A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice.

Over 20 years agO, BrOughtOn and cOlleagues hypOthesized that narcOlepsy is Best cOnsidered a disease Of state BOundary cOntrOl. 1 they argued that sleepiness, cataplexy, hallucinations, and many other symptoms could be viewed as a breakdown of "whatever neurochemical 'glues' or integrative neurophysiological mechanisms exist for sleep and wake state continuity." 1 This hypothesis is compelling, but it has been difficult to examine using conventional sleep scoring methods.More recently, our understanding of narcolepsy has been greatly advanced by the discovery that narcolepsy with cataplexy is caused by a loss of functional signaling by the orexin (hypocretin) neuropeptides. 2-5 the neurons producing orexins are active during wakefulness, 6-8 and direct activation of these neurons can awaken mice from sleep. 9 in addition, orexins probably stabilize wake and sleep; narcoleptic people, dogs, and mice lacking orexins have great difficulty remaining awake for long periods and also experience fragmented sleep. [10][11][12][13] in earlier work, we found that the fragmented wakefulness of orexin deficiency is not a consequence of abnormal sleep homeostasis, poor circadian control, or defective fundamental arousal systems. 10 however, conventional sleep scoring in 10-to 30-second epochs reveals little about the process of transitioning between states as cortical activity and behavior can change quite rapidly. Furthermore, conventional scoring simply identifies discrete states, so it can overlook important variations within states, such as the distinctions between light and deep nreM sleep or between drowsy wake and high levels of arousal. Therefore, to determine how orexin deficiency causes behavioral state instability we developed a state space analysis technique to examine the dynamics of sleep/wake behavior in orexin knockout (OXKO) mice, a model of narcolepsy.The previous application of state space techniques to sleep recordings used local field potential data, but the variability in these signals prevented comparisons between animals. [14][15][16] We adapted these techniques for analysis of EEG recordings in mice and developed metrics for inter-animal comparisons. State space techniques have high temporal resolution and analyze behavior as a continuum, rather than in discrete states, thus facilitating higher dimensional examination of state transitions. this approach enabled us to determine whether the state instability in this mouse model of narcolepsy reflects abnormal sleep/wake states, faster movements between states, or abnormal transition processes. METHODS AnimalsFounder OXKO mice were on a C57BL/6J-129/SvEV background (t. sakurai, Kanazawa university), and their offspring were backcrossed with C57BL/6J mice for 8 generations. We recorded sleep/wake behavior in 7 male OXKO mice and 6 wild type (Wt) littermates, all 5-6 months old and weighing 30-35 g. all experiments were approved by the institutional animal Study Objectives: Narcolepsy with cataplexy is caused by a loss of orexin (hypocretin) signaling, bu...

Diniz Behn CG, Booth V. Simulating microinjection experiments in a novel model of the rat sleep-wake regulatory network. J Neurophysiol 103: 1937-1953, 2010. First published January 27, 2010 doi:10.1152/jn.00795.2009. This study presents a novel mathematical modeling framework that is uniquely suited to investigating the structure and dynamics of the sleep-wake regulatory network in the brain stem and hypothalamus. It is based on a population firing rate model formalism that is modified to explicitly include concentration levels of neurotransmitters released to postsynaptic populations. Using this framework, interactions among primary brain stem and hypothalamic neuronal nuclei involved in rat sleep-wake regulation are modeled. The model network captures realistic rat polyphasic sleep-wake behavior consisting of wake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep states. Network dynamics include a cyclic pattern of NREM sleep, REM sleep, and wake states that is disrupted by simulated variability of neurotransmitter release and external noise to the network. Explicit modeling of neurotransmitter concentrations allows for simulations of microinjections of neurotransmitter agonists and antagonists into a key wake-promoting population, the locus coeruleus (LC). Effects of these simulated microinjections on sleep-wake states are tracked and compared with experimental observations. Agonist/antagonist pairs, which are presumed to have opposing effects on LC activity, do not generally induce opposing effects on sleep-wake patterning because of multiple mechanisms for LC activation in the network. Also, different agents, which are presumed to have parallel effects on LC activity, do not induce parallel effects on sleep-wake patterning because of differences in the state dependence or independence of agonist and antagonist action. These simulation results highlight the utility of formal mathematical modeling for constraining conceptual models of the sleepwake regulatory network.

Recent work in experimental neurophysiology has identified distinct neuronal populations in the rodent brain stem and hypothalamus that selectively promote wake and sleep. Mutual inhibition between these cell groups has suggested the conceptual model of a sleep-wake switch that controls transitions between wake and sleep while minimizing time spent in intermediate states. By combining wake- and sleep-active populations with populations governing transitions between different stages of sleep, a "sleep-wake network" of neuronal populations may be defined. To better understand the dynamics inherent in this network, we created a model sleep-wake network composed of coupled relaxation oscillation equations. Mathematical analysis of the deterministic model provides insight into the dynamics underlying state transitions and predicts mechanisms for each transition type. With the addition of noise, the simulated sleep-wake behavior generated by the model reproduces many qualitative and quantitative features of mouse sleep-wake behavior. In particular, the existence of simulated brief awakenings is a unique feature of the model. In addition to capturing the experimentally observed qualitative difference between brief and sustained wake bouts, the model suggests distinct network mechanisms for the two types of wakefulness. Because circadian and other factors alter the fine architecture of sleep-wake behavior, this model provides a novel framework to explore dynamical principles that may underlie normal and pathologic sleep-wake physiology.

