Sleep deprivation drives hepatic steatosis via sympathetic sprouting-induced ER stress in young male mice.

Sleep, Circadian Rhythms, and Psychomotor Vigilance

Chronic sleep restriction (SR) disrupts blood glucose regulation, leading to glucose intolerance and insulin resistance. Regular exercises, however, are known to enhance glycemic control. This study aimed to evaluate the regulatory effects of three distinct exercise protocols on blood glucose alterations caused by chronic rapid eye movement SR. Thirty-four Sprague-Dawley rats were allocated into five groups: control (CTRL), SR, SR plus aerobic exercise (SR+ExA), SR plus resistance exercise (SR+ExR), and SR plus combined exercises (SR+ExC). Except for the control group, all rats underwent 18 h of SR daily for 8 weeks using a modified multi-platform model. Exercise protocols included 30 min of swimming and/or vertical ladder climbing (15 repetitions/day) performed 3 days per week for 8 weeks. Following the intervention, glucose and insulin tolerance tests were conducted. Chronic SR increased blood glucose levels, while aerobic and/or resistance exercises effectively reduced or prevented this elevation. Glucose tolerance was significantly improved in all exercise groups compared to the sedentary group (intraperitoneal glucose tolerance test blood glucose 120 min: SR + ExA=95±7.7, SR + ExR=100±7.3, SR + ExC=90±12.6, SR=119±14.5mg/dL; P<0.05). Regular exercise may mitigate adverse metabolic effects of SR.

Differential effects of postpartum sleep restriction on maternal and offspring immunity in the rat.

The prefrontal cortex (PFC) mediates cognitive function that is sensitive to disruption by sleep loss, and molecular mechanisms regulating neural dysfunction induced by chronic sleep restriction (CSR), particularly in the PFC, have yet to be completely understood. The aim of the present study was to investigate the effect of chronic REM sleep restriction (REM-CSR) on the D1 receptor (D1R) and key molecules in D1R' signal pathways in PFC. We employed the modified multiple platform method to create the REM-CSR rat model. The ultrastructure of PFC was observed by electron microscopy. HPLC was performed to measure the DA level in PFC. The expressions of genes and proteins of related molecules were assayed by real-time PCR and Western blot, respectively. The general state and morphology of PFC in rats were changed by CSR, and DA level and the expression of D1R in PFC were markedly decreased (P < 0.01, P < 0.05); the expression of phosphor-PKAcα was significantly lowered in CSR rats (P < 0.05). The present results suggested that the alteration of neuropathology and D1R expression in PFC may be associated with CSR induced cognitive dysfunction, and the PKA pathway of D1R may play an important role in the impairment of advanced neural function.

Sleep disorders and sleep deficiency are important causes of adverse health effects and increased mortality in the United States and worldwide. Sleep deficiency can also result in myriad adverse behavioral consequences, including profound sleepiness, cognitive slowing, automatic behavior, attentional failures and performance degradation, errors, and accidents. It is important to recognize that sleepiness and sleep deficiency are not synonymous.

Changing Nomenclature from Nonalcoholic Fatty Liver Disease to Metabolic Dysfunction-Associated Fatty Liver Disease – Not Only Premature But Also Confusing

Chronic nocturnal sleep restriction results in accumulation of neurobehavioral impairment across days. The purpose of this study was to determine whether time of day modulates the effects of sleep restriction on objective daytime performance deficits and subjective sleepiness across days of chronic sleep restriction. There were N = 90 healthy adults (21-49 yr; 38 women) who participated in a 14-d laboratory protocol involving randomization to 1 of 18 schedules of restricted nocturnal sleep with and without a diurnal nap for 10 consecutive days. The total time available for daily sleep ranged from 4.2 h to 8.2 h across conditions. Performance lapses on the psychomotor vigilance test (PVT) and subjective sleepiness were measured each day every 2 h during scheduled wakefulness. Nonlinear mixed-effects regression was used to test the hypothesis that there would be an interaction between time of day and the accumulation (slope across days) of neurobehavioral sleepiness. In agreement with earlier studies, less sleep time resulted in faster accumulation of deficits across days. Time of day significantly affected this relationship for both PVT lapses and subjective sleepiness. The build-up rate of cumulative neurobehavioral deficits across days was largest at 0800 and became progressively smaller across the hours of the day, especially between 1600 and 2000. Following 8 d of sleep restricted to 4 h/d, subjects averaged 8.3 more PVT performance lapses at 0800 than at 1800. This study provides evidence that the circadian system has a substantial modulatory effect on cumulative impairment from chronic sleep restriction and that it facilitates a period of relatively protected alertness in the late afternoon/early evening hours when nocturnal sleep is chronically restricted.

