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1.  Identification of Redeye, a new sleep-regulating protein whose expression is modulated by sleep amount 
eLife  2014;3:e01473.
In this study, we report a new protein involved in the homeostatic regulation of sleep in Drosophila. We conducted a forward genetic screen of chemically mutagenized flies to identify short-sleeping mutants and found one, redeye (rye) that shows a severe reduction of sleep length. Cloning of rye reveals that it encodes a nicotinic acetylcholine receptor α subunit required for Drosophila sleep. Levels of RYE oscillate in light–dark cycles and peak at times of daily sleep. Cycling of RYE is independent of a functional circadian clock, but rather depends upon the sleep homeostat, as protein levels are up-regulated in short-sleeping mutants and also in wild type animals following sleep deprivation. We propose that the homeostatic drive to sleep increases levels of RYE, which responds to this drive by promoting sleep.
eLife digest
Almost all animals need to sleep, including most insects. In experiments in the 1980s, a group of rats that were completely deprived of sleep died within only a few weeks. Sleep has been implicated in processes including tissue repair, memory consolidation and, more recently, the removal of waste materials from the brain. However, a full understanding of why we sleep is still lacking.
As anyone who has experienced jetlag can testify, the timing of the sleep/wake cycle is governed by the circadian clock, which leads us to feel sleepy at certain points of the day–night cycle and alert at others. The duration of sleep is regulated by a second process called sleep/wake homeostasis. The longer we remain awake, the more the body’s need for sleep—or ‘sleep drive’—increases, until it becomes almost impossible to stay awake any longer. Whereas many components of the circadian clock have been identified, relatively little is known about the molecular basis of this second process.
Now, Shi et al. have identified a key component of the sleep/wake homeostatic system using the fruit fly and genetic model organism, Drosophila. Flies with a mutation in one particular gene, subsequently named redeye, were found to sleep only half as long as normal flies. While the insects were able to fall asleep, they would wake again only a few minutes later.
Redeye encodes a subunit of a receptor that has previously been implicated in the control of wakefulness, known as the nicotinic acetylcholine receptor. Mutant flies had normal circadian rhythms, suggesting that their sleep problems were the result of disrupted sleep/wake homeostasis. Consistent with this, levels of redeye showed two daily peaks, one corresponding to night-time sleep and the second to the time at which flies would normally take an afternoon siesta. This suggests that redeye signals an acute need for sleep, and then helps to maintain sleep once it is underway.
While redeye is not thought to be the factor that triggers sleep per se, it is directly under control of the sleep homeostat, and may be a useful biomarker for sleep deprivation. The fact that redeye was identified in fruit flies, a species whose genome has been fully sequenced, opens up the possibility of further studies to identify the genetic basis of sleep regulation.
PMCID: PMC3912633  PMID: 24497543
sleep; acetylcholine signaling; cycling; Sleepless/Lynx-1; D. melanogaster
2.  Tracking the Sleep Onset Process: An Empirical Model of Behavioral and Physiological Dynamics 
PLoS Computational Biology  2014;10(10):e1003866.
The sleep onset process (SOP) is a dynamic process correlated with a multitude of behavioral and physiological markers. A principled analysis of the SOP can serve as a foundation for answering questions of fundamental importance in basic neuroscience and sleep medicine. Unfortunately, current methods for analyzing the SOP fail to account for the overwhelming evidence that the wake/sleep transition is governed by continuous, dynamic physiological processes. Instead, current practices coarsely discretize sleep both in terms of state, where it is viewed as a binary (wake or sleep) process, and in time, where it is viewed as a single time point derived from subjectively scored stages in 30-second epochs, effectively eliminating SOP dynamics from the analysis. These methods also fail to integrate information from both behavioral and physiological data. It is thus imperative to resolve the mismatch between the physiological evidence and analysis methodologies. In this paper, we develop a statistically and physiologically principled dynamic framework and empirical SOP model, combining simultaneously-recorded physiological measurements with behavioral data from a novel breathing task requiring no arousing external sensory stimuli. We fit the model using data from healthy subjects, and estimate the instantaneous probability that a subject is awake during the SOP. The model successfully tracked physiological and behavioral dynamics for individual nights, and significantly outperformed the instantaneous transition models implicit in clinical definitions of sleep onset. Our framework also provides a principled means for cross-subject data alignment as a function of wake probability, allowing us to characterize and compare SOP dynamics across different populations. This analysis enabled us to quantitatively compare the EEG of subjects showing reduced alpha power with the remaining subjects at identical response probabilities. Thus, by incorporating both physiological and behavioral dynamics into our model framework, the dynamics of our analyses can finally match those observed during the SOP.
Author Summary
How can we tell when someone has fallen asleep? Understanding the way we fall asleep is an important problem in sleep medicine, since sleep disorders can disrupt the process of falling asleep. In the case of insomnia, subjects may fall asleep too slowly, whereas during sleep deprivation or narcolepsy, subjects fall asleep too quickly. Current methods for tracking the wake/sleep transition are time-consuming, subjective, and simplify the sleep onset process in a way that severely limits the accuracy, power, and scope of any resulting clinical metrics. In this paper, we describe a new physiologically principled method that dynamically combines information from brainwaves, muscle activity, and a novel minimally-disruptive behavioral task, to automatically create a continuous dynamic characterization of a person's state of wakefulness. We apply this method to a cohort of healthy subjects, successfully tracking the changes in wakefulness as the subjects fall asleep. This analysis reveals and statistically quantifies a subset of subjects who still respond to behavioral stimuli even though their brain would appear to be asleep by clinical measures. By developing an automated tool to precisely track the wake/sleep transition, we can better characterize and diagnose sleep disorders, and more precisely measure the effect of sleep medications.
PMCID: PMC4183428  PMID: 25275376
3.  Circadian Rhythms, Sleep Deprivation, and Human Performance 
Much of the current science on, and mathematical modeling of, dynamic changes in human performance within and between days is dominated by the two-process model of sleep–wake regulation, which posits a neurobiological drive for sleep that varies homeostatically (increasing as a saturating exponential during wakefulness and decreasing in a like manner during sleep), and a circadian process that neurobiologically modulates both the homeostatic drive for sleep and waking alertness and performance. Endogenous circadian rhythms in neurobehavioral functions, including physiological alertness and cognitive performance, have been demonstrated using special laboratory protocols that reveal the interaction of the biological clock with the sleep homeostatic drive. Individual differences in circadian rhythms and genetic and other components underlying such differences also influence waking neurobehavioral functions. Both acute total sleep deprivation and chronic sleep restriction increase homeostatic sleep drive and degrade waking neurobehavioral functions as reflected in sleepiness, attention, cognitive speed, and memory. Recent evidence indicating a high degree of stability in neurobehavioral responses to sleep loss suggests that these trait-like individual differences are phenotypic and likely involve genetic components, including circadian genes. Recent experiments have revealed both sleep homeostatic and circadian effects on brain metabolism and neural activation. Investigation of the neural and genetic mechanisms underlying the dynamically complex interaction between sleep homeostasis and circadian systems is beginning. A key goal of this work is to identify biomarkers that accurately predict human performance in situations in which the circadian and sleep homeostatic systems are perturbed.
