Non-rapid eye movement sleep determines resilience to social stress.

Resilience, the ability to overcome stressful conditions, is found in most mammals and varies significantly among individuals. A lack of resilience can lead to the development of neuropsychiatric and sleep disorders, often within the same individual. Despite extensive research into the brain mechanisms causing maladaptive behavioral-responses to stress, it is not clear why some individuals exhibit resilience. To examine if sleep has a determinative role in maladaptive behavioral-response to social stress, we investigated individual variations in resilience using a social-defeat model for male mice. Our results reveal a direct, causal relationship between sleep amount and resilience-demonstrating that sleep increases after social-defeat stress only occur in resilient mice. Further, we found that within the prefrontal cortex, a regulator of maladaptive responses to stress, pre-existing differences in sleep regulation predict resilience. Overall, these results demonstrate that increased NREM sleep, mediated cortically, is an active response to social-defeat stress that plays a determinative role in promoting resilience. They also show that differences in resilience are strongly correlated with inter-individual variability in sleep regulation.

To many of us, it may seem obvious that sleep is restorative: we feel better after a good night's rest. However, exactly how sleep benefits the brain and body remains poorly understood. One clue may lie in neuropsychiatric disorders: these conditions ­ such as depression and anxiety ­ are often accompanied by disrupted sleep. Additionally, these neuropsychiatric disorders are frequently caused or worsened by stress, which can also interfere with sleep. This close association between stress and sleep has led some to hypothesize that sleep serves to overcome the adverse effects of stress on the brain, but this hypothesis remains largely untested. One type of stress that is common to all mammals is social stress, defined as stress caused by social interactions. This means that mice and other rodents can be subjected to social stress in the laboratory to test hypotheses about the effects of stress on the brain. Importantly, in both animals and humans, there are individual differences in resilience, or the ability to overcome the adverse effects of stress. Based on this information, Bush et al. set out to establish whether sleep can regulate resilience to social stress in mice. When the mice were gently kept awake during their normal sleep time, resilience decreased and so the mice were less able to overcome the negative effects of stress. Conversely, increasing sleep, by activating an area of the brain responsible for initiating sleep, increased the mice's resilience to social stress. Thus, Bush et al. showed that changes in sleep do lead to changes in resilience. To find out whether resilience can be predicted by changes in sleeping patterns, Bush et al. studied how both resilient mice and those susceptible to stress slept before and after social stress. Resilient mice would often sleep more after social stress; meanwhile, few changes were observed in susceptible mice. Surprisingly, sleep quality also predicted resilience, with resilient mice sleeping better than susceptible mice even before exposure to social stress. To determine whether the differences in sleep that predict resilience can be detected as brain activity, Bush et al. placed electrodes in two regions of the prefrontal cortex ­ a part of the brain important for decision-making and social behaviors ­ to measure how mice recovered lost sleep. This experiment revealed that the changes in sleep that predict resilience are prominent in the prefrontal cortex. Overall, Bush et al. reveal that sleeping more and sleeping better promote resilience to social stress. Furthermore, the results suggests that lack of sleep may lead to increased risk of stress-related psychiatric conditions. Humans are one of the few species that choose to deprive themselves of sleep: Bush, et al. provide evidence that this choice may have significant consequences on mental health. Furthermore, this work creates a new model that lays the groundwork for future studies investigating how sleep can overcome stress on the brain.

Self-Reported Sleep Need, Subjective Resilience, and Cognitive Performance Following Sleep Loss and Recovery Sleep.

