Sleep Debt and Insulin Resistance: What's Worse, Sleep Deprivation or Sleep Restriction?

Objective To evaluate which condition of sleep debt has a greater negative impact on insulin resistance: sleep deprivation for 24 hours or 4 hours of sleep restriction for 4 nights. Materials and Methods In total, 28 healthy male subjects aged 18 to 40 years were recruited and randomly allocated to two groups: sleep deprivation (SD) and sleep restriction (SR). Each group underwent two conditions: regular sleep (11 pm to 7 am ) and total sleep deprivation for 24 hours (SD); regular sleep (11 pm to 7 am ) and 4 nights of sleep restriction (SR) (1 am to 5 am ). The oral glucose tolerance test (OGTT) was performed, and baseline glucose, insulin, free fatty acids (FFAs), and cortisol were measured. In addition, the area under the curve (AUC) for glucose and insulin, the homeostasis model assessment of insulin resistance (HOMA-IR), and the Matsuda Index (Insulin Sensitivity Index, ISI) were calculated. Results Glucose and insulin had a similar pattern between groups, except at the baseline, when insulin was higher in the sleep debt condition of the SR when compared with the SD ( p < 0.01). In the comparison between regular sleep and sleep debt, the SD had a higher insulin AUC ( p < 0.01) and FFAs ( p = 0.03) after sleep deprivation, and insulin and the insulin AUC increased ( p < 0.01 for both), while the ISI decreased ( p = 0.02) after sleep restriction in the SR. In baseline parameters covariate by the condition of regular sleep, insulin ( p = 0.02) and the HOMA-IR ( p < 0.01) were higher, and cortisol ( p = 0.04) was lower after sleep restriction when compared with sleep deprivation. Conclusion Sleep restriction for 4 consecutive nights is more detrimental to energy metabolism because of the higher insulin values and insulin resistance compared with an acute period of sleep deprivation of 24 hours.

Chronic sleep restriction during juvenility alters hedonic and anxiety-like behaviours in a sex-dependent fashion in adolescent Wistar rats.

Chronic reduction of sleep time in children and adolescents has been related to increased incidence of anxiety and depression. In rats, protocols of protracted sleep deprivation or chronic sleep restriction (CSR) are considered a stressor. In previous studies we showed that post-weaning CSR in male rats induces anxiety-like behaviour and changes in neurotransmission in emotion-related brain areas. In the present study we examined whether the effects of this adversity are sex-dependent. Twenty-two litters, containing four males and four females were distributed into control (CTL) and CSR groups. CSR began on postnatal day (PND) 21 and lasted for 21 days; each day the animals were placed onto small platforms immersed in water for 18 h and were allowed to sleep freely in their home-cages for the remaining 6 h. Throughout the CSR, all animals underwent the sucrose splash test once/week to assess their self-care and hedonic behaviours. Body weight was measured on PNDs 21 and 42. At the end of CSR period, the adolescents were allowed to sleep freely for 2 days, after which, behavioural tests began. Within each litter, one male and one female (pair) were not tested and provided blood and brain for determination of basal corticosterone (CORT) levels and hippocampal BDNF. One pair was tested in the sucrose preference test (SPT), one pair on the elevated plus maze (EPM) and one pair in the forced swim test (FST). CORT was measured after all conditions. CSR impaired self-care behaviour and body weight gain in males and females and increased relative adrenal weight only in males. There were no changes in sucrose intake in the SPT; CSR females displayed less immobility in the FST and CSR males displayed more anxiety-like behaviour in the EPM. CORT levels were similar between CTL and CSR males, whilst lower in CSR females than CTL ones in all experimental conditions. No changes in BDNF levels were detected in the dorsal hippocampus of CSR rats. The results indicate that CSR impaired self-care behaviour in both sexes, but only males displayed anxiety-like behaviour, whilst sleep recovery in females appeared to normalise their behaviour.

The Impact of Sleep: From Ancient Rituals to Modern Challenges.