PMCID: PMC3963479  PMID: 23899598
4.  Daily rhythms of the sleep-wake cycle 
The amount and timing of sleep and sleep architecture (sleep stages) are determined by several factors, important among which are the environment, circadian rhythms and time awake. Separating the roles played by these factors requires specific protocols, including the constant routine and altered sleep-wake schedules. Results from such protocols have led to the discovery of the factors that determine the amounts and distribution of slow wave and rapid eye movement sleep as well as to the development of models to determine the amount and timing of sleep. One successful model postulates two processes. The first is process S, which is due to sleep pressure (and increases with time awake) and is attributed to a 'sleep homeostat'. Process S reverses during slow wave sleep (when it is called process S'). The second is process C, which shows a daily rhythm that is parallel to the rhythm of core temperature. Processes S and C combine approximately additively to determine the times of sleep onset and waking. The model has proved useful in describing normal sleep in adults. Current work aims to identify the detailed nature of processes S and C. The model can also be applied to circumstances when the sleep-wake cycle is different from the norm in some way. These circumstances include: those who are poor sleepers or short sleepers; the role an individual's chronotype (a measure of how the timing of the individual's preferred sleep-wake cycle compares with the average for a population); and changes in the sleep-wake cycle with age, particularly in adolescence and aging, since individuals tend to prefer to go to sleep later during adolescence and earlier in old age. In all circumstances, the evidence that sleep times and architecture are altered and the possible causes of these changes (including altered S, S' and C processes) are examined.
PMCID: PMC3375033  PMID: 22738268
Adolescence; chronotype; circadian rhythm; endogenous component; exogenous component; old age; sleep homeostat; time awake
5.  A Physiologically Based Model of Orexinergic Stabilization of Sleep and Wake 
PLoS ONE  2014;9(3):e91982.
The orexinergic neurons of the lateral hypothalamus (Orx) are essential for regulating sleep-wake dynamics, and their loss causes narcolepsy, a disorder characterized by severe instability of sleep and wake states. However, the mechanisms through which Orx stabilize sleep and wake are not well understood. In this work, an explanation of the stabilizing effects of Orx is presented using a quantitative model of important physiological connections between Orx and the sleep-wake switch. In addition to Orx and the sleep-wake switch, which is composed of mutually inhibitory wake-active monoaminergic neurons in brainstem and hypothalamus (MA) and the sleep-active ventrolateral preoptic neurons of the hypothalamus (VLPO), the model also includes the circadian and homeostatic sleep drives. It is shown that Orx stabilizes prolonged waking episodes via its excitatory input to MA and by relaying a circadian input to MA, thus sustaining MA firing activity during the circadian day. During sleep, both Orx and MA are inhibited by the VLPO, and the subsequent reduction in Orx input to the MA indirectly stabilizes sustained sleep episodes. Simulating a loss of Orx, the model produces dynamics resembling narcolepsy, including frequent transitions between states, reduced waking arousal levels, and a normal daily amount of total sleep. The model predicts a change in sleep timing with differences in orexin levels, with higher orexin levels delaying the normal sleep episode, suggesting that individual differences in Orx signaling may contribute to chronotype. Dynamics resembling sleep inertia also emerge from the model as a gradual sleep-to-wake transition on a timescale that varies with that of Orx dynamics. The quantitative, physiologically based model developed in this work thus provides a new explanation of how Orx stabilizes prolonged episodes of sleep and wake, and makes a range of experimentally testable predictions, including a role for Orx in chronotype and sleep inertia.
PMCID: PMC3961294  PMID: 24651580
6.  Homeostatic regulation of sleep in the white-crowned sparrow (Zonotrichia leucophrys gambelii) 
BMC Neuroscience  2008;9:47.
Sleep is regulated by both a circadian and a homeostatic process. The homeostatic process reflects the duration of prior wakefulness: the longer one stays awake, the longer and/or more intense is subsequent sleep. In mammals, the best marker of the homeostatic sleep drive is slow wave activity (SWA), the electroencephalographic (EEG) power spectrum in the 0.5–4 Hz frequency range during non-rapid eye movement (NREM) sleep. In mammals, NREM sleep SWA is high at sleep onset, when sleep pressure is high, and decreases progressively to reach low levels in late sleep. Moreover, SWA increases further with sleep deprivation, when sleep also becomes less fragmented (the duration of sleep episodes increases, and the number of brief awakenings decreases). Although avian and mammalian sleep share several features, the evidence of a clear homeostatic response to sleep loss has been conflicting in the few avian species studied so far. The aim of the current study was therefore to ascertain whether established markers of sleep homeostasis in mammals are also present in the white-crowned sparrow (Zonotrichia leucophrys gambelii), a migratory songbird of the order Passeriformes. To accomplish this goal, we investigated amount of sleep, sleep time course, and measures of sleep intensity in 6 birds during baseline sleep and during recovery sleep following 6 hours of sleep deprivation.
Continuous (24 hours) EEG and video recordings were used to measure baseline sleep and recovery sleep following short-term sleep deprivation. Sleep stages were scored visually based on 4-sec epochs. EEG power spectra (0.5–25 Hz) were calculated on consecutive 4-sec epochs. Four vigilance states were reliably distinguished based on behavior, visual inspection of the EEG, and spectral EEG analysis: Wakefulness (W), Drowsiness (D), slow wave sleep (SWS) and rapid-eye movement (REM) sleep. During baseline, SWA during D, SWS, and NREM sleep (defined as D and SWS combined) was highest at the beginning of the major sleep period and declined thereafter. Moreover, peak SWA in both SWS and NREM sleep increased significantly immediately following sleep deprivation relative to baseline.
As in mammals, sleep deprivation in the white-crowned sparrow increases the intensity of sleep as measured by SWA.
PMCID: PMC2424059  PMID: 18505569
7.  Altered Circadian and Homeostatic Sleep Regulation in Prokineticin 2-Deficient Mice 
Sleep  2007;30(3):247-256.
Study Objectives
Sleep is regulated by circadian and homeostatic processes. Recent studies with mutant mice have indicated that circadian-related genes regulate sleep amount, as well as the timing of sleep. Thus a direct link between circadian and homeostatic regulation of sleep may exist, at least at the molecular level. Prokineticin 2 (PK2), which oscillates daily with high amplitude in the suprachiasmatic nuclei (SCN), has been postulated to be an SCN output molecule. In particular, mice lacking the PK2 gene (PK2−/−) have been shown to display significantly reduced rhythmicity for a variety of circadian physiological and behavioral parameters. We investigated the role of PK2 in sleep regulation.