OBJECTIVE: Individuals vary in response to sleep loss: some individuals are "vulnerable" and demonstrate cognitive decrements following insufficient sleep, while others are "resistant" and maintain baseline cognitive capability. Physiological markers (e.g., genetic polymorphisms) have been identified that can predict relative vulnerability. However, a quick, cost-effective, and feasible subjective predictor tool has not been developed. The objective of the present study was to determine whether two factors-"subjective sleep need" and "subjective resilience"-predict cognitive performance following sleep deprivation. METHODS: Twenty-seven healthy, sleep-satiated young adults participated. These individuals were screened for sleep disorders, comorbidities, and erratic sleep schedules. Prior to 40 hours of in-laboratory total sleep deprivation, participants were questioned on their subjective sleep need and completed a validated resilience scale. During and after sleep deprivation, participants completed a 5-minute psychomotor vigilance test every 2 hours. RESULTS: Both subjective resilience and subjective sleep need individually failed to predict performance during sleep loss. However, these two measures interacted to predict performance. Individuals with low resilience and low sleep need had poorer cognitive performance during sleep loss. However, in individuals with medium or high resilience, psychomotor vigilance test performance was not predicted by subjective sleep need. Higher resilience may be protective against sleep loss-related neurobehavioral impairments in the context of subjective sleep need. CONCLUSIONS: Following sleep loss (and recovery sleep), trait resilient individuals may outperform those with lower resiliency on real-world tasks that require continuous attention. Future studies should determine whether the present findings generalize to other, operationally relevant tasks and additional cognitive domains.

TNFα G308A genotype, resilience to sleep deprivation, and the effect of caffeine on psychomotor vigilance performance in a randomized, double-blind, placebo-controlled, crossover study.

The TNFα G308A gene polymorphism has been reported to influence performance impairment during total sleep deprivation (TSD). We investigated this effect in a randomized, double-blind, crossover laboratory study of repeated exposure to 48 h TSD with caffeine administration at different doses. In a retrospective analysis, we replicated the finding that the A allele of TNFα G308A, found in 4 of 12 study participants, confers resilience to performance impairment during TSD. There was no evidence of an interaction of TNFα genotype with the beneficial effect of caffeine (200 or 300 mg) on performance during TSD, suggesting distinct underlying mechanisms.

Earlier shift in race pacing can predict future performance during a single-effort ultramarathon under sleep deprivation.

OBJECTIVE: We constructed research camps at single-effort ultramarathons (50 and 100 miles) in order to study human endurance capabilities under extreme sleep loss and stress. It takes > 24h, on average, to run 100 miles on minimal sleep, allowing us to construct 24h human performance profiles (HPP). METHODS: We collected performance data plotted across time (race splits) and distance (dropout rates; n=257), self-reported sleep and training patterns (n=83), and endpoint data on cardiovascular fitness/adaptation to total sleep deprivation and extreme exercise/stress (n=127). RESULTS: In general, we found that self-reported napping was higher for 100-miler versus 50-miler runners and that ultra-endurance racing may possibly pre-select for early morning risers. We also compared HPPs between the first 50 miles completed by all runners in order to examine amplitude and acrophase differences in performance using a cosinor model. We showed that even though all runners slowed down over time, runners who completed a 100-miler ultramarathon had an earlier acrophase shift in race pace compared to non-finishers. DISCUSSION: We were able to identify time-dependent predictions on overall performance under minimal sleep, warranting the ultramarathon athlete as a unique demographic for future study of sleep and chronobiological relationships in the real world.

Effect of cognitive load and emotional valence of distractors on performance during sleep extension and subsequent sleep deprivation.

STUDY OBJECTIVES: The purpose of the present study was to assess the extent to which sleep extension followed by sleep deprivation impacts performance on an attentional task with varying cognitive and attentional demands that influence decisions. METHODS: Task performance was assessed at baseline, after 1 week of sleep extension, and after 40 h of total sleep deprivation. RESULTS: One week of sleep extension resulted in improved performance, particularly for high cognitive load decisions regardless of the emotional salience of attentional distractors. Those who extended sleep the most relative to their habitual sleep duration showed the greatest improvement in general performance during sleep extension. However, a higher percentage of time spent in slow-wave sleep (SWS) on the last night of the sleep extension phase was negatively correlated with performance on more difficult high cognitive load items, possibly reflecting a relatively higher level of residual sleep need. Sleep deprivation generally resulted in impaired performance, with a nonsignificant trend toward greater performance decrements in the presence of emotionally salient distractors. Performance overall, but specifically for high cognitive load decisions, during total sleep deprivation was negatively correlated with longer sleep and higher SWS percentage during subsequent recovery sleep. CONCLUSIONS: The present findings suggest two possibilities: those who performed relatively poorly during sleep deprivation were more vulnerable because (1) they utilized mental resources (i.e. accrued sleep debt) at a relatively faster rate during wakefulness, and/or (2) they failed to "pay down" pre-study sleep debt to the same extent as better-performing participants during the preceding sleep extension phase.