We previously found that Mertk and its ligand Gas6, astrocytic genes involved in phagocytosis, are upregulated after acute sleep deprivation. These results suggested that astrocytes may engage in phagocytic activity during extended wake, but direct evidence was lacking. Studies in humans and rodents also found that sleep loss increases peripheral markers of inflammation, but whether these changes are associated with neuroinflammation and/or activation of microglia, the brain's resident innate immune cells, was unknown. Here we used serial block-face scanning electron microscopy to obtain 3D volume measurements of synapses and surrounding astrocytic processes in mouse frontal cortex after 6-8 h of sleep, spontaneous wake, or sleep deprivation (SD) and after chronic (∼5 d) sleep restriction (CSR). Astrocytic phagocytosis, mainly of presynaptic components of large synapses, increased after both acute and chronic sleep loss relative to sleep and wake. MERTK expression and lipid peroxidation in synaptoneurosomes also increased to a similar extent after short and long sleep loss, suggesting that astrocytic phagocytosis may represent the brain's response to the increase in synaptic activity associated with prolonged wake, clearing worn components of heavily used synapses. Using confocal microscopy, we then found that CSR but not SD mice show morphological signs of microglial activation and enhanced microglial phagocytosis of synaptic elements, without obvious signs of neuroinflammation in the CSF. Because low-level sustained microglia activation can lead to abnormal responses to a secondary insult, these results suggest that chronic sleep loss, through microglia priming, may predispose the brain to further damage.SIGNIFICANCE STATEMENT We find that astrocytic phagocytosis of synaptic elements, mostly of presynaptic origin and in large synapses, is upregulated already after a few hours of sleep deprivation and shows a further significant increase after prolonged and severe sleep loss, suggesting that it may promote the housekeeping of heavily used and strong synapses in response to the increased neuronal activity of extended wake. By contrast, chronic sleep restriction but not acute sleep loss activates microglia, promotes their phagocytic activity, and does so in the absence of overt signs of neuroinflammation, suggesting that like many other stressors, extended sleep disruption may lead to a state of sustained microglia activation, perhaps increasing the brain's susceptibility to other forms of damage.

To evaluate the effects of acute sleep deprivation and chronic sleep restriction on vigilance, performance, and self-perception of sleepiness. Habitual night followed by 1 night of total sleep loss (acute sleep deprivation) or 5 consecutive nights of 4 hr of sleep (chronic sleep restriction) and recovery night. Eighteen healthy middle-aged male participants (age [(± standard deviation] = 49.7 ± 2.6 yr, range 46-55 yr). Multiple sleep latency test trials, Karolinska Sleepiness Scale scores, simple reaction time test (lapses and 10% fastest reaction times), and nocturnal polysomnography data were recorded. Objective and subjective sleepiness increased immediately in response to sleep restriction. Sleep latencies after the second and third nights of sleep restriction reached levels equivalent to those observed after acute sleep deprivation, whereas Karolinska Sleepiness Scale scores did not reach these levels. Lapse occurrence increased after the second day of sleep restriction and reached levels equivalent to those observed after acute sleep deprivation. A statistical model revealed that sleepiness and lapses did not progressively worsen across days of sleep restriction. Ten percent fastest reaction times (i.e., optimal alertness) were not affected by acute or chronic sleep deprivation. Recovery to baseline levels of alertness and performance occurred after 8-hr recovery night. In middle-aged study participants, sleep restriction induced a high increase in sleep propensity but adaptation to chronic sleep restriction occurred beyond day 3 of restriction. This sleepiness attenuation was underestimated by the participants. One recovery night restores daytime sleepiness and cognitive performance deficits induced by acute or chronic sleep deprivation. Philip P; Sagaspe P; Prague M; Tassi P; Capelli A; Bioulac B; Commenges D; Taillard J. Acute versus chronic partial sleep deprivation in middle-aged people: differential effect on performance and sleepiness. SLEEP 2012;35(7):997-1002.