Although sleep is crucial for mental and physical health, insufficient sleep is a growing problem in our modern society. In general, adults need approximately eight hours of sleep per night, but this is often unfeasible nowadays. This sleep restriction has been observed, and it has worsened, throughout the past two centuries; therefore, it is more attributed to socioeconomic changes than to biological adaptations. The most important factors to contribute to this sleep restriction were the popularization of artificial light and industrialization. The present manuscript briefly overviews, from a socioanthropological perspective, the reasons why sleep has been impacted, disclosing its effects on individuals and on society.

Impact of sleep restriction in B-1 cells activation and differentiation.

B-1 lymphocytes are a subtype of B cells with functional and phenotypic features that differ from conventional B lymphocytes. These cells are mainly located in mice's pleural and peritoneal cavities and express unconventional B cell surface markers. B-1 cells participate in immunity by producing antibodies, cytokines, and chemokines and physically interacting with other immune cells. In addition, B-1 cells can differentiate into mononuclear phagocyte-like cells and phagocytize several pathogens. However, the activation and differentiation of B-1 cells are not entirely understood. It is known that several factors can influence B-1 cells, such as pathogens components and the immune response. This work aimed to evaluate the influence of chronic stress on B-1 cell activation and differentiation into phagocytes. The experimental sleep restriction was used as a stress model since the sleep alteration alters several immune cells' functions. Thus, mice were submitted to sleep restriction for 21 consecutive days, and the activation and differentiation of B-1 cells were analyzed. Our results demonstrated that B-1 cells initiated the differentiation process into mononuclear phagocytes after the period of sleep restriction. In addition, we detected a significant decrease in lymphoid lineage commitment factors (EBF, E2A, Blnk) (*P < 0.05) and an increase in the G-CSFR gene (related to the myeloid lineage commitment factor) (****P < 0.0001), as compared to control mice no submitted to sleep restriction. An increase in the co-stimulatory molecules CD80 and CD86 (**P < 0.01 and *P < 0.05, respectively) and a higher production of nitric oxide (NO) (*P < 0.05) and reactive oxygen species (ROS) (*P < 0.05) were also observed in B-1 cells from mice submitted to sleep restriction. Nevertheless, B-1 cells from sleep-restricted mice showed a significant reduction in the Toll-like receptors (TLR)-2, -6, and -9, and interleukine-10 (IL-10) cytokine expression (***P < 0.001) as compared to control. Sleep-restricted mice intraperitoneally infected withL. amazonensispromastigotes showed a reduction in the average internalized parasites (*P < 0.05) by B-1 cells. These findings suggest that sleep restriction interferes with B-1 lymphocyte activation and differentiation. In addition, b-1 cells assumed a more myeloid profile but with a lower phagocytic capacity in this stress condition.

Chronic rapid eye movement sleep restriction during juvenility has long-term effects on anxiety-like behaviour and neurotransmission of male Wistar rats.

Modernity imposes a toll on the sleep time of young population, with concomitant increase in symptoms of anxiety and depression. Whether there is a causal relationship between these events are only now being experimentally tested in humans and rodents. In a previous study, we showed that chronic sleep deprivation in juvenile-adolescent male rats led to increased anxiety-like behaviour and changes in noradrenaline and serotonin in the amygdala and hippocampus. In the present study we investigated whether early chronic sleep restriction affects emotional behaviour, stress response and neurochemistry in adulthood. From 21 to 42 days of age, Wistar male rats were submitted to sleep restriction by the multiple platform method or allowed to sleep freely. Forty-five days after this period, rats were tested in the elevated plus maze (EPM) and blood samples were collected from non-tested rats or 30 and 60 min after the EPM for determination of plasma corticosterone levels. Levels of monoamines were determined in the frontal cortex, hippocampus, amygdala and hypothalamus 60 min after the EPM. Sleep restriction resulted in increased anxiety-like behaviour, decreased noradrenaline levels in the amygdala and dopamine levels in the ventral hippocampus. Anxiety index was positively correlated with increased serotonin metabolism in the frontal cortex and greater dopamine metabolism in the ventral hippocampus, and negatively correlated with dopamine levels in the ventral hippocampus. These results suggest that sleep restriction in juvenility and adolescence induces persistent changes in emotional behaviour in adult male rats and that levels of anxiety are correlated with increased serotonin and dopamine metabolism in specific brain areas.