Examination of Sleep and Injury Among College Football Athletes.

Burke, TM, Lisman, PJ, Maguire, K, Skeiky, L, Choynowski, JJ, CapaldiII, VF, Wilder, JN, Brager, AJ, and Dobrosielski, DA. Examination of sleep and injury among college football athletes. J Strength Cond Res 34(3): 609-616, 2020-The purpose of this study was to characterize subjective sleep metrics in collegiate football players at the start of the season, determine the relationship between preseason subjective sleep measures and in-season objective sleep characteristics, and examine the association between subjective and objective sleep metrics and incidence of time-loss injury during the competitive season. Ninety-four Division I football players completed 5 validated sleep-related questionnaires to assess sleep quality, insomnia severity, daytime sleepiness, sleep apnea risk, and circadian preference before the start of the season. Clinical thresholds for sleep questionnaires were used to determine risk of sleep disorders. Continuous wrist actigraphy was collected throughout the season to generalize sleep behaviors. Time-loss injury incidence data were recorded and used for analysis. Results indicated that 67.4% (60 of 89) of athletes scored above clinical threshold in at least 1 questionnaire to indicate sleep disorder risk. At the start of the season, players subjectively reported an average sleep duration of 7:16 ± 1:18 hours:minutes, which was in contrast to the 6:04 ± 0:41 hours:minutes measured through actigraphy during the season. Logistic regression models adjusted for age and body mass index revealed no significant associations between injury and subjective (odds ratio [OR] = 1.00; 95% confidence interval [CI] = 0.99-1.01) and objective (OR = 1.01; 95% CI = 0.99-1.02) sleep duration or measures attained from sleep questionnaires (ORs ranged from 1.01 to 2.87). Sleep metrics (quantity and quality) were not associated with increased risk of injury in this cohort of collegiate football players.

Sleep in the United States Military.

The military lifestyle often includes continuous operations whether in training or deployed environments. These stressful environments present unique challenges for service members attempting to achieve consolidated, restorative sleep. The significant mental and physical derangements caused by degraded metabolic, cardiovascular, skeletomuscular, and cognitive health often result from insufficient sleep and/or circadian misalignment. Insufficient sleep and resulting fatigue compromises personal safety, mission success, and even national security. In the long-term, chronic insufficient sleep and circadian rhythm disorders have been associated with other sleep disorders (e.g., insomnia, obstructive sleep apnea, and parasomnias). Other physiologic and psychologic diagnoses such as post-traumatic stress disorder, cardiovascular disease, and dementia have also been associated with chronic, insufficient sleep. Increased co-morbidity and mortality are compounded by traumatic brain injury resulting from blunt trauma, blast exposure, and highly physically demanding tasks under load. We present the current state of science in human and animal models specific to service members during- and post-military career. We focus on mission requirements of night shift work, sustained operations, and rapid re-entrainment to time zones. We then propose targeted pharmacological and non-pharmacological countermeasures to optimize performance that are mission- and symptom-specific. We recognize a critical gap in research involving service members, but provide tailored interventions for military health care providers based on the large body of research in health care and public service workers.

Sleep, napping and alertness during an overwintering mission at Belgrano II Argentine Antarctic station.

