Circadian Input Research Articles

Metabolic and circadian inputs encode anticipatory biogenesis of hepatic fed microRNAs.

Starvation and refeeding are mostly unanticipated in the wild in terms of duration, frequency, and nutritional value of the refed state. Notwithstanding this, organisms mount efficient and reproducible responses to restore metabolic homeostasis. Hence, it is intuitive to invoke expectant molecular mechanisms that build anticipatory responses to enable physiological toggling during fed-fast cycles. In this regard, we report anticipatory biogenesis of oscillatory hepatic microRNAs that peak during a fed state and inhibit starvation-responsive genes. Our results clearly demonstrate that the levels of primary and precursor microRNA transcripts increase during a fasting state, in anticipation of a fed response. We delineate the importance of both metabolic and circadian cues in orchestrating hepatic fed microRNA homeostasis in a physiological setting. Besides illustrating metabo-endocrine control, our findings provide a mechanistic basis for the overarching influence of starvation on anticipatory biogenesis. Importantly, by using pharmacological agents that are widely used in clinics, we point out the high potential of interventions to restore homeostasis of hepatic microRNAs, whose deregulated expression is otherwise well established to cause metabolic diseases.

LocoBox: Modular Hardware and Open-Source Software for Circadian Entrainment and Behavioral Monitoring in Home Cages

Day–night locomotor activities are the most readily observed outputs of the circadian (~24-h period) clock in many animals. Temporal patterns of the light–dark schedule serve as input to the clock. While circadian activity patterns under various lighting conditions have been observed and documented, the full extent of circadian locomotor activities by genotype and entrainment remains uncharacterized. To facilitate large-scale, parallel cataloging of circadian input–output patterns, we created the LocoBox, an easy-to-construct and easy-to-operate system that can control environmental light with flexible entrainment scenarios combined with the T-cycle and measure locomotor activities in individual home cages. The LocoBox is made using economical, common components, and normal breeding cages can be used for long-term recording. We provide details of the components and blueprints, along with software programs for Arduino and a Python-based graphical user interface (GUI), so that the system can be easily replicated in other laboratories.

A brainstem to circadian system circuit links Tau pathology to sundowning-related disturbances in an Alzheimer’s disease mouse model

Alzheimer’s disease (AD) patients exhibit progressive disruption of entrained circadian rhythms and an aberrant circadian input pathway may underlie such dysfunction. Here we examine AD-related pathology and circadian dysfunction in the APPSwe-Tau (TAPP) model of AD. We show these mice exhibit phase delayed body temperature and locomotor activity with increases around the active-to-rest phase transition. Similar AD-related disruptions are associated with sundowning, characterized by late afternoon and early evening agitation and aggression, and we show TAPP mice exhibit increased aggression around this transition. We show such circadian dysfunction and aggression coincide with hyperphosphorylated Tau (pTau) development in lateral parabrachial (LPB) neurons, with these disturbances appearing earlier in females. Finally, we show LPB neurons, including those expressing dynorphin (LPBdyn), project to circadian structures and are affected by pTau, and LPBdyn ablations partially recapitulate the hyperthermia of TAPP mice. Altogether we link pTau in a brainstem circadian input pathway to AD-related disturbances relevant to sundowning.

Modeling pulsativity in the hypothalamic–pituitary–adrenal hormonal axis

A new mathematical model for biological rhythms in the hypothalamic–pituitary–adrenal (HPA) axis is proposed. This model takes the form of a system of impulsive time-delay differential equations which include pulsatile release of adrenocorticotropin (ACTH) by the pituitary gland and a time delay for the release of glucocorticoid hormones by the adrenal gland. Numerical simulations demonstrate that the model’s response to periodic and circadian inputs from the hypothalamus are consistent with those generated by recent models which do not include a pulsatile pituitary. In contrast the oscillatory phenomena generated by the impulsive delay equation mode occur even if the time delay is zero. The observation that the time delay merely introduces a small phase shift suggesting that the effects of the adrenal gland are “downstream” to the origin of pulsativity. In addition, the model accounts for the occurrence of ultradian oscillations in an isolated pituitary gland. These observations suggest that principles of pulse modulated control, familiar to control engineers, may have an increasing role to play in understanding the HPA axis.

Arabidopsis thaliana PRR7 Provides Circadian Input to the CCA1 Promoter in Shoots but not Roots.