Impact of sleep restriction in B-1 cells activation and differentiation

B-1 lymphocytes are a subtype of B cells with functional and phenotypic features that differ from conventional B lymphocytes. These cells are mainly located in mice’s pleural and peritoneal cavities and express unconventional B cell surface markers. B-1 cells participate in immunity by producing antibodies, cytokines, and chemokines and physically interacting with other immune cells. In addition, B-1 cells can differentiate into mononuclear phagocyte-like cells and phagocytize several pathogens. However, the activation and differentiation of B-1 cells are not entirely understood. It is known that several factors can influence B-1 cells, such as pathogens components and the immune response. This work aimed to evaluate the influence of chronic stress on B-1 cell activation and differentiation into phagocytes. The experimental sleep restriction was used as a stress model since the sleep alteration alters several immune cells' functions. Thus, mice were submitted to sleep restriction for 21 consecutive days, and the activation and differentiation of B-1 cells were analyzed. Our results demonstrated that B-1 cells initiated the differentiation process into mononuclear phagocytes after the period of sleep restriction. In addition, we detected a significant decrease in lymphoid lineage commitment factors (EBF, E2A, Blnk) (*P < 0.05) and an increase in the G-CSFR gene (related to the myeloid lineage commitment factor) (****P < 0.0001), as compared to control mice no submitted to sleep restriction. An increase in the co-stimulatory molecules CD80 and CD86 (**P < 0.01 and *P < 0.05, respectively) and a higher production of nitric oxide (NO) (*P < 0.05) and reactive oxygen species (ROS) (*P < 0.05) were also observed in B-1 cells from mice submitted to sleep restriction. Nevertheless, B-1 cells from sleep-restricted mice showed a significant reduction in the Toll-like receptors (TLR)-2, −6, and −9, and interleukine-10 (IL-10) cytokine expression (***P < 0.001) as compared to control. Sleep-restricted mice intraperitoneally infected with L. amazonensis promastigotes showed a reduction in the average internalized parasites (*P < 0.05) by B-1 cells. These findings suggest that sleep restriction interferes with B-1 lymphocyte activation and differentiation. In addition, b-1 cells assumed a more myeloid profile but with a lower phagocytic capacity in this stress condition.

Metabolic Disturbances Induced by Sleep Restriction as Potential Triggers for Alzheimer's Disease.

Sleep has a major role in learning, memory consolidation, and metabolic function. Although it is known that sleep restriction increases the accumulation of amyloid ß peptide (Aß) and the risk to develop Alzheimer's disease (AD), the mechanism behind these effects remains unknown. In this review, we discuss how chronic sleep restriction induces metabolic and cognitive impairments that could result in the development of AD in late life. Here, we integrate evidence regarding mechanisms whereby metabolic signaling becomes disturbed after short or chronic sleep restriction in the context of cognitive impairment, particularly in the accumulation of Aß in the brain. We also discuss the role of the blood-brain barrier in sleep restriction with an emphasis on the transport of metabolic signals into the brain and Aß clearance. This review presents the unexplored possibility that the alteration of peripheral metabolic signals induced by sleep restriction, especially insulin resistance, is responsible for cognitive deficit and, subsequently, implicated in AD development.

Chronic sleep restriction triggers inadequate napping habits in adolescents: a population-based study.