During Antarctic isolation personnel are exposed to extreme photoperiods. A frequent observation is a sleep onset phase delay during winter. It is not known if, as a result, daytime sleeping in the form of naps increases. We sought to assess sleep patterns - with focus on daytime sleeping - and alertness in a Latin American crew overwintering in Argentine Antarctic station Belgrano II. Measurements were collected in 13 males during March, May, July, September and November, and included actigraphy and psychomotor vigilance tasks. Sleep duration significantly decreased during winter. A total of eight participants took at least one weekly nap across all measurement points. During winter, the nap onset was delayed, its duration increased and its efficiency improved. We observed a significant effect of seasonality in the association of evening alertness with sleep onset. Our results replicate previous findings regarding sleep during overwintering in Antarctica, adding the description of the role of napping and the report of a possible modulatory effect of seasonality in the relation between sleep and alertness. Napping should be considered as an important factor in the scheduling of activities of multicultural crews that participate in Antarctica.

Objective changes in activity levels following sleep extension as measured by wrist actigraphy.

OBJECTIVE/BACKGROUND: It is widely established that insufficient sleep can lead to adverse health outcomes. Paradoxically, epidemiologic research suggests that individuals who report habitual nightly sleep greater than 9 h also are at risk for adverse health outcomes. Further, studies have shown that long sleepers have decreased activity levels, which may partially explain the relationship between long sleep duration and mortality. The influence of sleep extension (longer time in bed) on levels of daily activity has not yet been established. The current study examined whether a week of sleep extension altered activity levels within the subsequent daily waking active and sleep period in order to determine whether increased time in bed indeed is related to decreased activity levels. METHODS: A total of 26 healthy volunteers wore wrist accelerometer devices (Actiwatch 2.0, Philips) in order to objectively measure sleep and activity for six days during their normal schedules and for six days during a sleep extension (10 h time in bed) intervention. RESULTS: There were no significant or clinically-relevant differences in 24-h activity or activity during the active or sleep period between baseline and sleep extension conditions. There were no main or interaction effects of day and condition when daily activity counts were compared between baseline and sleep extension conditions for the 24 h period (Day: F(5, 21) = 1.92, p = 0.12; Condition: F(1,25) = 2.93, p = 0.09; Day by Condition: F(5,21) = 0.32, p = 0.83), Active Waking Period (Day: F(5,25) = 1.53, p = 0.18; Condition: F(1,25) = 0.26, p = 0.61; Day by Condition: F(5,21) = 0.55, p = 0.74) or Nightly Sleep (Day: F(5,21) = 0.86, p = 0.51; Condition: F(1,25) = 1.78, p = 0.19; Day by Condition: F(5,21) = 0.79, p = 0.56) periods. In contrast, there was a main effect of condition when examining sleep duration by day between conditions (Day: F(5,21) = 1.60, p = 0.16; Condition: F(1,25) = 167.31, p < 0.001; Day by Condition: F(5,21) = 2.31, p = 0.07), such that sleep duration was longer during the sleep extension condition. DISCUSSION: Sleep duration increased during six days of a sleep extension protocol but activity levels remained similar to their baseline (normal) sleep schedule. The current findings suggest that extending time in bed alone does not alter waking activity counts in young healthy adults. The link between extended sleep and adverse health outcomes may be attributable to other phenotypic factors, or other biological correlates of extended sleep and poor health.

A Review of Environmental Barriers to Obtaining Adequate Sleep in the Military Operational Context.

