rhythms indicates a mechanism essential for the micro-architecture of spontaneous sleep-stage and arousal transitions within a novel, non-homeostatic paradigm of sleep regulation. [ABSTRACT FROM AUTHOR]

Distilling insomnia genome-wide association study (GWAS) variants, Palermo and colleagues identified several genes that participate in sleep regulation in two different model organisms. This workflow sets off an innovative strategy to extract biological relevance from large human genomic databases. [ABSTRACT FROM AUTHOR]

Betulinic acid (BA) is a major constituent of Zizyphus seeds that have been long used as therapeutic agents for sleep-related issues in Asia. BA is a pentacyclic triterpenoid. It also possesses various anti-cancer and anti-inflammatory effects. Current commercially available sleep aids typically use GABAergic regulation, for which many studies are being actively conducted. However, few studies have focused on acetylcholine receptors that regulate wakefulness. In this study, we utilized BA as an antagonist of α3β4 nicotinic acetylcholine receptors (α3β4 nAChRs) known to regulate rapid-eye-movement (REM) sleep and wakefulness. Effects of BA on α3β4 nAChRs were concentration-dependent, reversible, voltage-independent, and non-competitive. Site-directed mutagenesis and molecular-docking studies confirmed the binding of BA at the molecular level and showed that the α3 subunit L257 and the β4 subunit I263 residues affected BA binding. These data demonstrate that BA can bind to a binding site different from the site for the receptor’s ligand, acetylcholine (ACh). This suggests that BA may be an effective antagonist that is unaffected by large amounts of ACh released during wakefulness and REM sleep. Based on the above experimental results, BA is likely to be a therapeutically useful sleep aid and sedative.

Due to the multifactorial and complex nature of rest, we focus on phenotypes related to sleep. Sleep regulation is a multifactorial process. In this chapter, we focus on those phenotypes inherent to sleep that are highly prevalent in the population, and that can be modulated by lifestyle, such as sleep quality and duration, insomnia, restless leg syndrome and daytime sleepiness. We, therefore, leave in the background those phenotypes that constitute infrequent pathologies or for which the current level of scientific evidence does not favour the implementation of practical approaches of this type. Similarly, the regulation of sleep quality is intimately linked to the regulation of the circadian rhythm. Although this relationship is discussed in the sections that require it, the in-depth study of circadian rhythm regulation at the molecular level deserves a separate chapter, and this is how it is dealt with in this volume., (Copyright © 2024. Published by Elsevier Inc.)

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Background: Sleep quality in early life has implications for individual and family well-being [19]. Parenting in the early months may be highly influential on infant sleep patterns and trajectories.Method: This study used observational and survey data to investigate how sleeping arrangement and two types of nighttime interventions at one and three months (non-distress-initiated and distress-initiated) are associated with infants' sleep development across the first nine months. Distress-initiated interventions were identified as parents' responses to infants' distress signals whereas non-distress initiated interventions were identified as parents' behaviors in response to non-distressed vocalizations or while infants were asleep.Results: Analysis from 107 families revealed that infant night wakings decreased over time as expected. The link between early non-distress initiated interventions and rate of change in infant night wakings was significantly moderated by sleep arrangement such that solitary sleeping infants who experienced higher levels of non-distress-initiated interventions showed a less steep decline across time in infant night wakings compared to solitary infants who experienced low levels of non-distress-initiated interventions. Results also showed that higher levels of distress-initiated interventions at one and three months were associated with a steeper decrease in infant night wakings for both solitary and cosleeping infants. Notably, these findings were not replicated when parental interventions as predictors of infant sleep were examined at later points in the first year.Conclusions: Results inform conceptualizations of parenting competence in infant sleep contexts during the first few months of life and how best to promote infant sleep regulation across the first year. [ABSTRACT FROM AUTHOR]

Vladyslav V VyazovskiyDepartment of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UKAbstract: A commonly held view is that extended wakefulness is causal for a broad spectrum of deleterious effects at molecular, cellular, network, physiological, psychological, and behavioral levels. Consequently, it is often presumed that sleep plays an active role in providing renormalization of the changes incurred during preceding waking. Not surprisingly, unequivocal empirical evidence supporting such a simple bi-directional interaction between waking and sleep is often limited or controversial. One difficulty is that, invariably, a constellation of many intricately interrelated factors, including the time of day, specific activities or behaviors during preceding waking, metabolic status and stress are present at the time of measurement, shaping the overall effect observed. In addition to this, although insufficient or disrupted sleep is thought to prevent efficient recovery of specific physiological variables, it is also often difficult to attribute specific changes to the lack of sleep proper. Furthermore, sleep is a complex phenomenon characterized by a multitude of processes, whose unique and distinct contributions to the purported functions of sleep are difficult to determine, because they are interrelated. Intensive research effort over the last decades has greatly progressed current understanding of the cellular and physiological processes underlying the regulation of vigilance states. Notably, it also highlighted the infinite complexity within both waking and sleep, and revealed a number of fundamental conceptual and technical obstacles that need to be overcome in order to fully understand these processes. A promising approach could be to view sleep not as an entity, which has specific function(s) and is subject to direct regulation, but as a manifestation of the process of metaregulation, which enables efficient moment-to-moment integration between internal and external factors, preceding history and current homeostatic needs.Keywords: sleep, wakefulness, sleep homeostasis, sleep regulation, exercise, EEG