BACKGROUND: The prevalence of chronic sleep restriction during adolescence is a major public health issue. Napping has been adopted to alleviate sleep pressure complaints. However, it also has the potential to amplify sleep restriction due to a vicious cycle triggered by delayed sleep times. The aim of this study was to investigate sleep and napping habits in a sample of Brazilian adolescents. METHODS: This study enrolled 1554 high school students and included the evaluation of sleep times, daytime sleepiness, sleep quality, and circadian preference. The students were asked about their napping routine, ie its frequency and duration per week. RESULTS: The adolescent sleep recommendation was achieved by only 27.6% of the sample. Napping habit was reported by 58.1%, with 36.2% of nappers informing naps in 1-2 times per week. Prolonged naps were reported by 44.9% of nappers. Nappers had later median bedtime (23:30) and reduced time in bed (TIB) (median = 07:00 h) compared to non-nappers. The frequency of nappers who did not achieve satisfactory TIB was higher than non-nappers. In addition, nappers reported increased daytime sleepiness and poor sleep quality. Later bedtimes and reduced TIB were associated with longer nap duration. Increased sleepiness and poor sleep quality were linked to a higher nap frequency. CONCLUSIONS: This exploratory survey demonstrated a severe sleep restriction faced by Brazilian adolescents. Napping can be an efficient strategy to counteract sleep restriction, but it needs to be adopted with caution due to the detrimental effects of frequent and prolonged naps on nocturnal sleep.

Effects of sleep modulation during pregnancy in the mother and offspring: Evidences from preclinical research.

Disturbed sleep during gestation may lead to adverse outcomes for both mother and child. Animal research plays an important role in providing insights into this research field by enabling ethical and methodological requirements that are not possible in humans. Here, we present an overview and discuss the main research findings related to the effects of prenatal sleep deprivation in animal models. Using systematic review approaches, we retrieved 42 articles dealing with some type of sleep alteration. The most frequent research topics in this context were maternal sleep deprivation, maternal behaviour, offspring behaviour, development of sleep-wake cycles in the offspring, hippocampal neurodevelopment, pregnancy viability, renal physiology, hypertension and metabolism. This overview indicates that the number of basic studies in this field is growing, and provides biological plausibility to suggest that sleep disturbances might be detrimental to both mother and offspring by promoting increased risk at the behavioural, hormonal, electrophysiological, metabolic and epigenetic levels. More studies on the effects of maternal sleep deprivation are needed, in light of their major translational perspective.

Response speed measurements on the psychomotor vigilance test: how precise is precise enough?

STUDY OBJECTIVES: The psychomotor vigilance test (PVT) is frequently used to measure behavioral alertness in sleep research on various software and hardware platforms. In contrast to many other cognitive tests, PVT response time (RT) shifts of a few milliseconds can be meaningful. It is, therefore, important to use calibrated systems, but calibration standards are currently missing. This study investigated the influence of system latency bias and its variability on two frequently used PVT performance metrics, attentional lapses (RTs ≥500 ms) and response speed, in sleep-deprived and alert participants. METHODS: PVT data from one acute total (N = 31 participants) and one chronic partial (N = 43 participants) sleep deprivation protocol were the basis for simulations in which response bias (±15 ms) and its variability (0-50 ms) were systematically varied and transgressions of predefined thresholds (i.e. ±1 for lapses, ±0.1/s for response speed) recorded. RESULTS: Both increasing bias and its variability caused deviations from true scores that were higher for the number of lapses in sleep-deprived participants and for response speed in alert participants. Threshold transgressions were typically rare (i.e. <5%) if system latency bias was less than ±5 ms and its standard deviation was ≤10 ms. CONCLUSIONS: A bias of ±5 ms with a standard deviation of ≤10 ms could be considered maximally allowable margins for calibrating PVT systems for timing accuracy. Future studies should report the average system latency and its standard deviation in addition to adhering to published standards for administering and analyzing the PVT.

Chronic REM sleep restriction in young rats increases energy expenditure with no change in food intake.