The core of the plant circadian clock involves multiple interlocking gene expression loops and post-translational controls along with inputs from light and metabolism. The complexity of the interactions is such that few specific functions can be ascribed to single components. In previous work, we reported differences in the operation of the clocks in Arabidopsis shoots and roots, including the effects of mutations of key clock components. Here, we have used luciferase imaging to study prr7 mutants expressing CCA1::LUC and GI::LUC markers. In mature shoots expressing CCA1::LUC, loss of PRR7 radically altered behaviour in light:dark cycles and caused loss of rhythmicity in constant light but had little effect on roots. In contrast, in mature plants expressing GI::LUC, loss of PRR7 had little effect in light:dark cycles but in constant light increased the circadian period in shoots and reduced it in roots. We conclude that most or all of the circadian input to the CCA1 promoter in shoots is mediated by PRR7 and that loss of PRR7 has organ-specific effects. The results emphasise the differences in operation of the shoot and root clocks, and the importance of studying clock mutants in both light:dark cycles and constant light.

Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia

Electrical activity in the heart exhibits 24-hour rhythmicity, and potentially fatal arrhythmias are more likely to occur at specific times of day. Here, we demonstrate that circadian clocks within the brain and heart set daily rhythms in sinoatrial (SA) and atrioventricular (AV) node activity, and impose a time-of–day dependent susceptibility to ventricular arrhythmia. Critically, the balance of circadian inputs from the autonomic nervous system and cardiomyocyte clock to the SA and AV nodes differ, and this renders the cardiac conduction system sensitive to decoupling during abrupt shifts in behavioural routine and sleep-wake timing. Our findings reveal a functional segregation of circadian control across the heart’s conduction system and inherent susceptibility to arrhythmia.

Light/Clock Influences Membrane Potential Dynamics to Regulate Sleep States.

The circadian rhythm is a fundamental process that regulates the sleep–wake cycle. This rhythm is regulated by core clock genes that oscillate to create a physiological rhythm of circadian neuronal activity. However, we do not know much about the mechanism by which circadian inputs influence neurons involved in sleep–wake architecture. One possible mechanism involves the photoreceptor cryptochrome (CRY). In Drosophila, CRY is receptive to blue light and resets the circadian rhythm. CRY also influences membrane potential dynamics that regulate neural activity of circadian clock neurons in Drosophila, including the temporal structure in sequences of spikes, by interacting with subunits of the voltage-dependent potassium channel. Moreover, several core clock molecules interact with voltage-dependent/independent channels, channel-binding protein, and subunits of the electrogenic ion pump. These components cooperatively regulate mechanisms that translate circadian photoreception and the timing of clock genes into changes in membrane excitability, such as neural firing activity and polarization sensitivity. In clock neurons expressing CRY, these mechanisms also influence synaptic plasticity. In this review, we propose that membrane potential dynamics created by circadian photoreception and core clock molecules are critical for generating the set point of synaptic plasticity that depend on neural coding. In this way, membrane potential dynamics drive formation of baseline sleep architecture, light-driven arousal, and memory processing. We also discuss the machinery that coordinates membrane excitability in circadian networks found in Drosophila, and we compare this machinery to that found in mammalian systems. Based on this body of work, we propose future studies that can better delineate how neural codes impact molecular/cellular signaling and contribute to sleep, memory processing, and neurological disorders.

Circadian regulation of muscle growth independent of locomotor activity

Muscle tissue shows diurnal variations in function, physiology, and metabolism. Whether such variations are dependent on the circadian clock per se or are secondary to circadian differences in physical activity and feeding pattern is unclear. By measuring muscle growth over 12-h periods in live prefeeding larval zebrafish, we show that muscle grows more during day than night. Expression of dominant negative CLOCK (ΔCLK), which inhibits molecular clock function, ablates circadian differences and reduces muscle growth. Inhibition of muscle contraction reduces growth in both day and night, but does not ablate the day/night difference. The circadian clock and physical activity are both required to promote higher muscle protein synthesis during the day compared to night, whereas markers of protein degradation, murf messenger RNAs, are higher at night. Proteasomal inhibitors increase muscle growth at night, irrespective of physical activity, but have no effect during the day. Although physical activity enhances TORC1 activity, and the TORC1 inhibitor rapamycin inhibits clock-driven daytime growth, no effect on muscle growth at night was detected. Importantly, day/night differences in 1) muscle growth, 2) protein synthesis, and 3) murf expression all persist in entrained larvae under free-running constant conditions, indicating circadian drive. Removal of circadian input by exposure to either permanent darkness or light leads to suboptimal muscle growth. We conclude that diurnal variations in muscle growth and metabolism are a circadian property that is independent of, but augmented by, physical activity, at least during development.