EEG/EMG sleep-wake patterns were recorded in PK2−/− mice and their wild-type littermate controls under baseline and challenged conditions.
Measurements and Results
PK2−/− mice exhibited reduced total sleep time under entrained light-dark and constant darkness conditions. The reduced sleep time in PK2−/− mice occurred predominantly during the light period and was entirely due to a decrease in non-rapid eye movement (NREM) sleep time. However, PK2−/− mice showed increased rapid eye movement (REM) sleep time in both light and dark periods. After sleep deprivation, compensatory rebound in NREM sleep, REM sleep, and EEG delta power was attenuated in PK2−/− mice. In addition, PK2−/− mice had an impaired response to sleep disturbance caused by cage change in the light phase.
These results indicate that PK2 plays roles in both circadian and homeostatic regulation of sleep. PK2 may also be involved in maintaining the awake state in the presence of behavioral challenges.
PMCID: PMC2673012  PMID: 17425220
Sleep; prokineticin 2; sleep homeostasis; circadian genes; EEG; behavioral challenge
8.  A Homeostatic Sleep-Stabilizing Pathway in Drosophila Composed of the Sex Peptide Receptor and Its Ligand, the Myoinhibitory Peptide 
PLoS Biology  2014;12(10):e1001974.
A ligand of the sex peptide receptor maintains sleep stability and homeostasis by inhibiting wakefulness-promoting neurons in Drosophila.
Sleep, a reversible quiescent state found in both invertebrate and vertebrate animals, disconnects animals from their environment and is highly regulated for coordination with wakeful activities, such as reproduction. The fruit fly, Drosophila melanogaster, has proven to be a valuable model for studying the regulation of sleep by circadian clock and homeostatic mechanisms. Here, we demonstrate that the sex peptide receptor (SPR) of Drosophila, known for its role in female reproduction, is also important in stabilizing sleep in both males and females. Mutants lacking either the SPR or its central ligand, myoinhibitory peptide (MIP), fall asleep normally, but have difficulty in maintaining a sleep-like state. Our analyses have mapped the SPR sleep function to pigment dispersing factor (pdf) neurons, an arousal center in the insect brain. MIP downregulates intracellular cAMP levels in pdf neurons through the SPR. MIP is released centrally before and during night-time sleep, when the sleep drive is elevated. Sleep deprivation during the night facilitates MIP secretion from specific brain neurons innervating pdf neurons. Moreover, flies lacking either SPR or MIP cannot recover sleep after the night-time sleep deprivation. These results delineate a central neuropeptide circuit that stabilizes the sleep state by feeding a slow-acting inhibitory input into the arousal system and plays an important role in sleep homeostasis.
Author Summary
Sleep is a common trait in animals, from insects to mammals, and it needs to be coordinated with other critical activities such as feeding and reproduction. However, the mechanisms by which this is achieved are not fully understood. The fruit fly Drosophila melanogaster has become a key model organism for sleep research and it has been shown that reproduction is one of the factors that can modulate sleep in these animals. Researchers have observed that mating reduces the daytime sleep of female flies and shown that the seminal fluid protein Sex Peptide (SP), a ligand of the Sex Peptide Receptor (SPR) that is transferred to females during copulation, is responsible for this reduction of siesta sleep. Here, we investigated further the role of SPR in sleep regulation in Drosophila. We show that SPR is required for sleep stabilization in both sexes and that in mutant flies lacking SPR or its ligand myoinhibitory peptide (MIP) sleep is fragmented independently of reproduction. Unlike SP, MIP is expressed in the brain of both sexes and acts on SPR to silence specific neurons that keep flies awake, stabilizing sleep. Hence, our results reveal that SPR interacts with two distinct ligands to control different behaviors: SP for reproduction and MIP for sleep.
PMCID: PMC4204809  PMID: 25333796
9.  Increased Cerebral Blood Flow Velocity in Children with Mild Sleep-Disordered Breathing 
Pediatrics  2006;118(4):e1100-e1108.
Sleep-disordered breathing describes a spectrum of upper airway obstruction in sleep from simple primary snoring, estimated to affect 10% of preschool children, to the syndrome of obstructive sleep apnea. Emerging evidence has challenged previous assumptions that primary snoring is benign. A recent report identified reduced attention and higher levels of social problems and anxiety/depressive symptoms in snoring children compared with controls. Uncertainty persists regarding clinical thresholds for medical or surgical intervention in sleep-disordered breathing, underlining the need to better understand the pathophysiology of this condition. Adults with sleep-disordered breathing have an increased risk of cerebrovascular disease independent of atherosclerotic risk factors. There has been little focus on cerebrovascular function in children with sleep-disordered breathing, although this would seem an important line of investigation, because studies have identified abnormalities of the systemic vasculature. Raised cerebral blood flow velocities on transcranial Doppler, compatible with raised blood flow and/or vascular narrowing, are associated with neuropsychological deficits in children with sickle cell disease, a condition in which sleep-disordered breathing is common. We hypothesized that there would be cerebral blood flow velocity differences in sleep-disordered breathing children without sickle cell disease that might contribute to the association with neuropsychological deficits.
Thirty-one snoring children aged 3 to 7 years were recruited from adenotonsillectomy waiting lists, and 17 control children were identified through a local Sunday school or as siblings of cases. Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Severity of sleep-disordered breathing in snoring children was categorized by attended polysomnography. Weight, height, and head circumference were measured in all of the children. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained. Both sleep-disordered breathing children and the age- and BMI-similar controls were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), Neuropsychological Test Battery for Children (NEPSY) visual attention and visuomotor integration, and IQ assessment (Wechsler Preschool and Primary Scale of Intelligence Version III). Transcranial Doppler was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 PM and 7 PM in all of the patients and the majority of controls while awake. Time-averaged mean of the maximal cerebral blood flow velocities was measured in the left and right middle cerebral artery and the higher used for analysis.
Twenty-one snoring children had an apnea/hypopnea index <5, consistent with mild sleep-disordered breathing below the conventional threshold for surgical intervention. Compared with 17 nonsnoring controls, these children had significantly raised middle cerebral artery blood flow velocities. There was no correlation between cerebral blood flow velocities and BMI or systolic or diastolic blood pressure indices. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean pulse oxygen saturation, lowest pulse oxygen saturation, accumulated time at pulse oxygen saturation <90%, or respiratory arousals when examined in separate bivariate correlations or in aggregate when entered simultaneously. Similarly, there was no significant association between cerebral blood flow velocities and parental estimation of child’s exposure to sleep-disordered breathing. However, it is important to note that whereas the sleep-disordered breathing group did not exhibit significant hypoxia at the time of study, it was unclear to what extent this may have been a feature of their sleep-disordered breathing in the past. IQ measures were in the average range and comparable between groups. Measures of processing speed and visual attention were significantly lower in sleep-disordered breathing children compared with controls, although within the average range. There were similar group differences in parental-reported executive function behavior. Although there were no direct correlations, adjusting for cerebral blood flow velocities eliminated significant group differences between processing speed and visual attention and decreased the significance of differences in Behavior Rating Inventory of Executive Function scores, suggesting that cerebral hemodynamic factors contribute to the relationship between mild sleep-disordered breathing and these outcome measures.