NEW FINDINGS: What is the central question of this study? What are the effects of different periods of REM sleep restriction (7, 14 and 21 days) on metabolic parameters in young rats? What is the main finding and its importance? Animals submitted to each period of REM sleep deprivation showed a negative energy balance, with reduced body weight gain, body energy gain and gross food efficiency, less body fat content, and increased energy expenditure. There was no increase in food intake after any of the REM sleep restriction periods. In young rats, negative energy balance is not compensated by increased dietary intake as observed in adult rats. ABSTRACT: Reduced sleep is associated with metabolic alterations, not only in adults, but also in children and adolescents. Several studies have shown that sleep restricted (SR) adult rats exhibit metabolic changes, followed by increased food intake, but few have evaluated these functions in young animals. The aim of the present study was to establish the metabolic parameters of young rats subjected to different periods of REM sleep restriction and to propose a correction factor for the correct measurement of food intake. Young male Wistar rats were distributed in control and SR groups for 7, 14 or 21 days. Sleep restriction was performed by the single platform method for 18 h. Regardless of the length of sleep restriction, all SR rats had a negative energy balance, evidenced by reduction in body weight gain, body energy gain and gross food efficiency, accompanied by increased energy expenditure. In addition, sleep restriction reduced body fat content throughout the entire period. Discounting food spillage, there was no increase in food intake by SR rats. In conclusion, the present study revealed metabolic changes in SR young rats after different lengths of REM sleep restriction and that weight loss and increased energy expenditure were not compensated by increased dietary intake as occurs in adult rats, indicating that young rats use other mechanisms to cope with the negative energy balance caused by sleep restriction. In addition, we propose a correction factor for food intake, to prevent overestimation of this parameter, due to food spillage in the water containers.

Developing preliminary blood metabolomics-based biomarkers of insufficient sleep in humans.

STUDY OBJECTIVE: Identify small molecule biomarkers of insufficient sleep using untargeted plasma metabolomics in humans undergoing experimental insufficient sleep. METHODS: We conducted a crossover laboratory study where 16 normal-weight participants (eight men; age 22 ± 5 years; body mass index < 25 kg/m2) completed three baseline days (9 hours sleep opportunity per night) followed by 5-day insufficient (5 hours sleep opportunity per night) and adequate (9 hours sleep opportunity per night) sleep conditions. Energy balanced diets were provided during baseline, with ad libitum energy intake provided during the insufficient and adequate sleep conditions. Untargeted plasma metabolomics analyses were performed using blood samples collected every 4 hours across the final 24 hours of each condition. Biomarker models were developed using logistic regression and linear support vector machine (SVM) algorithms. RESULTS: The top-performing biomarker model was developed by linear SVM modeling, consisted of 65 compounds, and discriminated insufficient versus adequate sleep with 74% overall accuracy and a Matthew's Correlation Coefficient of 0.39. The compounds in the top-performing biomarker model were associated with ATP Binding Cassette Transporters in Lipid Homeostasis, Phospholipid Metabolic Process, Plasma Lipoprotein Remodeling, and sphingolipid metabolism. CONCLUSION: We identified potential metabolomics-based biomarkers of insufficient sleep in humans. Although our current biomarkers require further development and validation using independent cohorts, they have potential to advance our understanding of the negative consequences of insufficient sleep, improve diagnosis of poor sleep health, and could eventually help identify targets for countermeasures designed to mitigate the negative health consequences of insufficient sleep.

Chronic sleep loss disrupts blood-testis and blood-epididymis barriers, and reduces male fertility.