INTRODUCTION: Sleep loss is ubiquitous in military settings, and it can be deleterious to cognitive, physiological, and operational functioning. This is especially true in the military operational context (e.g., training, garrison, combat) where continuous operations prevent adequate time for rest and recuperation. Furthermore, even when servicemembers do have opportunities for sleep, environmental disruptors in the military operational context make it difficult to obtain restorative sleep. Such environmental disruptors are potentially preventable or reversible, yet there is little public awareness of how to minimize or eliminate these sleep disruptors. Therefore, the goal of this review was to outline prominent environmental sleep disruptors, describe how they occur in the military operational context, and also discuss feasible strategies to mitigate these disruptors. MATERIALS AND METHODS: We discuss four factors - light, noise, temperature, and air pollution - that have previously been identified as prominent sleep disruptors in non-military settings. Additionally, we extracted publicly-available yearly temperature and pollution data, from the National Oceanic and Atmospheric Association and the Environmental Protection Agency, respectively, for major prominent military installations in the continental US in order to identify the sites at which servicemembers are at the greatest risk for environmental sleep disruptions. RESULTS: Based on previous literature, we concluded light and noise are the most easily mitigatable sleep-disrupting environmental factors. Air pollution and temperature, on the other hand, are more difficult to mitigate. We also propose that harsh/uncomfortable sleeping surface is a fifth critical, previously unexplored sleep disruptor in the military operational context. Furthermore, we identified several problematic military sites for air pollution for temperature. Specifically, each branch has major installations located in regions with extreme heat (especially the Army), and each branch has at least one major installation in a high air pollution region. These findings show that even when in training or garrison in the US, military servicemembers are at risk for having sleep disruption due to environmental factors. CONCLUSIONS: Environmental disruptors, such as light, noise, temperature, and air pollution, can negatively impact sleep in the military operational context. Simple, feasible steps can be taken to reduce sleep disruptions that are caused by light and noise. Yet there is a need for research and development on tools to mitigate air pollution, extreme temperatures, and inhospitable sleeping surfaces. Leadership at the discussed military bases and training facilities should focus on improving the sleep environment for individuals under their command. Such interventions could ultimately improve warfighter health, wellness, and operational performance, leading to greater warfighter readiness and lethality.

Sleep extension reduces pain sensitivity.

INTRODUCTION: Insufficient sleep increases pain sensitivity in healthy individuals. Additionally, extending sleep (eg, increasing nocturnal sleep time or adding a mid-day nap) has been shown to restore pain sensitivity to baseline levels in sleep deprived/restricted individuals. Whether sleep extension can reduce pain sensitivity beyond baseline levels in non-sleep restricted/deprived individuals remains unknown. METHODS: In a sample of 27 healthy, pain-free, normally-sleeping individuals (17 males, mean age ∼24 yrs), we examined the impact of five nights of sleep extension on pain sensitivity. Pain threshold (elapsed time until the participant reported pain) and pain tolerance (total time the participant kept the hand submerged in the cold water) were measured using the Cold Pressor Task. Furthermore, we assessed the extent to which self-reported sleep amount in relation to the minimal subjective sleep requirement for adequate performance (sleep credit) was associated with pain sensitivity changes. RESULTS: On average individuals slept almost 2 extra hours per night. Our results indicate that sleep extension increases pain tolerance beyond baseline levels. However, sleep extension did not impact pain threshold. We also found that individuals with a smaller sleep credit (ie, those who habitually obtain less sleep than they feel they need) experienced greater increases in pain tolerance after extending sleep. CONCLUSIONS: The present findings suggest that sleep extension may increase pain tolerance but not pain threshold in healthy individuals who normally sleep the recommended amount. Our findings also support the idea that sleep credit may be a strong indicator of sleep debt in the context of pain sensitivity.

A systematic review and meta-analysis of sleep architecture and chronic traumatic brain injury.

Sleep quality appears to be altered by traumatic brain injury (TBI). However, whether persistent post-injury changes in sleep architecture are present is unknown and relatively unexplored. We conducted a systematic review and meta-analysis to assess the extent to which chronic TBI (>6 months since injury) is characterized by changes to sleep architecture. We also explored the relationship between sleep architecture and TBI severity. In the fourteen included studies, sleep was assessed with at least one night of polysomnography in both chronic TBI participants and controls. Statistical analyses, performed using Comprehensive Meta-Analysis software, revealed that chronic TBI is characterized by relatively increased slow wave sleep (SWS). A meta-regression showed moderate-severe TBI is associated with elevated SWS, reduced stage 2, and reduced sleep efficiency. In contrast, mild TBI was not associated with any significant alteration of sleep architecture. The present findings are consistent with the hypothesis that increased SWS after moderate-severe TBI reflects post-injury cortical reorganization and restructuring. Suggestions for future research are discussed, including adoption of common data elements in future studies to facilitate cross-study comparability, reliability, and replicability, thereby increasing the likelihood that meaningful sleep (and other) biomarkers of TBI will be identified.