Cerebral blood flow velocities measured by noninvasive transcranial Doppler provide evidence for increased cerebral blood flow and/or vascular narrowing in childhood sleep-disordered breathing; the relationship with neuropsychological deficits requires further exploration. A number of physiologic changes might alter cerebral blood flow and/or vessel diameter and, therefore, affect cerebral blood flow velocities. We were able to explore potential confounding influences of obesity and hypertension, neither of which explained our findings. Second, although cerebral blood flow velocities increase with increasing partial pressure of carbon dioxide and hypoxia, it is unlikely that the observed differences could be accounted for by arterial blood gas tensions, because all of the children in the study were healthy, with no cardiorespiratory disease, other than sleep-disordered breathing in the snoring group. Although arterial partial pressure of oxygen and partial pressure of carbon dioxide were not monitored during cerebral blood flow velocity measurement, assessment was undertaken during the afternoon/early evening when the child was awake, and all of the sleep-disordered breathing children had normal resting oxyhemoglobin saturation at the outset of their subsequent sleep studies that day. Finally, there is an inverse linear relationship between cerebral blood flow and hematocrit in adults, and it is known that iron-deficient erythropoiesis is associated with chronic infection, such as recurrent tonsillitis, a clinical feature of many of the snoring children in the study. Preoperative full blood counts were not performed routinely in these children, and, therefore, it was not possible to exclude anemia as a cause of increased cerebral blood flow velocity in the sleep-disordered breathing group. However, hemoglobin levels were obtained in 4 children, 2 of whom had borderline low levels (10.9 and 10.2 g/dL). Although there was no apparent relationship with cerebral blood flow velocity in these children (cerebral blood flow velocity values of 131 and 130 cm/second compared with 130 and 137 cm/second in the 2 children with normal hemoglobin levels), this requires verification. It is of particular interest that our data suggest a relationship among snoring, increased cerebral blood flow velocities and indices of cognition (processing speed and visual attention) and perhaps behavioral (Behavior Rating Inventory of Executive Function) function. This finding is preliminary: a causal relationship is not established, and the physiologic mechanisms underlying such a relationship are not clear. Prospective studies that quantify cumulative exposure to the physiologic consequences of sleep-disordered breathing, such as hypoxia, would be informative.
PMCID: PMC1995426  PMID: 17015501
sleep disordered breathing; cerebral blood flow; transcranial Doppler; executive function; neuropsychological function
10.  The Perilipin Homologue, Lipid Storage Droplet 2, Regulates Sleep Homeostasis and Prevents Learning Impairments Following Sleep Loss 
PLoS Biology  2010;8(8):e1000466.
Starvation, which is common in the wild, appears to initiate a genetic program that allows fruitflies to remain awake without the sleepiness and cognitive impairments that typically follow sleep deprivation.
Extended periods of waking result in physiological impairments in humans, rats, and flies. Sleep homeostasis, the increase in sleep observed following sleep loss, is believed to counter the negative effects of prolonged waking by restoring vital biological processes that are degraded during sleep deprivation. Sleep homeostasis, as with other behaviors, is influenced by both genes and environment. We report here that during periods of starvation, flies remain spontaneously awake but, in contrast to sleep deprivation, do not accrue any of the negative consequences of prolonged waking. Specifically, the homeostatic response and learning impairments that are a characteristic of sleep loss are not observed following prolonged waking induced by starvation. Recently, two genes, brummer (bmm) and Lipid storage droplet 2 (Lsd2), have been shown to modulate the response to starvation. bmm mutants have excess fat and are resistant to starvation, whereas Lsd2 mutants are lean and sensitive to starvation. Thus, we hypothesized that bmm and Lsd2 may play a role in sleep regulation. Indeed, bmm mutant flies display a large homeostatic response following sleep deprivation. In contrast, Lsd2 mutant flies, which phenocopy aspects of starvation as measured by low triglyceride stores, do not exhibit a homeostatic response following sleep loss. Importantly, Lsd2 mutant flies are not learning impaired after sleep deprivation. These results provide the first genetic evidence, to our knowledge, that lipid metabolism plays an important role in regulating the homeostatic response and can protect against neuronal impairments induced by prolonged waking.
Author Summary
It is well established in humans that sleep deficits lead to adverse outcomes, including cognitive impairments and an increased risk for obesity. Given the relationship between sleep and lipid stores, we hypothesized that metabolic pathways play a role in sleep regulation and contribute to deficits induced by sleep loss. Since starvation has a large impact on metabolic pathways and is an environmental condition that is encountered by animals living in the wild, we examined its effects on sleep in the fruit fly Drosophila melanogaster. Interestingly, when flies are starved they display an immediate increase in waking. However, in contrast to sleep deprivation, waking induced by starvation does not result in increased sleepiness or impairments in short-term memory. To identify the mechanisms underlying these processes, we evaluated mutants for genes that have been shown to alter an animal's response to starvation. Interestingly, brummer mutants, which are fat, show an exaggerated response to sleep loss. In contrast, mutants for Lipid storage droplet 2 are lean and are able to stay awake without becoming sleepy or showing signs of cognitive impairment. These results indicate that while sleep loss can alter lipids, lipid enzymes may, in turn, play a role in regulating sleep and influence the response to sleep deprivation.
PMCID: PMC2930866  PMID: 20824166
11.  Partial sleep in the context of augmentation of brain function 
Inability to solve complex problems or errors in decision making is often attributed to poor brain processing, and raises the issue of brain augmentation. Investigation of neuronal activity in the cerebral cortex in the sleep-wake cycle offers insights into the mechanisms underlying the reduction in mental abilities for complex problem solving. Some cortical areas may transit into a sleep state while an organism is still awake. Such local sleep would reduce behavioral ability in the tasks for which the sleeping areas are crucial. The studies of this phenomenon have indicated that local sleep develops in high order cortical areas. This is why complex problem solving is mostly affected by local sleep, and prevention of local sleep might be a potential way of augmentation of brain function. For this approach to brain augmentation not to entail negative consequences for the organism, it is necessary to understand the functional role of sleep. Our studies have given an unexpected answer to this question. It was shown that cortical areas that process signals from extero- and proprioreceptors during wakefulness, switch to the processing of interoceptive information during sleep. It became clear that during sleep all “computational power” of the brain is directed to the restoration of the vital functions of internal organs. These results explain the logic behind the initiation of total and local sleep. Indeed, a mismatch between the current parameters of any visceral system and the genetically determined normal range would provide the feeling of tiredness, or sleep pressure. If an environmental situation allows falling asleep, the organism would transit to a normal total sleep in all cortical areas. However, if it is impossible to go to sleep immediately, partial sleep may develop in some cortical areas in the still behaviorally awake organism. This local sleep may reduce both the “intellectual power” and the restorative function of sleep for visceral organs.