Sleep loss increases blood-brain barrier permeability. As the blood-brain barrier and the blood-tissue barriers in the reproductive tract (blood-testis and blood-epididymis barriers) share common characteristics, we hypothesized that sleep restriction may also modify their barrier function. Previous reports showed that sleep loss decreased sperm viability and progressive fast mobility, which may be a consequence of altered blood-testis and blood-epididymis barrier. Therefore, we quantified changes in blood-testis and blood-epididymis barrier after sleep loss and related them to male fertility. Adult male Wistar rats were sleep restricted using the multiple-platform technique in a protocol of 20 hr daily sleep deprivation plus 4 hr of sleep recovery in the home-cage. At the 10th day, barrier permeability assays were performed with Na-fluorescein, 10 kDa Cascade blue-dextrans and Evans blue, and the expression of tight junction proteins, actin and androgen receptor was quantified. At the 10th day of sleep restriction and after sleep recovery days 1-7, males were placed with sexually receptive females, sexual behaviour was tested, and the percentage of pregnancies was calculated. Sleep restriction increased the barrier permeability to low- and high-molecular-weight tracers, and decreased the expression of tight junction proteins, actin and androgen receptor. Concomitantly, sleep restriction reduced the percentage of ejaculating males and the number of pregnancies. Sleep recovery for 2-3 days progressively re-established fertility, as indicated by a higher percentage of ejaculating males and impregnated females. In conclusion, chronic sleep loss alters fertility concomitantly with the disruption of the blood-tissue barriers at the reproductive tract, the mechanism involves androgen signalling.

Trait-like vulnerability of higher-order cognition and ability to maintain wakefulness during combined sleep restriction and circadian misalignment.

STUDY OBJECTIVES: Determine stability of individual differences in executive function, cognitive processing speed, selective visual attention, and maintenance of wakefulness during simulated sustained operations with combined sleep restriction and circadian misalignment. METHODS: Twenty healthy adults (eight female), aged 25.7 (±4.2 SD), body mass index (BMI) 22.3 (±2.1) kg/m2 completed an 18-day protocol twice. Participants maintained habitual self-selected 8-hour sleep schedules for 2 weeks at home prior to a 4-day laboratory visit that included one sleep opportunity per day: 8 hours on night 1, 3 hours on night 2, and 3 hours on mornings 3 and 4. After 3 days of unscheduled sleep at home, participants repeated the entire protocol. Stability and task dependency of individual differences in performance were quantified by intra-class correlation coefficients (ICC) and Kendall's Tau, respectively. RESULTS: Performance on Stroop, Visual Search, and the Maintenance of Wakefulness Test were highly consistent within individuals during combined sleep restriction and circadian misalignment. Individual differences were trait-like as indicated by ICCs (0.54-0.96) classified according to standard criteria as moderate to almost perfect. Individual differences on other performance tasks commonly reported in sleep studies showed fair to almost perfect ICCs (0.22-0.94). Kendall's rank correlations showed that individual vulnerability to sleep restriction and circadian misalignment varied by task and by metric within a task. CONCLUSIONS: Consistent vulnerability of higher-order cognition and maintenance of wakefulness to combined sleep restriction and circadian misalignment has implications for the development of precision countermeasure strategies for workers performing safety-critical tasks, e.g. military, police, health care workers and emergency responders.

Effects of sleep restriction during pregnancy on lipids and glucose homeostasis of female offspring submitted to ovariectomy.

Sleep shortening during pregnancy may alter the mother's environment, affecting the offspring. Thus, the present study evaluated the metabolic profile of female offspring from sleep-restricted rats during the last week of pregnancy. Pregnant Wistar rats were distributed into two groups: control (C) and sleep restriction (SR). The SR was performed 20 h/day, from 14th to 20th day of pregnancy. At 2 months, half of the offspring were subjected to ovariectomy (OVX); the others, to sham surgery. Studied groups were Csham, Covx, SRsham and SRovx. Cholesterol (HDL, LDL and C-total), triglycerides (TG) and glucose and insulin tolerance tests (GTT-ITT) were evaluated at 8 months. RSsham presented higher values of TG, while SRovx presented higher TG, LDL and C-total. Basal glucose concentration was increased in SRsham and SRovx. These data suggest that SR during pregnancy may be a risk factor for the development of diseases in adult female offspring.

Too Late and Not Enough: School Year Sleep Duration, Timing, and Circadian Misalignment Are Associated with Reduced Insulin Sensitivity in Adolescents with Overweight/Obesity.