To identify features in the compensatory mechanisms of sleep regulation in response to acute sleep deprivation after chronic sleep restriction in rats. Male Wistar rats 7-8 months old underwent 5-day sleep restriction: 3 h of sleep deprivation and 1 h of sleep opportunity repeating throughout each day. Six-hour acute total sleep deprivation was performed at the beginning of daylight hours on the 3rd day after sleep restriction. Polysomnogramms were recorded throughout the day before chronic sleep restriction, on the 2nd recovery day after chronic sleep restriction and after acute sleep deprivation. The control group was not subjected to chronic sleep restriction. The animals after chronic sleep restriction had the compensatory increase in total sleep time in response to acute sleep deprivation weaker than in control animals. Animals after sleep restriction had the compensatory increase in the time of slow-wave sleep (SWS) only in the first 6 hours after acute sleep deprivation, whereas in control animals the period of compensation of SWS lasted 12 hours. A compensatory increase in slow-wave activity (SWA) was observed in both groups of animals, but in animals experiencing chronic sleep restriction the amplitude of SWA after acute sleep deprivation was less than in control animals. A compensatory increase in REM sleep in sleep restricted animals occurred immediately after acute sleep deprivation and coincides with a compensatory increase in SWS and SWA, whereas in control conditions these processes are spaced in time. Compensatory reactions in response to acute sleep deprivation (sleep homeostasis) are weakened in animals subjected to chronic sleep restriction, as the reaction time and amplitude are reduced.

Chronic sleep restriction (CSR) impairs sustained attention in humans, as commonly assessed with the psychomotor vigilance task (PVT). To further investigate the mechanisms underlying performance deficits during CSR, we examined the effect of CSR on performance on a rat version of PVT (rPVT). Adult male rats were trained on a rPVT that required them to press a bar when they detected irregularly presented, brief light stimuli, and were then tested during CSR. CSR consisted of 100 or 148 h of continuous cycles of 3-h sleep deprivation (using slowly rotating wheels) alternating with a 1-h sleep opportunity (3/1 protocol). After 28 h of CSR, the latency of correct responses and the percentages of lapses and omissions increased, whereas the percentage of correct responses decreased. Over 52-148 h of CSR, all performance measures showed partial or nearly complete recovery, and were at baseline levels on the first or second day after CSR. There were large interindividual differences in the magnitude of performance impairment during CSR, suggesting differential vulnerability to the effects of sleep loss. Wheel-running controls showed no changes in performance. A 28-h period of the 3/1 chronic sleep restriction (CSR) protocol disrupted performance on a sustained attention task in rats, as sleep deprivation does in humans. Performance improved after longer periods of CSR, suggesting allostatic adaptation, contrary to some reports of progressive deterioration in psychomotor vigilance task performance during CSR in humans. However, as observed in humans, there were individual differences among rats in the vulnerability of their attention performance to CSR.

Sleep is critical for brain development and synaptic plasticity. In male wild-type mice, chronic sleep restriction during development results in long-lasting impairments in behavior including hypoactivity, decreased sociability, and increased repetitive behavior. Disordered sleep is characteristic of many neurodevelopmental disorders. Moreover, the severity of behavioral symptoms is correlated with the degree of disordered sleep. We hypothesized that chronic developmental sleep restriction in a mouse model of fragile X syndrome (FXS) would exacerbate behavioral phenotypes. To test our hypothesis, we sleep-restricted Fmr1 knockout (KO) mice for 3 h per day from P5 to P52 and subjected mice to behavioral tests beginning on P42. Contrary to our expectations, sleep restriction improved the hyperactivity and lack of preference for social novelty phenotypes in Fmr1 KO mice but had no measurable effect on repetitive activity. Sleep restriction also resulted in changes in regional distribution of myelin basic protein, suggesting effects on myelination. These findings have implications for the role of disrupted sleep in the severity of symptoms in FXS.