PMCID: PMC4013465  PMID: 24822040
local sleep; cerebral cortex; slow wave sleep; sleep function; visceral control
12.  Circadian Phase and Its Relationship to Nighttime Sleep in Toddlers 
Journal of biological rhythms  2013;28(5):322-331.
Circadian phase and its relation to sleep are increasingly recognized as fundamental factors influencing human physiology and behavior. Dim light melatonin onset (DLMO) is a reliable marker of the timing of the circadian clock, which has been used in experimental, clinical, and descriptive studies in the past few decades. Although DLMO and its relationship to sleep have been well documented in school-aged children, adolescents, and adults, very little is known about these processes in early childhood. The purpose of this study was 1) to describe circadian phase and phase angles of entrainment in toddlers and 2) to examine associations between DLMO and actigraphic measures of children's nighttime sleep. Participants were 45 healthy toddlers aged 30 to 36 months (33.5 ± 2.2 months; 21 females). After sleeping on a parent-selected schedule for 5 days (assessed with actigraphy and diaries), children participated in an in-home DLMO assessment involving the collection of saliva samples every 30 minutes for 6 hours. Average bedtime was 2015 ± 0036 h, average sleep onset time was 2043 ± 0043 h, average midsleep time was 0143 ± 0038 h, and average wake time was 0644 ± 0042 h. Average DLMO was 1929 ± 0051 h, with a 3.5-hour range. DLMO was normally distributed; however, the distribution of the bedtime, sleep onset time, and midsleep phase angles of entrainment were skewed. On average, DLMO occurred 47.8 ± 47.6 minutes (median = 39.4 minutes) before bedtime, 74.6 ± 48.0 minutes (median = 65.4 minutes) before sleep onset time, 6.2 ± 0.7 hours (median = 6.1 hours) before midsleep time, and 11.3 ± 0.7 hours before wake time. Toddlers with later DLMOs had later bedtimes (r = 0.46), sleep onset times (r = 0.51), midsleep times (r = 0.66), and wake times (r = 0.65) (all p < 0.001). Interindividual differences in toddlers’ circadian phase are large and associated with their sleep timing. The early DLMOs of toddlers indicate a maturational delay in the circadian timing system between early childhood and adolescence. These findings are a first step in describing the fundamental properties of the circadian system in toddlers and have important implications for understanding the emergence of sleep problems and the consequences of circadian misalignment in early childhood.
PMCID: PMC3925345  PMID: 24132058
circadian phase; melatonin; DLMO; sleep; phase angle of entrainment; early childhood; toddlers; children
13.  Prevalence, Patterns, and Persistence of Sleep Problems in the First 3 Years of Life 
Pediatrics  2012;129(2):e276-e284.
Examine the prevalence, patterns, and persistence of parent-reported sleep problems during the first 3 years of life.
Three hundred fifty-nine mother/child pairs participated in a prospective birth cohort study. Sleep questionnaires were administered to mothers when children were 6, 12, 24, and 36 months old. Sleep variables included parent response to a nonspecific query about the presence/absence of a sleep problem and 8 specific sleep outcome domains: sleep onset latency, sleep maintenance, 24-hour sleep duration, daytime sleep/naps, sleep location, restlessness/vocalization, nightmares/night terrors, and snoring.
Prevalence of a parent-reported sleep problem was 10% at all assessment intervals. Night wakings and shorter sleep duration were associated with a parent-reported sleep problem during infancy and early toddlerhood (6–24 months), whereas nightmares and restless sleep emerged as associations with report of a sleep problem in later developmental periods (24–36 months). Prolonged sleep latency was associated with parent report of a sleep problem throughout the study period. In contrast, napping, sleep location, and snoring were not associated with parent-reported sleep problems. Twenty-one percent of children with sleep problems in infancy (compared with 6% of those without) had sleep problems in the third year of life.
Ten percent of children are reported to have a sleep problem at any given point during early childhood, and these problems persist in a significant minority of children throughout early development. Parent response to a single-item nonspecific sleep query may overlook relevant sleep behaviors and symptoms associated with clinical morbidity.
PMCID: PMC3357046  PMID: 22218837
sleep problems; infants; toddlers; prevalence; persistence
14.  Taking the Lag out of Jet Lag through Model-Based Schedule Design 
PLoS Computational Biology  2009;5(6):e1000418.
Travel across multiple time zones results in desynchronization of environmental time cues and the sleep–wake schedule from their normal phase relationships with the endogenous circadian system. Circadian misalignment can result in poor neurobehavioral performance, decreased sleep efficiency, and inappropriately timed physiological signals including gastrointestinal activity and hormone release. Frequent and repeated transmeridian travel is associated with long-term cognitive deficits, and rodents experimentally exposed to repeated schedule shifts have increased death rates. One approach to reduce the short-term circadian, sleep–wake, and performance problems is to use mathematical models of the circadian pacemaker to design countermeasures that rapidly shift the circadian pacemaker to align with the new schedule. In this paper, the use of mathematical models to design sleep–wake and countermeasure schedules for improved performance is demonstrated. We present an approach to designing interventions that combines an algorithm for optimal placement of countermeasures with a novel mode of schedule representation. With these methods, rapid circadian resynchrony and the resulting improvement in neurobehavioral performance can be quickly achieved even after moderate to large shifts in the sleep–wake schedule. The key schedule design inputs are endogenous circadian period length, desired sleep–wake schedule, length of intervention, background light level, and countermeasure strength. The new schedule representation facilitates schedule design, simulation studies, and experiment design and significantly decreases the amount of time to design an appropriate intervention. The method presented in this paper has direct implications for designing jet lag, shift-work, and non-24-hour schedules, including scheduling for extreme environments, such as in space, undersea, or in polar regions.
Author Summary
Traveling across several times zones can cause an individual to experience “jet lag,” which includes trouble sleeping at night and trouble remaining awake during the day. A major cause of these effects is the desynchronization between the body's internal circadian clock and local environmental cues. A well-known intervention to resynchronize an individual's clock with the environment is appropriately timed light exposure. Used as an intervention, properly timed light stimuli can reset an individual's internal circadian clock to align with local time, resulting in more efficient sleep, a decrease in fatigue, and an increase in cognitive performance. The contrary is also true: poorly timed light exposure can prolong the resynchronization process. In this paper, we present a computational method for automatically determining the proper placement of these interventional light stimuli. We used this method to simulate shifting sleep–wake schedules (as seen in jet lag situations) and design interventions. Essential to our approach is the use of mathematical models that simulate the body's internal circadian clock and its effect on human performance. Our results include quicker design of multiple schedule alternatives and predictions of substantial performance improvements relative to no intervention. Therefore, our methods allow us to use these models not only to assess schedules but also to interactively design schedules that will result in improved performance.