The regulation of sleep and the response to sleep deprivation rely on multiple biochemical pathways. A critical connection is the link between sleep and metabolism. Metabolic changes can disrupt sleep, and conversely decreased sleep can alter the metabolic environment. There is building evidence that lipid metabolism, in particular, is a critical part of mounting the homeostatic response to sleep deprivation. We have evaluated an acyl-CoA synthetase, pudgy (pdgy), for its role in sleep and response to sleep deprivation. When pdgy transcript levels are decreased through transposable element disruption of the gene, mutant flies showed lower total sleep times and increased sleep fragmentation at night compared to genetic controls. Consistent with disrupted sleep, mutant flies had a decreased lifespan compared to controls. pdgy disrupted fatty acid handling as pdgy mutants showed increased sensitivity to starvation and exhibited lower fat stores. Moreover, the response to sleep deprivation is reduced when compared to a control flies. When we decreased the transcript levels for pdgy using RNAi, the response to sleep deprivation was decreased compared to background controls. In addition, when the pdgy transcription is rescued throughout the fly, the response to sleep deprivation is restored. These data demonstrate that the regulation and function of acyl-CoA synthetase plays a critical role in regulating sleep and the response to sleep deprivation. Endocrine and metabolic signals that alter transcript levels of pdgy impact sleep regulation or interfere with the homeostatic response to sleep deprivation.

Sleep difficulties are commonly reported following traumatic brain injury (TBI), but few studies have systematically examined the neurophysiological characteristics of sleep. Sleep EEG was quantified over multiple nights to examine mechanisms underlying sleep disruption in individuals who had sustained a TBI and to explore the relationship between sleep disruption and waking function. Sleep was recorded from 20 individuals with a TBI (18-64 years) and 20 age-matched controls over two uninterrupted nights, as well as during a night where auditory stimuli were delivered. All participants underwent neuropsychological testing and waking performance assessment. Compared to controls, the TBI group had subjective complaints of falling asleep, delayed sleep onset on polysomnography (PSG), less Slow Wave (< 1 Hz) and delta (1-4 Hz) EEG power in non-REM sleep, fewer spontaneous and evoked k-complexes, reduced periodicity of spontaneous k-complexes, and lower amplitude of evoked k-complexes. While for controls, the density, duration and periodicity of sleep spindles diminished with deepening of non-REM as typically observed, this pattern was disrupted in the TBI group with peak spindle presentation occurring in Stage 3 sleep. Night-to-night-stability of Stage 2 spindles was high for controls but absent for the TBI group. Greater injury severity was related to fewer evoked k-complexes and lower spindle density. Greater spindle production predicted better waking function in the TBI group. Taken together, these data demonstrate impairment in sleep regulatory and inhibitory mechanisms as factors underlying sleep complaints following a TBI. Spindle generation may be adaptive or a marker of resiliency following TBI.

Animals continuously alternate between sleep and wake states throughout their life. The daily organization of sleep and wakefulness is orchestrated by circadian, homeostatic, and motivational processes. Over the last decades, much progress has been made toward determining the neuronal populations involved in sleep/wake regulation. Here, we will discuss how the application of advanced in vivo tools for cell type–specific manipulations now permits the functional interrogation of different features of sleep/wake state regulation: initiation, maintenance, and structural organization. We will specifically focus on recent studies examining the roles of wake-promoting neuronal populations.

The regulation of sleep and the response to sleep deprivation rely on multiple biochemical pathways. A critical connection is the link between sleep and metabolism. Metabolic changes can disrupt sleep, and conversely decreased sleep can alter the metabolic environment. There is building evidence that lipid metabolism, in particular, is a critical part of mounting the homeostatic response to sleep deprivation. We have evaluated an acyl-CoA synthetase, pudgy (pdgy), for its role in sleep and response to sleep deprivation. When pdgy transcript levels are decreased through transposable element disruption of the gene, mutant flies showed lower total sleep times and increased sleep fragmentation at night compared to genetic controls. Consistent with disrupted sleep, mutant flies had a decreased lifespan compared to controls. pdgy disrupted fatty acid handling as pdgy mutants showed increased sensitivity to starvation and exhibited lower fat stores. Moreover, the response to sleep deprivation is reduced when compared to a control flies. When we decreased the transcript levels for pdgy using RNAi, the response to sleep deprivation was decreased compared to background controls. In addition, when the pdgy transcription is rescued throughout the fly, the response to sleep deprivation is restored. These data demonstrate that the regulation and function of acyl-CoA synthetase plays a critical role in regulating sleep and the response to sleep deprivation. Endocrine and metabolic signals that alter transcript levels of pdgy impact sleep regulation or interfere with the homeostatic response to sleep deprivation. [ABSTRACT FROM AUTHOR]

This review details tumor necrosis factor alpha (TNF) biology and its role in sleep, and describes how TNF medications influence sleep/wake activity. Substantial evidence from healthy young animals indicates acute enhancement or inhibition of endogenous brain TNF respectively promotes and inhibits sleep. In contrast, the role of TNF in sleep in most human studies involves pathological conditions associated with chronic elevations of systemic TNF and disrupted sleep. Normalization of TNF levels in such patients improves sleep. A few studies involving normal healthy humans and their TNF levels and sleep are consistent with the animal studies but are necessarily more limited in scope. TNF can act on established sleep regulatory circuits to promote sleep and on the cortex within small networks, such as cortical columns, to induce sleep-like states. TNF affects multiple synaptic functions, e.g., its role in synaptic scaling is firmly established. The TNF-plasticity actions, like its role in sleep, can be local network events suggesting that sleep and plasticity share biochemical regulatory mechanisms and thus may be inseparable from each other. We conclude that TNF is involved in sleep regulation acting within an extensive tightly orchestrated biochemical network to niche-adapt sleep in health and disease. [ABSTRACT FROM AUTHOR]