Bmal1 function in skeletal muscle regulates sleep.

Sleep loss can severely impair the ability to perform, yet the ability to recover from sleep loss is not well understood. Sleep regulatory processes are assumed to lie exclusively within the brain mainly due to the strong behavioral manifestations of sleep. Whole-body knockout of the circadian clock gene Bmal1 in mice affects several aspects of sleep, however, the cells/tissues responsible are unknown. We found that restoring Bmal1 expression in the brains of Bmal1-knockout mice did not rescue Bmal1-dependent sleep phenotypes. Surprisingly, most sleep-amount, but not sleep-timing, phenotypes could be reproduced or rescued by knocking out or restoring BMAL1 exclusively in skeletal muscle, respectively. We also found that overexpression of skeletal-muscle Bmal1 reduced the recovery response to sleep loss. Together, these findings demonstrate that Bmal1 expression in skeletal muscle is both necessary and sufficient to regulate total sleep amount and reveal that critical components of normal sleep regulation occur in muscle.

Homeostatic effects of exercise and sleep on metabolic processes in mice with an overexpressed skeletal muscle clock.

Brain and muscle-ARNT-like factor (Bmal1/BMAL1) is an essential transcriptional/translational factor of circadian clocks. Loss of function of Bmal1/BMAL1 is highly disruptive to physiological and behavioral processes. In light of these previous findings, we examined if transgenic overexpression of Bmal1/BMAL1 in skeletal muscle could alter metabolic processes. First, we characterized in vivo and ex vivo metabolic phenotypes of muscle overexpressed mice (male and female) compared to wild-type littermates (WT). Second, we examined in vivo and ex vivo metabolic processes in the presence of positive and negative homeostatic challenges: high-intensity treadmill running (positive) and acute sleep deprivation (negative). In vivo measures of metabolic processes included body composition, respiratory exchange ratio (RER; VCO2/VO2), energy expenditure, total activity counts, and food intake collected from small animal indirect calorimetry. Ex vivo measure of insulin sensitivity in skeletal muscle was determined from radioassays. RER was lower for muscle overexpressed females compared to female WTs. There were no genotype-dependent differences in metabolic phenotypes for males. With homeostatic challenges, muscle overexpressed mice had lower energy expenditure after high-intensity treadmill running. Acute sleep deprivation reduced insulin sensitivity in skeletal muscle in overexpressed male mice, but not male WTs. The present study contributes to a body of evidence showing pleiotropic, non-circadian, and homeostatic effects of altered Bmal1/BMAL1 expression on metabolic processes, demonstrating a critical need to further investigate the broad and complex actions of Bmal1/BMAL1 on physiology and behavior.

Game Times and Higher Winning Percentages of West Coast Teams of the National Football League Correspond With Reduced Prevalence of Regular Season Injury.

Brager, AJ and Mistovich, RJ. Game times and higher winning percentages of west coast teams of the National Football League correspond with reduced prevalence of regular season injury. J Strength Cond Res 31(2): 462-467, 2017-West coast teams of the National Football League are more statistically likely to win home night games against east coast opponents. The alignment of game times with daily rhythms of alertness is thought to contribute to this advantage. This study aims to determine whether rates of turnovers and injuries during the regular season, putative measures of mental and physical fatigue, impact winning percentages. Regular season schedules and rates of turnovers for each of the 32 teams were obtained from Pro-Football-Reference. We developed our own metric of injury risk for each position obtained from depth charts and regular season schedules. This metric compared cumulative weeks on injury reserve with cumulative time zone travel. West coast teams traveled 4 times as often as east coast teams. However, teams traveling eastward won twice as many games. There was no relationship between the extent and direction of travel and number of turnovers. Losing teams had more turnovers. The offensive and defensive lines in Central Time (CT) were placed on injury reserve 4 times as often as offensive and defensive lines in Pacific Time (PT). Injury prevalence in CT vs. PT was most prominent midseason. Plotting midseason game time relative to biological time revealed that PT teams play games closer to endogenous peaks in alertness, whereas CT teams play games closer to endogenous troughs in alertness. Overall, closer alignment of game time with the endogenous "alerting" signal may protect west coast teams from fatigue-related injuries and suggests for modified strength and conditioning programs.