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During hibernation, animals cycle between torpor and arousal. These cycles involve dramatic but poorly understood mechanisms of dynamic physiological regulation at the level of gene expression. Each cycle, Brown Adipose Tissue (BAT) drives periodic arousal from torpor by generating essential heat. We applied digital transcriptome analysis to precisely timed samples to identify molecular pathways that underlie the intense activity cycles of hibernator BAT. A cohort of transcripts increased during torpor, paradoxical because transcription effectively ceases at these low temperatures. We show that this increase occurs not by elevated transcription but rather by enhanced stabilization associated with maintenance and/or extension of long poly(A) tails. Mathematical modeling further supports a temperature-sensitive mechanism to protect a subset of transcripts from ongoing bulk degradation instead of increased transcription. This subset was enriched in a C-rich motif and genes required for BAT activation, suggesting a model and mechanism to prioritize translation of key proteins for thermogenesis.DOI: http://dx.doi.org/10.7554/eLife.04517.001

Diniz Behn CG, Kopell N, Brown EN, Mochizuki T, Scammell TE. Delayed orexin signaling consolidates wakefulness and sleep: physiology and modeling. J Neurophysiol 99: 3090 -3103, 2008. First published April 16, 2008 doi:10.1152/jn.01243.2007. Orexin-producing neurons are clearly essential for the regulation of wakefulness and sleep because loss of these cells produces narcolepsy. However, little is understood about how these neurons dynamically interact with other wake-and sleep-regulatory nuclei to control behavioral states. Using survival analysis of wake bouts in wild-type and orexin knockout mice, we found that orexins are necessary for the maintenance of long bouts of wakefulness, but orexin deficiency has little impact on wake bouts Ͻ1 min. Since orexin neurons often begin firing several seconds before the onset of waking, this suggests a surprisingly delayed onset (Ͼ1 min) of functional effects. This delay has important implications for understanding the control of wakefulness and sleep because increasing evidence suggests that different mechanisms are involved in the production of brief and sustained wake bouts. We incorporated these findings into a mathematical model of the mouse sleep/wake network. Orexins excite monoaminergic neurons and we hypothesize that orexins increase the monoaminergic inhibition of sleep-promoting neurons in the ventrolateral preoptic nucleus. We modeled orexin effects as a time-dependent increase in the strength of inhibition from wake-to sleep-promoting populations and the resulting simulated behavior accurately reflects the fragmented sleep/wake behavior of narcolepsy and leads to several predictions. By integrating neurophysiology of the sleep/wake network with emergent properties of behavioral data, this model provides a novel framework for investigating network dynamics and mechanisms associated with normal and pathologic sleep/wake behavior. I N T R O D U C T I O NOrexin-producing neurons play an essential role in the regulation of wakefulness and sleep. Loss of the orexin neurons or the orexin neuropeptides (orexin-A and -B, also known as hypocretin-1 and -2) causes narcolepsy, a common sleep disorder characterized by excessive daytime sleepiness, rapid eye movement (REM) sleep soon after sleep onset, disturbed nocturnal sleep, and cataplexy (Dauvilliers et al. 2007;Scammell 2003). Mice, rats, and dogs with disrupted orexin signaling all have sleepiness and cataplexy strikingly similar to that seen in people with narcolepsy (Beuckmann et al. 2004; Chemelli et al. 1999;Hungs and Mignot 2001).These features of narcolepsy highlight the necessity of orexins, but little is understood about how the orexin neurons dynamically interact with other wake-and sleep-regulatory nuclei to modulate sleep/wake behavior. The orexin neurons are strictly wake-active (Lee et al. 2005;Mileykovskiy et al. 2005) and send excitatory projections to many state-regulatory nuclei . Although orexin knockout (OXKO) mice have normal hourly amounts of wakefulness and sleep, their wake bouts are much s...

The dynamics of sleep and wake are strongly linked to the circadian clock. Many models have accurately predicted behaviour resulting from dynamic interactions between these two systems without specifying physiological substrates for these interactions. By contrast, recent experimental work has identified much of the relevant physiology for circadian and sleep-wake regulation, but interaction dynamics are difficult to study experimentally. To bridge these approaches, we developed a neuronal population model for the dynamic, bidirectional, neurotransmitter-mediated interactions of the sleepwake and circadian regulatory systems in nocturnal rats. This model proposes that the central circadian pacemaker, located within the suprachiasmatic nucleus (SCN) of the hypothalamus, promotes sleep through single neurotransmitter-mediated signalling to sleep-wake regulatory populations. Feedback projections from these populations to the SCN alter SCN firing patterns and fine-tune this modulation. Although this model reproduced circadian variation in sleep-wake dynamics in nocturnal rats, it failed to describe the sleep-wake dynamics observed in SCN-lesioned rats. We thus propose two alternative, physiologically based models in which neurotransmitter-and neuropeptidemediated signalling from the SCN to sleep-wake populations introduces mechanisms to account for the behaviour of both the intact and SCN-lesioned rat. These models generate testable predictions and offer a new framework for modelling sleep-wake and circadian interactions.