Introduction The neurophysiological mechanisms underlying long-term neurological and cognitive disorders associated with chronic sleep restriction (CSR) are not fully understood. Here we evaluated how the sleep-wake cycle changes during and after a period of sleep restriction in rats, and whether CSR results in neurodegeneration in monoaminergic brain structures. Methods For CSR, 7-8-month-old Wistar rats underwent cycles of 3 h of sleep deprivation (SD) and 1 h of sleep opportunity (SO) continuously for 5 days on the orbital shaker. Telemetric sleep recordings were made before, during, and after CSR. Neurodegeneration in brain monoaminergic structures was assessed immunohistochemically. Results During SD, wakefulness comprised 85% of the total registration time; the remaining time was represented by drowsiness with low EEG delta power. Rapid eye movement sleep (REMS) was absent. During CSR, slow-wave sleep (SWS) and REMS were reduced by 62% and 57%. Total SWS time during SO periods increased on the first CSR day, but decreased to the baseline by the fifth CSR day. SWS EEG delta power (a measure of sleep intensity) decreased gradually from the first to the fifth CSR day. REMS total time remained elevated during all SO periods. During the first recovery day after CSR, SWS did not change, but REMS increased by 30%. No changes in total sleep time were found on the second recovery day but sleep intensity was decreased. In 14 days after CSR, all sleep parameters returned to the baseline. We revealed a loss of 24% of noradrenergic locus coeruleus neurons, 29% and 17% of dopaminergic neurons in the substantia nigra, the ventral tegmental area as well as in their striatal terminals. Conclusion We consider CSR as a damaging factor leading to a gradual suppression of homeostatic mechanisms governing sleep recovery. CSR can provoke neurodegeneration in monoaminergic structures involved in the regulation of emotional behavior, sleep, and autonomic functions. Support (if any) Ministry of Science and Higher Education of the Russian Federation grant (No. 075-15-2020-916 dated November 13, 2020) for the establishment and development of the Pavlovsky Center “Integrative Physiology for Medicine, High-Tech Healthcare and Stress Resilience Technologies”.

The adolescent brain may be uniquely affected by acute sleep deprivation (ASD) and chronic sleep restriction (CSR), but direct evidence is lacking. We used electron microscopy to examine how ASD and CSR affect pyramidal neurons in the frontal cortex of adolescent mice, focusing on mitochondria, endosomes, and lysosomes that together perform most basic cellular functions, from nutrient intake to prevention of cellular stress. Adolescent (1-mo-old) mice slept (S) or were sleep deprived (ASD, with novel objects and running wheels) during the first 6-8 h of the light period, chronically sleep restricted (CSR) for > 4 days (using novel objects, running wheels, social interaction, forced locomotion, caffeinated water), or allowed to recover sleep (RS) for ∼32 h after CSR. Ultrastructural analysis of 350 pyramidal neurons was performed (S = 82; ASD = 86; CSR = 103; RS = 79; 4 to 5 mice/group). Several ultrastructural parameters differed in S versus ASD, S versus CSR, CSR versus RS, and S versus RS, although the different methods used to enforce wake may have contributed to some of the differences between short and long sleep loss. Differences included larger cytoplasmic area occupied by mitochondria in CSR versus S, and higher number of secondary lysosomes in CSR versus S and RS. We also found that sleep loss may unmask interindividual differences not obvious during baseline sleep. Moreover, using a combination of 11 ultrastructural parameters, we could predict in up to 80% of cases whether sleep or wake occurred at the single cell level. Ultrastructural analysis may be a powerful tool to identify which cellular organelles, and thus which cellular functions, are most affected by sleep and sleep loss.

To examine total sleep duration in infancy and the associations of insufficient sleep duration with later weight gain and the risk of overweight in a longitudinal twin cohort study. The data for this study are from the Longitudinal Twin Study (LoTiS), a twin-pregnancy birth cohort study that was carried out in China (n = 186 pairs). The sleep data were collected at 6 months using the Brief Infant Sleep Questionnaire that was completed by parents with the assistance of a research assistant. Anthropometric data were obtained from the children's health clinic records at 6, 12, 18, and 24 months. There were no significant differences between infants with insufficient sleep and those with sufficient sleep in terms of height, weight, body mass index, incidence of overweight, and body fat mass, while infants with insufficient sleep duration were predisposed to gain excessive weight from 6 to 12 and 6 to 18 months of age (all P < .05). After adjusting for confounding variables, insufficient sleep duration was found to be correlated with excessive weight gain from 6 to 18 months of age (odds ratio: 3.47; 95% confidence interval, 1.23-9.78). The relationship was more pronounced in monozygotic twins than in dizygotic twins. Insufficient total sleep duration at the age of 6 months is correlated with the risk of excessive weight gain at 18 months of age in twins, particularly in monozygotic twins. Registry: Chinese Clinical Trial Register; Name: Unraveling the complex interplay between genes and environment in specifying early life determinants of illness in infancy: a longitudinal prenatal study of Chinese Twins. URL: http://www.chictr.org.cn/showproj.aspx?proj=13839; Identifier: ChiCTR-OOC-16008203. Yu J, Jin H, Wen L, et al. Insufficient sleep during infancy is correlated with excessive weight gain in childhood: a longitudinal twin cohort study. J Clin Sleep Med. 2021;17(11):2147-2154.