PMCID: PMC2691990  PMID: 19543382
15.  Mammalian Sleep Dynamics: How Diverse Features Arise from a Common Physiological Framework 
PLoS Computational Biology  2010;6(6):e1000826.
Mammalian sleep varies widely, ranging from frequent napping in rodents to consolidated blocks in primates and unihemispheric sleep in cetaceans. In humans, rats, mice and cats, sleep patterns are orchestrated by homeostatic and circadian drives to the sleep–wake switch, but it is not known whether this system is ubiquitous among mammals. Here, changes of just two parameters in a recent quantitative model of this switch are shown to reproduce typical sleep patterns for 17 species across 7 orders. Furthermore, the parameter variations are found to be consistent with the assumptions that homeostatic production and clearance scale as brain volume and surface area, respectively. Modeling an additional inhibitory connection between sleep-active neuronal populations on opposite sides of the brain generates unihemispheric sleep, providing a testable hypothetical mechanism for this poorly understood phenomenon. Neuromodulation of this connection alone is shown to account for the ability of fur seals to transition between bihemispheric sleep on land and unihemispheric sleep in water. Determining what aspects of mammalian sleep patterns can be explained within a single framework, and are thus universal, is essential to understanding the evolution and function of mammalian sleep. This is the first demonstration of a single model reproducing sleep patterns for multiple different species. These wide-ranging findings suggest that the core physiological mechanisms controlling sleep are common to many mammalian orders, with slight evolutionary modifications accounting for interspecies differences.
Author Summary
The field of sleep physiology has made huge strides in recent years, uncovering the neurological structures which are critical to sleep regulation. However, given the small number of species studied in such detail in the laboratory, it remains to be seen how universal these mechanisms are across the whole mammalian order. Mammalian sleep is extremely diverse, and the unihemispheric sleep of dolphins is nothing like the rapidly cycling sleep of rodents, or the single daily block of humans. Here, we use a mathematical model to demonstrate that the established sleep physiology can indeed account for the sleep of a wide range of mammals. Furthermore, the model gives insight into why the sleep patterns of different species are so distinct: smaller animals burn energy more rapidly, resulting in more rapid sleep–wake cycling. We also show that mammals that sleep unihemispherically may have a single additional neuronal pathway which prevents sleep-promoting neurons on opposite sides of the hypothalamus from activating simultaneously. These findings suggest that the basic physiology controlling sleep evolved before mammals, and illustrate the functional flexibility of this simple system.
PMCID: PMC2891699  PMID: 20585613
16.  Dynamical properties of the two-process model for sleep-wake cycles in infantile autism 
Cognitive Neurodynamics  2008;2(3):221-228.
The two-process model is a scheme for the timing of sleep that consists of homeostatic (Process S) and circadian (Process C) variables. The two-process model exhibits abnormal sleep patterns such as internal desynchronization or sleep fragmentation. Early infants with autism often experience sleep difficulties. Large day-by-day changes are found in the sleep onset and waking times in autistic children. Frequent night waking is a prominent property of their sleep. Further, the sleep duration of autistic children is often fragmented. These sleep patterns in infants with autism are not fully understood yet. In the present study, the sleep patterns in autistic children were reproduced by a modified two-process model using nonlinear analysis. A nap term was introduced into the original two-process model to reproduce the sleep patterns in early infants. The nap term and the time course of Process S are mentioned in the present study. Those parameters led to bifurcation of the sleep-wake cycle in the modified two-process model. In a certain range of these parameter sets, a small external noise was amplified, and an irregular sleep-wake cycle appeared. The short duration of sleep led to another irregular sleep onset or waking. Consequently, an irregular sleep-wake cycle appeared in early infantile autism.
PMCID: PMC2518747  PMID: 19003487
Autism; Two-process model; Sleep cycle
Brain research  2009;1298:37-45.
Age-related changes in brain function include those affecting learning, memory, and sleep-wakefulness. Sleep-wakefulness is an essential behavior that results from the interaction of multiple brain regions, peptides and neurotransmitters. The biological function(s) of sleep, however, remains unknown, due to a paucity of information available at the cellular level. Aged rats exhibit alterations in the circadian and homeostatic influences associated with sleep-wake regulation. We recently showed that alterations in cortical profiles occur after timed bouts of spontaneous sleep in young rats. Examination of the cellular response to sleep-wake in old rats may thus provide insight(s) into the biological function(s) of sleep. To test this hypothesis, we monitored cortical profiles in the frontal cortex of young and old Sprague-Dawley rats after timed bouts of spontaneous sleep-wake behavior. Proteins were separated by two-dimensional electrophoresis (2-DE), visualized by fluorescent staining, imaged, and analyzed as a function of behavioral state and age. Old rats showed a 6-fold increase in total protein expression, independent of the behavioral state at sacrifice. When analyzed according to age and behavioral state, there was a decrease (~46%) in the number of phospho-spots present during SWS in aged animals. SWS-associated spots present only in old animals were associated with multiple functions including vesicular transport, cell signaling, oxidation state, cytoskeletal support, and energy metabolism. These data suggest that the intracellular response to the signaling associated with spontaneous sleep is affected by age and is consistent with the idea that the ability of sleep to fulfill its’ function(s) may become diminished with age.
PMCID: PMC2778600  PMID: 19729003
two-dimensional electrophoresis (2DE); mass spectrometry; sleep-associated proteins; spontaneous sleep bouts; aging
18.  Cul3 and the BTB Adaptor Insomniac Are Key Regulators of Sleep Homeostasis and a Dopamine Arousal Pathway in Drosophila 
PLoS Genetics  2012;8(10):e1003003.
Sleep is homeostatically regulated, such that sleep drive reflects the duration of prior wakefulness. However, despite the discovery of genes important for sleep, a coherent molecular model for sleep homeostasis has yet to emerge. To better understand the function and regulation of sleep, we employed a reverse-genetics approach in Drosophila. An insertion in the BTB domain protein CG32810/insomniac (inc) exhibited one of the strongest baseline sleep phenotypes thus far observed, a ∼10 h sleep reduction. Importantly, this is coupled to a reduced homeostatic response to sleep deprivation, consistent with a disrupted sleep homeostat. Knockdown of the INC-interacting protein, the E3 ubiquitin ligase Cul3, results in reduced sleep duration, consolidation, and homeostasis, suggesting an important role for protein turnover in mediating INC effects. Interestingly, inc and Cul3 expression in post-mitotic neurons during development contributes to their adult sleep functions. Similar to flies with increased dopaminergic signaling, loss of inc and Cul3 result in hyper-arousability to a mechanical stimulus in adult flies. Furthermore, the inc sleep duration phenotype can be rescued by pharmacological inhibition of tyrosine hydroxylase, the rate-limiting enzyme for dopamine biosynthesis. Taken together, these results establish inc and Cul3 as important new players in setting the sleep homeostat and a dopaminergic arousal pathway in Drosophila.