Mathematical modeling of depressive disorders: Circadian driving, bistability and dynamical transitions

The hypothalamus–pituitary–adrenal (HPA) axis is a key neuroendocrine system implicated in stress response, major depression disorder, and post-traumatic stress disorder. We present a new, compact dynamical systems model for the response of the HPA axis to external stimuli, representing stressors or therapeutic intervention, in the presence of a circadian input. Our work builds upon previous HPA axis models where hormonal dynamics are separated into slow and fast components. Several simplifications allow us to derive an effective model of two equations, similar to a multiplicative-input FitzHugh-Nagumo system, where two stable states, a healthy and a diseased one, arise. We analyze the effective model in the context of state transitions driven by external shocks to the hypothalamus, but also modulated by circadian rhythms. Our analyses provide mechanistic insight into the effects of the circadian cycle on input driven transitions of the HPA axis and suggest a circadian influence on exposure or cognitive behavioral therapy in depression, or post-traumatic stress disorder treatment.

Expression of antimicrobial peptide genes oscillates along day/night rhythm protecting mice skin from bacteria.

Antimicrobial peptides (AMPs) are important components of the innate immune system and are involved in skin protection against environmental insults and in wound healing. Herein, we assessed the gene expression of chemerin (Rarres2), cathelicidin CRAMP (Camp), and three β-defensins (Defb1, Defb3, and Defb14) in mouse skin during light/dark cycle (LD 12:12) and constant darkness (DD). Next, we examined the survival of bacteria applied on the skin at specific times during the day. We found that the expression of Rarres2, Camp, and Defb1 was the highest at 4h after the beginning of darkness, during high activity of mice. These rhythms, however, were not maintained under DD in the skin but were present in the liver. This indicated that in the case of skin, a circadian input was masked by daily changes of light in the environment. In contrast, Defb3 and Defb14 showed the highest mRNA levels when the mice slept, and these rhythmic mRNA oscillations were maintained under DD. This shows that Rarres2, Camp, and Defb1 levels in the skin are correlated with high locomotor activity in mice and they are controlled by daily changes of light and dark. Alternatively, oscillations in the mRNA levels of Defb3 and Defb14 seem to protect skin and heal wounds during sleep. These rhythms are maintained under DD, indicating that they are regulated by a circadian clock. Our study suggests that daily AMP expression affects the survival of bacteria on the surface of skin, which depends on the phase of AMP cycling.

Anatomical and ultrastructural analysis of the posterior optic tubercle in the locust Schistocerca gregaria

Locusts, like other insects, partly rely on a sun compass mechanism for spatial orientation during seasonal migrations. To serve as a useful guiding cue throughout the day, however, the sun's apparent movement has to be accounted for. In locusts, a neural pathway from the accessory medulla, the circadian pacemaker, via the posterior optic tubercle, to the protocerebral bridge, part of the internal sky compass, has been proposed to mediate the required time compensation. Toward a better understanding of neural connectivities within the posterior optic tubercle, we investigated this neuropil using light and electron microscopy. Based on vesicle content, four types of synaptic profile were distinguished within the posterior optic tubercle. Immunogold labeling showed that pigment-dispersing hormone immunoreactive neurons from the accessory medulla, containing large dense-core vesicles, have presynaptic terminals in the posterior optic tubercle. Ultrastructural examination of two Neurobiotin-injected tangential neurons of the protocerebral bridge revealed that these neurons are postsynaptic in the posterior optic tubercle. Our data, therefore, support a role of the posterior optic tubercles in mediating circadian input to the insect sky compass.