OBJECTIVES: To examine the relationship between insulin resistance (IR) and sleep/circadian health in overweight/obese adolescents. We hypothesized that insufficient and delayed sleep would be associated with IR in this population. STUDY DESIGN: Thirty-one adolescents (mean age, 16.0 ± 1.4 years; 77% female) with body mass index ≥90th percentile for age/sex were recruited from outpatient clinics at a children's hospital. Participants underwent 1 week of objective home sleep monitoring with wrist actigraphy during the academic year. A 3-hour oral glucose tolerance test was conducted, followed by in-laboratory salivary dim-light melatonin sampling every 30-60 minutes from 5 p.m. to noon the next day. Regression analyses between sleep and circadian variables with IR were examined. RESULTS: Longer sleep time and time in bed on weekends and weekdays and earlier weekday bedtime were significantly associated with better insulin sensitivity. Participants who obtained less than the median duration of sleep per night (6.6 hours) had evidence of IR with compensatory insulin secretion compared with those obtaining ≥6.6 hours of sleep. A wider phase angle between bedtime and melatonin onset, indicating a later circadian timing of sleep onset, was significantly associated with IR. CONCLUSIONS: Short sleep duration, later weekday bedtime, and later circadian timing of sleep were associated with IR in a cohort of adolescents with overweight/obesity during the school year. Further research is needed to better understand the physiology underlying these observations and to evaluate the impact of improved sleep and circadian health on metabolic health in this at-risk population.

Chronic Sleep Restriction Impairs the Antitumor Immune Response in Mice.

OBJECTIVES: Sleep regulates immune function reciprocally and can affect the parameters that are directly involved in the immune response. Sleep deprivation is considered to be a stress-causing factor and is associated with impaired immune activity. It causes increased glucocorticoid concentrations by activating the hypothalamic-pituitary-adrenal axis; this can lead to a series of disorders that are associated with the prolonged or increased secretion of these hormones. The aim of this study was to evaluate the effects of sleep restriction (SR) on the development of pulmonary experimental metastasis and the modulation of the tumor immune response. METHODS: The SR protocol was accomplished by depriving C57BL/6 male mice of sleep for 18 h/day for 2, 7, 14, and 21 days. The modified multiple-platforms method was used for SR. RESULTS: The results showed that cytotoxic cells (i.e., natural killer [NK] and CD8+ T cells) were reduced in number and regulatory T cells were predominant in the tumor microenvironment. Sleep-restricted mice also exhibited a reduced number of dendritic cells in their lymph nodes, which may have contributed to the ineffective activation of tumor-specific T cells. Peripheral CD4+ and CD8+ T cells were also reduced in the sleep-restricted mice, thus indicating an immunosuppressive status. CONCLUSIONS: Sleep dep-rivation induces failure in the activity of cells that are im-portant to the tumor immune response, both in the tumor microenvironment and on the periphery. This leads to the early onset and increased growth rate of lung metastasis.

Chronic sleep restriction increases pain sensitivity over time in a periaqueductal gray and nucleus accumbens dependent manner.

Painful conditions and sleep disturbances are major public health problems worldwide and one directly affects the other. Sleep loss increases pain prevalence and severity; while pain disturbs sleep. However, the underlying mechanisms are largely unknown. Here we asked whether chronic sleep restriction for 6 h daily progressively increases pain sensitivity and if this increase is reversed after two days of free sleep. Also, whether the pronociceptive effect of chronic sleep restriction depends on the periaqueductal grey and on the nucleus accumbens, two key regions involved in the modulation of pain and sleep-wake cycle. We showed that sleep restriction induces a pronociceptive effect characterized by a significant decrease in the mechanical paw withdrawal threshold in rats. Such effect increases progressively from day 3 to day 12 remaining stable thereafter until day 26. Two consecutive days of free sleep were not enough to reverse the effect, not even to attenuate it. This pronociceptive effect depends on the periaqueductal grey and on the nucleus accumbens, since it was prevented by their excitotoxic lesion. Complementarily, chronic sleep restriction significantly increased c-Fos protein expression within the periaqueductal grey and the nucleus accumbens and this correlates with the intensity of the pronociceptive effect, suggesting that the greater the neural activity in this regions, the greater the effect. These findings may contribute not only to understand why painful conditions are more prevalent and severe among people who sleep poorly, but also to develop therapeutic strategies to prevent this, increasing the effectiveness of pain management in this population.