Author Summary
Sleep is an essential behavior that encompasses roughly a third of our lives; however, the underlying function remains a mystery. The fruit fly has emerged as an important model system for understanding sleep behavior, exhibiting several behavioral and genetic similarities with mammalian sleep, including consolidated immobility, an elevation of arousal threshold to a range of stimuli, homeostatic drive, and manipulation by proven stimulants and sedatives. We tested disruptions of candidate sleep genes and identified a gene called insomniac that exhibits one of the strongest and most robust sleep phenotypes to date, including a suppressed homeostatic response to sleep deprivation. We find similar phenotypes for a gene previously shown to interact with inc and a known regulator of protein degradation, Cul3, linking sleep homeostasis to protein turnover. Importantly, we find that insomniac functions in a known arousal system in the brain, as defined by the neurotransmitter dopamine. This work provides an important insight into the genetic basis of sleep homeostasis with the discovery of a new molecular component of a dopaminergic arousal pathway. Given the conservation of fly and mammalian systems, these studies may lead to new insights into the molecules that mediate sleep homeostasis and arousal in humans.
PMCID: PMC3464197  PMID: 23055946
19.  Aging in Mice Reduces the Ability to Sustain Sleep/Wake States 
PLoS ONE  2013;8(12):e81880.
One of the most significant problems facing older individuals is difficulty staying asleep at night and awake during the day. Understanding the mechanisms by which the regulation of sleep/wake goes awry with age is a critical step in identifying novel therapeutic strategies to improve quality of life for the elderly. We measured wake, non-rapid eye movement (NREM) and rapid-eye movement (REM) sleep in young (2–4 months-old) and aged (22–24 months-old) C57BL6/NIA mice. We used both conventional measures (i.e., bout number and bout duration) and an innovative spike-and-slab statistical approach to characterize age-related fragmentation of sleep/wake. The short (spike) and long (slab) components of the spike-and-slab mixture model capture the distribution of bouts for each behavioral state in mice. Using this novel analytical approach, we found that aged animals are less able to sustain long episodes of wakefulness or NREM sleep. Additionally, spectral analysis of EEG recordings revealed that aging slows theta peak frequency, a correlate of arousal. These combined analyses provide a window into the mechanisms underlying the destabilization of long periods of sleep and wake and reduced vigilance that develop with aging.
PMCID: PMC3864844  PMID: 24358130
20.  A role for cryptochromes in sleep regulation 
BMC Neuroscience  2002;3:20.
The cryptochrome 1 and 2 genes (cry1 and cry2) are necessary for the generation of circadian rhythms, as mice lacking both of these genes (cry1,2-/-) lack circadian rhythms. We studied sleep in cry1,2-/- mice under baseline conditions as well as under conditions of constant darkness and enforced wakefulness to determine whether cryptochromes influence sleep regulatory processes.
Under all three conditions, cry1,2-/- mice exhibit the hallmarks of high non-REM sleep (NREMS) drive (i.e., increases in NREMS time, NREMS consolidation, and EEG delta power during NREMS). This unexpected phenotype was associated with elevated brain mRNA levels of period 1 and 2 (per1,2), and albumin d-binding protein (dbp), which are known to be transcriptionally inhibited by CRY1,2. To further examine the relationship between circadian genes and sleep homeostasis, we examined wild type mice and rats following sleep deprivation and found increased levels of per1,2 mRNA and decreased levels of dbp mRNA specifically in the cerebral cortex; these changes subsided with recovery sleep. The expression of per3, cry1,2, clock, npas2, bmal1, and casein-kinase-1ε did not change with sleep deprivation.
These results indicate that mice lacking cryptochromes are not simply a genetic model of circadian arrhythmicity in rodents and functionally implicate cryptochromes in the homeostatic regulation of sleep.
PMCID: PMC149230  PMID: 12495442
circadian genes; oscillatory network of transcriptional factors; EEG slow-wave activity
21.  Mathematical Models for Sleep-Wake Dynamics: Comparison of the Two-Process Model and a Mutual Inhibition Neuronal Model 
PLoS ONE  2014;9(8):e103877.
Sleep is essential for the maintenance of the brain and the body, yet many features of sleep are poorly understood and mathematical models are an important tool for probing proposed biological mechanisms. The most well-known mathematical model of sleep regulation, the two-process model, models the sleep-wake cycle by two oscillators: a circadian oscillator and a homeostatic oscillator. An alternative, more recent, model considers the mutual inhibition of sleep promoting neurons and the ascending arousal system regulated by homeostatic and circadian processes. Here we show there are fundamental similarities between these two models. The implications are illustrated with two important sleep-wake phenomena. Firstly, we show that in the two-process model, transitions between different numbers of daily sleep episodes can be classified as grazing bifurcations. This provides the theoretical underpinning for numerical results showing that the sleep patterns of many mammals can be explained by the mutual inhibition model. Secondly, we show that when sleep deprivation disrupts the sleep-wake cycle, ostensibly different measures of sleepiness in the two models are closely related. The demonstration of the mathematical similarities of the two models is valuable because not only does it allow some features of the two-process model to be interpreted physiologically but it also means that knowledge gained from study of the two-process model can be used to inform understanding of the behaviour of the mutual inhibition model. This is important because the mutual inhibition model and its extensions are increasingly being used as a tool to understand a diverse range of sleep-wake phenomena such as the design of optimal shift-patterns, yet the values it uses for parameters associated with the circadian and homeostatic processes are very different from those that have been experimentally measured in the context of the two-process model.
PMCID: PMC4118955  PMID: 25084361
22.  Re-Patterning Sleep Architecture in Drosophila through Gustatory Perception and Nutritional Quality 
PLoS Genetics  2012;8(5):e1002668.
Organisms perceive changes in their dietary environment and enact a suite of behavioral and metabolic adaptations that can impact motivational behavior, disease resistance, and longevity. However, the precise nature and mechanism of these dietary responses is not known. We have uncovered a novel link between dietary factors and sleep behavior in Drosophila melanogaster. Dietary sugar rapidly altered sleep behavior by modulating the number of sleep episodes during both the light and dark phase of the circadian period, independent of an intact circadian rhythm and without affecting total sleep, latency to sleep, or waking activity. The effect of sugar on sleep episode number was consistent with a change in arousal threshold for waking. Dietary protein had no significant effect on sleep or wakefulness. Gustatory perception of sugar was necessary and sufficient to increase the number of sleep episodes, and this effect was blocked by activation of bitter-sensing neurons. Further addition of sugar to the diet blocked the effects of sweet gustatory perception through a gustatory-independent mechanism. However, gustatory perception was not required for diet-induced fat accumulation, indicating that sleep and energy storage are mechanistically separable. We propose a two-component model where gustatory and metabolic cues interact to regulate sleep architecture in response to the quantity of sugar available from dietary sources. Reduced arousal threshold in response to low dietary availability may have evolved to provide increased responsiveness to cues associated with alternative nutrient-dense feeding sites. These results provide evidence that gustatory perception can alter arousal thresholds for sleep behavior in response to dietary cues and provide a mechanism by which organisms tune their behavior and physiology to environmental cues.