The Effect of Long Distance Running on the Pattern of Production of Salivary Cortisol on Rest Days

INTRODUCTIONCortisol is a glucocorticoid synthesized from cholesterol by the zona fasciculate of the adrenal cortex and is controlled by way of a negative feedback pathway within the hypothalamic‐pituitary‐adrenal (HPA) system. HPA axis receives strong circadian input and plays an essential role in the regulation of stress responses. Cortisol spikes in the morning upon waking up, and then decreases throughout the day, but exercise modifies this pattern of production. Physical exercise activates HPA axis to maintain proper blood glucose levels during these times of energy expenditure. According to previous studies endurance‐trained athletes possess a significantly higher level of circulating cortisol than power trained athletes immediately after exercise. Cortisol is known to have debilitating effects on factors related to bone mineral density (BMD). Consequently, the chronic increase in cortisol in long‐distance runners can lead to adverse effects such as decreased BMD and can contribute to stress fractures. The purpose of this study is to evaluate cortisol levels during days of rest to determine the possible change in the pattern of cortisol production stimulated by repetitive prolonged previous exposure to the physical activity rather than actual stimulus.METHODSMissouri Southern State University (MSSU) Institutional Review Board approval was gained before data collection. A participant group was gathered including 12 males from the men’s cross‐country team at MSSU in the fall of 2019. Participants completed a demographic questionnaire stating the number of hours per week actively participating in sport specified workouts, average hours of sleep per night, and a list of supplements being consumed. Participants gave saliva samples within pre‐determined time intervals before, during, and after their workouts as well as during the same times during days of rest. Samples were collected on two training days and one rest day a week on three separate weeks for a total of 27 samples per athlete. In addition to saliva samples, a stress assessment was filled out by every athlete each day of collection. All samples were placed in a freezer at 0 degrees Celsius until collections were completed and analyzed. Samples were evaluated via ELISA by a competitive immunoenzymatic colorimetric method for the quantitative determination of cortisol concentration. ELISA absorptions were analyzed with linear regression to calculate cortisol concentrations.CONCLUSIONThe result of this study will assist in a better understanding of the hypothalamic‐pituitary‐adrenal axis function. Furthermore, while allowing the endurance‐trained athlete to efficiently and properly recover, it will aid in reducing the risk of injury and overtraining syndrome.

Homer1a Undergoes Bimodal Transcriptional Regulation by CREB and the Circadian Clock

Accumulating evidence points to a significant link between disrupted circadian rhythms and neuronal disfunctions, though the molecular mechanisms underlying this connection are virtually unexplored. The transcript Homer1a, an immediate early gene related to postsynaptic signaling, has been demonstrated to exhibit robust circadian oscillation in the brain, which supports the hypothesis that Homer1a mediates the communication between circadian inputs and neuronal activity. Here, we determined how the circadian clock is implicated in Homer1a gene regulation by using circadian clock Bmal1-mutant mice either in the presence or absence of stress stimulation. The Homer1 gene generates multiple transcripts, but only the short variant Homer1a responds to acute stress with sleep deprivation (SD) in mice. Chromatin immunoprecipitation assays revealed that both transcription factor CREB and the circadian clock component BMAL1 bind to the Homer1 promoter in mouse brain. Importantly, circadian Homer1a gene expression is unaltered in the absence of BMAL1, while its immediate early response to SD relies on BMAL1. Deletion of Bmal1 results in attenuated CREB activity in mouse brain, which appears to contribute to decreased expression of Homer1a in response to SD. In conclusion, Homer1a undergoes bimodal control by the circadian clock and CREB.

Spatiotemporal gating of SIRT1 functions by O-GlcNAcylation is essential for liver metabolic switching and prevents hyperglycemia

Inefficient physiological transitions are known to cause metabolic disorders. Therefore, investigating mechanisms that constitute molecular switches in a central metabolic organ like the liver becomes crucial. Specifically, upstream mechanisms that control temporal engagement of transcription factors, which are essential to mediate physiological fed-fast-refed transitions are less understood. SIRT1, a NAD+-dependent deacetylase, is pivotal in regulating hepatic gene expression and has emerged as a key therapeutic target. Despite this, if/how nutrient inputs regulate SIRT1 interactions, stability, and therefore downstream functions are still unknown. Here, we establish nutrient-dependent O-GlcNAcylation of SIRT1, within its N-terminal domain, as a crucial determinant of hepatic functions. Our findings demonstrate that during a fasted-to-refed transition, glycosylation of SIRT1 modulates its interactions with various transcription factors and a nodal cytosolic kinase involved in insulin signaling. Moreover, sustained glycosylation in the fed state causes nuclear exclusion and cytosolic ubiquitin-mediated degradation of SIRT1. This mechanism exerts spatiotemporal control over SIRT1 functions by constituting a previously unknown molecular relay. Of note, loss of SIRT1 glycosylation discomposed these interactions resulting in aberrant gene expression, mitochondrial dysfunctions, and enhanced hepatic gluconeogenesis. Expression of nonglycosylatable SIRT1 in the liver abrogated metabolic flexibility, resulting in systemic insulin resistance, hyperglycemia, and hepatic inflammation, highlighting the physiological costs associated with its overactivation. Conversely, our study also reveals that hyperglycosylation of SIRT1 is associated with aging and high-fat-induced obesity. Thus, we establish that nutrient-dependent glycosylation of SIRT1 is essential to gate its functions and maintain physiological fitness.