Sleep Is Critical for Remote Preconditioning-Induced Neuroprotection.

STUDY OBJECTIVES: Episodes of brief limb ischemia (remote preconditioning) in mice induce tolerance to modeled ischemic stroke (focal brain ischemia). Since stroke outcomes are in part dependent on sleep-wake history, we sought to determine if sleep is critical for the neuroprotective effect of limb ischemia. METHODS: EEG/EMG recording electrodes were implanted in mice. After a 24 h baseline recording, limb ischemia was induced by tightening an elastic band around the left quadriceps for 10 minutes followed by 10 minutes of release for two cycles. Two days following remote preconditioning, a second 24 h EEG/EMG recording was completed and was immediately followed by a 60-minute suture occlusion of the middle cerebral artery (modeled ischemic stroke). This experiment was then repeated in a model of circadian and sleep abnormalities (Bmal1 knockout [KO] mice sleep 2 h more than wild-type littermates). Brain infarction was determined by vital dye staining, and sleep was assessed by trained identification of EEG/EMG recordings. RESULTS: Two days after limb ischemia, wild-type mice slept an additional 2.4 h. This additional sleep was primarily comprised of non-rapid eye movement (NREM) sleep during the middle of the light-phase (i.e., naps). Repeating the experiment but preventing increases in sleep after limb ischemia abolished tolerance to ischemic stroke. In Bmal1 knockout mice, remote preconditioning did not increase daily sleep nor provide tolerance to subsequent focal ischemia. CONCLUSIONS: These results suggest that sleep induced by remote preconditioning is both sufficient and necessary for its neuroprotective effects on stroke outcome.

Maternal Ube3a Loss Disrupts Sleep Homeostasis But Leaves Circadian Rhythmicity Largely Intact.

Individuals with Angelman syndrome (AS) suffer sleep disturbances that severely impair quality of life. Whether these disturbances arise from sleep or circadian clock dysfunction is currently unknown. Here, we explored the mechanistic basis for these sleep disorders in a mouse model of Angelman syndrome (Ube3a(m-/p+) mice). Genetic deletion of the maternal Ube3a allele practically eliminates UBE3A protein from the brain of Ube3a(m-/p+) mice, because the paternal allele is epigenetically silenced in most neurons. However, we found that UBE3A protein was present in many neurons of the suprachiasmatic nucleus--the site of the mammalian circadian clock--indicating that Ube3a can be expressed from both parental alleles in this brain region in adult mice. We found that while Ube3a(m-/p+) mice maintained relatively normal circadian rhythms of behavior and light-resetting, these mice exhibited consolidated locomotor activity and skipped the timed rest period (siesta) present in wild-type (Ube3a(m+/p+)) mice. Electroencephalographic analysis revealed that alterations in sleep regulation were responsible for these overt changes in activity. Specifically, Ube3a(m-/p+) mice have a markedly reduced capacity to accumulate sleep pressure, both during their active period and in response to forced sleep deprivation. Thus, our data indicate that the siesta is governed by sleep pressure, and that Ube3a is an important regulator of sleep homeostasis. These preclinical findings suggest that therapeutic interventions that target mechanisms of sleep homeostasis may improve sleep quality in individuals with AS. SIGNIFICANCE STATEMENT: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of expression of the maternal copy of the UBE3A gene. Individuals with AS have severe sleep dysfunction that affects their cognition and presents challenges to their caregivers. Unfortunately, current treatment strategies have limited efficacy due to a poor understanding of the mechanisms underlying sleep disruptions in AS. Here we demonstrate that abnormal sleep patterns arise from a deficit in accumulation of sleep drive, uncovering the Ube3a gene as a novel genetic regulator of sleep homeostasis. Our findings encourage a re-evaluation of current treatment strategies for sleep dysfunction in AS, and suggest that interventions that promote increased sleep drive may alleviate sleep disturbances in individuals with AS.