Author Summary
Sleep is a fundamental biological process regulated by evolutionarily conserved molecular mechanisms. In this work, we demonstrate a novel link between gustatory perception of sugar and sleep patterning in D. melanogaster. The presence of low dietary sugar reduced the arousal threshold for waking, leading to repartitioning of sleep into a larger number of episodes throughout the day. Gustatory perception was both required and sufficient for this effect. Further addition of sugar to the dietary environment suppressed the effects of gustatory perception through a gustatory-independent mechanism. Although the quantity of dietary sugar also regulated fat accumulation, gustatory perception was not required, indicating that diet-induced changes in obesity and sleep behavior may be mechanistically separable. These findings illustrate a mechanism for the regulation of behavioral state by the availability of dietary nutrients through the interplay between gustatory and non-gustatory factors.
PMCID: PMC3342939  PMID: 22570630
23.  Revisiting spontaneous internal desynchrony using a quantitative model of sleep physiology 
Journal of biological rhythms  2011;26(5):441-453.
Early attempts to ascertain free-running human circadian period generated 3 surprising results: (1) Periods of 25 hours (considerably longer than the now established 24.2 h intrinsic period) with sleep delayed to later circadian phases than during entrainment; (2) Spontaneous internal desynchrony of circadian rhythms and sleep/wake cycles; the former with an approximately 24.9 h period, the latter with a longer (28-68 h) or shorter (12-20 h) period; (3) Bicircadian (48-50 h) sleep/wake cycles. All three results are reproduced by Kronauer et al.'s (1982) coupled oscillator model, but the physiological basis for that phenomenological model is unclear. We use a physiologically-based model of hypothalamic and brainstem nuclei to investigate alternative physiological mechanisms that could underlie internal desynchrony. We demonstrate that experimental observations can be reproduced by changes in two pathways: promotion of orexinergic (Orx) wake signals, and attenuation of the circadian signal reaching hypothalamic nuclei. We reason that delayed sleep is indicative of an additional wake-promoting drive, which may be of behavioral origin, associated with removal of daily schedules and instructions given to participants. We model this by increasing Orx tone during wake, which reproduces the observed period lengthening and delayed sleep. Weakening circadian input to the ventrolateral preoptic nucleus (possibly mediated by the dorsomedial hypothalamus) causes desynchrony, with sleep/wake cycle period determined by degree of Orx up-regulation. During desynchrony, sleep/wake cycles are driven by sleep homeostasis, yet sleep bout length maintains some circadian phase dependence. The model predicts sleep episodes are shortest when started near the temperature minimum, consistent with experimental findings. The model also correctly predicts that it is possible to transition to bicircadian rhythms from either a synchronized or desynchronized state. Our findings suggest that feedback from behavioral choices to physiology could play an important role in spontaneous internal desynchrony.
PMCID: PMC3557950  PMID: 21921298
sleep; mathematical model; spontaneous desynchrony; internal desynchrony; self-selected schedule; bicircadian; behavioral input
24.  Circadian Misalignment, Reward-Related Brain Function, and Adolescent Alcohol Involvement 
Alcoholism, clinical and experimental research  2013;37(4):10.1111/acer.12003.
Developmental changes in sleep and circadian rhythms that occur during adolescence may contribute to reward-related brain dysfunction, and consequently increase the risk of alcohol use disorders (AUDs).
This review (a) describes marked changes in circadian rhythms, reward-related behavior and brain function, and alcohol involvement that occur during adolescence, (b) offers evidence that these parallel developmental changes are associated, and (c) posits a conceptual model by which misalignment between sleep-wake timing and endogenous circadian timing may increase the risk of adolescent AUDs by altering reward-related brain function.
The timing of sleep shifts later throughout adolescence, in part due to developmental changes in endogenous circadian rhythms, which tend to become more delayed. This tendency for delayed sleep and circadian rhythms is at odds with early school start times during secondary education, leading to misalignment between many adolescents’ sleep-wake schedules and their internal circadian timing. Circadian misalignment is associated with increased alcohol use and other risk-taking behaviors, as well as sleep loss and sleep disturbance. Growing evidence indicates that circadian rhythms modulate the reward system, suggesting that circadian misalignment may impact adolescent alcohol involvement by altering reward-related brain function. Neurocognitive function is also subject to sleep and circadian influence, and thus circadian misalignment may also impair inhibitory control and other cognitive processes relevant to alcohol use. Specifically, circadian misalignment may further exacerbate the cortical-subcortical imbalance within the reward circuit, an imbalance thought to explain increased risk-taking and sensation-seeking during adolescence. Adolescent alcohol use is highly contexualized, however, and thus studies testing this model will also need to consider factors that may influence both circadian misalignment and alcohol use.
This review highlights growing evidence supporting a path by which circadian misalignment may disrupt reward mechanisms, which may in turn accelerate the transition from alcohol use to AUDs in vulnerable adolescents.
PMCID: PMC3843484  PMID: 23360461
circadian rhythms; sleep; reward function; adolescence; alcohol use disorders
25.  The periodicity of sleep duration – an infradian rhythm in spontaneous living 
The sleep–wake cycle is a process not only dictated by homeostatic and circadian factors but also by social and environmental influences. Thus, the total sleep time partly reflects sleep need, which is integral to the dynamics of sleep loss recovery. This study explored the nature of the observed oscillations in total sleep time in healthy adults under spontaneous living conditions. Actigraph-measured sleep data for 13 healthy young male adults were collected over 14 consecutive days and analyzed for habitual sleep duration. The total sleep time periodicity was modeled using the cosinor method for each individual across the 14 days. The findings confirm the existence of periodicity in habitual sleep duration as there were clear periodic patterns in the majority of the participants. Although exclusive to each individual, the observed oscillations may be a resultant response of homeostatic sleep need, circadian timing, and/or social and environmental influences. These findings instigate further indepth studies into the periodicity of sleep duration in healthy individuals to provide a better understanding of sleep need in short versus long sleepers, in predicting work performance, and reducing sleepiness-related accidents following shift work, and how this periodicity may impact sleep treatment outcome in clinical populations.
PMCID: PMC3630914  PMID: 23616728
sleep regulation; homeostasis; habitual sleep; spontaneous living; healthy males

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