Network-Specific Synchronization of Electrical Slow-Wave Oscillations Regulates Sleep Drive in Drosophila.

Slow-wave rhythms characteristic of deep sleep oscillate in the delta band (0.5-4Hz) and can be found across various brain regions in vertebrates. Across phyla, however, an understanding of the mechanisms underlying oscillations and how these link to behavior remains limited. Here, we discover compound delta oscillations in the sleep-regulating R5 network of Drosophila. We find that the power of these slow-wave oscillations increases with sleep need and is subject to diurnal variation. Optical multi-unit voltage recordings reveal that single R5 neurons get synchronized by activating circadian input pathways. We show that this synchronization depends on NMDA receptor (NMDAR) coincidence detector function, and that an interplay of cholinergic and glutamatergic inputs regulates oscillatory frequency. Genetically targeting the coincidence detector function of NMDARs in R5, and thus the uncovered mechanism underlying synchronization, abolished network-specific compound slow-wave oscillations. It also disrupted sleep and facilitated light-induced wakening, establishing a role for slow-wave oscillations in regulating sleep and sensory gating. We therefore propose that the synchronization-based increase in oscillatory power likely represents an evolutionarily conserved, potentially "optimal," strategy for constructing sleep-regulating sensory gates.

Multispectral estimation of retinal photoreceptoral inputs

Integrated multispectral devices provide convenient means for assessing the inputs to the five known photoreceptors present in the human retina. These photoreceptors drive relevant visual and non-visual pathways that control key aspects of human physiology. In this Letter we show that standard metrics of retinal photoreceptoral exposure can be quantitatively estimated, to within a 5%, by means of 12 multispectral channels, 20 nm wide (FWHM), distributed across the visible range. Full Text: PDF ReferencesD.M. Berson, F.A. Dunn, M. Takao, "Phototransduction by Retinal Ganglion Cells That Set the Circadian Clock", Science 295, 1070 (2002). CrossRef R.J. Lucas et al. "Measuring and using light in the melanopsin age", Trends in Neurosciences 37, 1 (2014). CrossRef Commission Internationale de l'Eclairage. TN 003:2015 Report on the First International Workshop on Circadian and Neurophysiological Photometry, 2013. CIE, 2015. DirectLink A. Sánchez de Miguel et al, "Evaluating Human Photoreceptoral Inputs from Night-Time Lights Using RGB Imaging Photometry", Journal of Imaging 5(4), 49 (2019). CrossRef M.S. Rea, M.G. Figueiro, A. Bierman, R. Hamner. "Modelling the spectral sensitivity of the human circadian system", Lighting Research and Technology 44, 386 (2012). CrossRef D. Cao, P.A. Barrionuevo, "Estimating photoreceptor excitations from spectral outputs of a personal light exposure measurement device", Chronobiology International 32(2), 270 (2015). CrossRef P.B. Liebelt, An Introduction to Optimal Estimation (Reading, MA, Addison-Wesley, 1967). CrossRef J. Escofet, S. Bará, "Reducing the circadian input from self-luminous devices using hardware filters and software applications", Lighting Research and Technology 49, 481 (2017). CrossRef

Hematopoietic-Extrinsic Cues Dictate Circadian Redistribution of Mature and Immature Hematopoietic Cells in Blood and Spleen.

Circadian oscillations in circulating leukocyte subsets including immature hematopoietic cells have been appreciated; the origin and nature of these alterations remain elusive. Our analysis of wild-type C57BL/6 mice under constant darkness confirmed circadian fluctuations of circulating leukocytes and clonogenic cells in blood and spleen but not bone marrow. Clock gene deficient Bmal1−/− mice lacked this regulation. Cell cycle analyses in the different hematopoietic compartments excluded circadian changes in total cell numbers, rather favoring shifting hematopoietic cell redistribution as the underlying mechanism. Transplant chimeras demonstrate that circadian rhythms within the stroma mediate the oscillations independently of hematopoietic-intrinsic cues. We provide evidence of circadian CXCL12 regulation via clock genes in vitro and were able to confirm CXCL12 oscillation in bone marrow and blood in vivo. Our studies further implicate cortisol as the conveyor of circadian input to bone marrow stroma and mediator of the circadian leukocyte oscillation. In summary, we establish hematopoietic-extrinsic cues as causal for circadian redistribution of circulating mature/immature blood cells.