Chronic REM Sleep Restriction in Juvenile Male Rats Induces Anxiety-Like Behavior and Alters Monoamine Systems in the Amygdala and Hippocampus.

Adolescence is marked by major physiological changes, including those in the sleep-wake cycle, such as phase delay, which may result in reduced sleep hours. Sleep restriction and/or deprivation in adult rats activate stress response and seem to be a risk factor for triggering emotional disorders. In the present study, we sought to evaluate the behavioral and neurobiological consequences of prolonged REM sleep restriction in juvenile male rats. Immediately after weaning, on postnatal day 21, three males from each litter were submitted to REM sleep deprivation and the other three animals were maintained in their home-cages. REM sleep restriction (REMSR) was accomplished by placing the animals in the modified multiple platform method for 18 h and 6 h in the home-cage, where they could sleep freely; the sleep restriction lasted 21 consecutive days, during which all animals were measured and weighed every 3 days. After the end of this period, all animals were allowed to sleep freely for 2 days, and then the behavioral tests were performed for evaluation of depressive and anxiety-like profiles (sucrose negative contrast test and elevated plus maze, EPM). Blood sampling was performed 5 min before and 30 and 60 min after the EPM for determination of corticosterone plasma levels. The adrenals were weighed and brains collected and dissected for monoamine levels and receptor protein expression. REMSR impaired the physical development of adolescents, persisting for a further week. Animals submitted to REMSR exhibited higher basal corticosterone levels and a greater anxiety index in the EPM, characteristic of an anxious profile. These animals also exhibited higher noradrenaline levels in the amygdala and ventral hippocampus, without any change in the expression of ß1-adrenergic receptors, as well as higher serotonin and reduced turnover in the dorsal hippocampus, with diminished expression of 5-HT1A. Finally, greater concentration of BDNF was observed in the dorsal hippocampus in chronically sleep-restricted animals. Chronic REMSR during puberty impaired physical development and induced anxiety-like behavior, attributed to increased noradrenaline and serotonin levels in the amygdala and hippocampus.

Repeated Administration Effects on Psychomotor Vigilance Test Performance.

Study Objectives: The Psychomotor Vigilance Test (PVT) is reported to be free of practice effects that can otherwise confound the effects of sleep loss and circadian misalignment on performance. This differentiates the PVT from more complex cognitive tests. To the best of our knowledge, no study has systematically investigated practice effects on the PVT across multiple outcome domains, depending on administration interval, and in ecologically more valid settings. Methods: We administered a validated 3-minute PVT (PVT-B) 16 times in 45 participants (23 male, mean ± SD age 32.6 ± 7.3 years, range 25-54 years) with administration intervals of ≥10 days, ≤5 days, or 4 times per day. We investigated linear and logarithmic trends across repeated administrations in 10 PVT-B outcome variables. Results: The fastest 10% of response times (RT; plin = .0002), minimum RT (plog = .0010), and the slowest 10% of reciprocal RT (plog = .0124) increased while false starts (plog = 0.0050) decreased with repeated administration, collectively decreasing RT variability (plog = .0010) across administrations. However, the observed absolute changes were small (e.g., -0.03 false starts per administration, linear fit) and are probably irrelevant in practice. Test administration interval did not modify the effects of repeated administration on PVT-B performance (all p > .13 for interaction). Importantly, mean and median RT, response speed, and lapses, which are among the most frequently used PVT outcomes, did not change systematically with repeated administration. Conclusions: PVT-B showed stable performance across repeated administrations. Combined with its high sensitivity, this corroborates the status of the PVT as the de facto gold standard measure of the neurobehavioral effects of sleep loss and circadian misalignment.