Normal peripheral circadian phase in the old-old with abnormal circadian behavior.

Almost all organisms maintain a circadian clock from birth to death to synchronize their own physiology and behavior with the earth's rotation. However, extensive studies based on animal experiments have showed that aging results in circadian dysfunction. Human studies have also indicated age-associated abnormal phase, reduced amplitude and enhanced fragmentation in circadian physiology and behavior, thereby strongly implying age-related dysfunction of the clock machinery. Here, we carried out functional assessment of the circadian clock machinery in elderly patients aged 83-94 with severe dementia who showed abnormal circadian behavior. To investigate whether or not the systemic pathway from the circadian input to peripheral clocks functioned normally, the circadian phase in peripheral clock gene expression rhythms was evaluated using plucked hair tissues. Unexpectedly, the phase in all volunteer patients was within a range similar to that of healthy subjects. The circadian pathway from external inputs to peripheral clocks may therefore function normally, even in the old-old with severe dementia.

Inhibition of p38 MAPK activity leads to cell type-specific effects on the molecular circadian clock and time-dependent reduction of glioma cell invasiveness

BackgroundThe circadian clock is the basis for biological time keeping in eukaryotic organisms. The clock mechanism relies on biochemical signaling pathways to detect environmental stimuli and to regulate the expression of clock-controlled genes throughout the body. MAPK signaling pathways function in both circadian input and output pathways in mammals depending on the tissue; however, little is known about the role of p38 MAPK, an established tumor suppressor, in the mammalian circadian system. Increased expression and activity of p38 MAPK is correlated with poor prognosis in cancer, including glioblastoma multiforme; however, the toxicity of p38 MAPK inhibitors limits their clinical use. Here, we test if timed application of the specific p38 MAPK inhibitor VX-745 reduces glioma cell invasive properties in vitro.MethodsThe levels and rhythmic accumulation of active phosphorylated p38 MAPK in different cell lines were determined by western blots. Rhythmic luciferase activity from clock gene luciferase reporter cells lines was used to test the effect of p38 MAPK inhibition on clock properties as determined using the damped sine fit and Levenberg–Marquardt algorithm. Nonlinear regression and Akaike’s information criteria were used to establish rhythmicity. Boyden chamber assays were used to measure glioma cell invasiveness following time-of-day-specific treatment with VX-745. Significant differences were established using t-tests.ResultsWe demonstrate the activity of p38 MAPK cycles under control of the clock in mouse fibroblast and SCN cell lines. The levels of phosphorylated p38 MAPK were significantly reduced in clock-deficient cells, indicating that the circadian clock plays an important role in activation of this pathway. Inhibition of p38 MAPK activity with VX-745 led to cell-type-specific period changes in the molecular clock. In addition, phosphorylated p38 MAPK levels were rhythmic in HA glial cells, and high and arrhythmic in invasive IM3 glioma cells. We show that inhibition of p38 MAPK activity in IM3 cells at the time of day when the levels are normally low in HA cells under control of the circadian clock, significantly reduced IM3 invasiveness.ConclusionsGlioma treatment with p38 MAPK inhibitors may be more effective and less toxic if administered at the appropriate time of the day.

Computer Simulation of Noise Effects of the Neighborhood of Stimulus Threshold for a Mathematical Model of Homeostatic Regulation of Sleep-Wake Cycles

The noise effects on a homeostatic regulation of sleep-wake cycles’ neuronal mathematical model determined by the hypocretin/orexin and the local glutamate interneurons spatiotemporal behaviors are studied within the neighborhood of stimulus threshold in this work; the neuronal noise added to the stimulus, the conductance, and the activation variable of the modulation function are investigated, respectively, based on a circadian input skewed in sine function. The computer simulation results suggested that the increased amplitude of external current input will lead to the fact that awakening time is advanced but the sleepy time remains the same; for the bigger conductance and modulation noise, the regulatory mechanism of the model sometimes will be collapsed and the coupled two neurons of the model show very irregular activities; the falling asleep or wake transform appears at nondeterminate time.