Ultradian Research Articles

Behavioural phenotypes of Dicer knockout in the mouse SCN

AbstractThe suprachiasmatic nucleus (SCN) is the master clock that directly dictates behavioural rhythms to anticipate the earth's light/dark cycles. Although post‐transcriptional regulators called microRNAs have been implicated in physiological SCN function, how the absence of the entire mature miRNome impacts SCN output has not yet been explored. To study the behavioural consequences of miRNA depletion in the SCN, we first generated a mouse model in which Dicer is inactivated in the SCN by crossing Syt10Cre mice with Dicerflox mice to study behavioural consequences of miRNA depletion in the SCN. Loss of all mature miRNAs in the SCN shortened the circadian period length by ~37 minutes at the tissue level and by ~45 minutes at the locomotor activity level. Moreover, knockout animals exhibited a reduction in the precision of the circadian rhythm with more variable activity onsets under both LD 12:12 and DD conditions. We also observed that knockouts with higher onset variations were inclined to develop ultradian rhythms under constant light. In a second mouse model, recombination of Dicerflox via Cre delivery specifically in the SCN resulted in loss of behavioural rhythms in some animals depending on the injection efficiency. Together, our observations highlight the importance of microRNAs for a physiological SCN function and their pivotal role in robust circadian oscillations.

Central pattern generator control of a vertebrate ultradian sleep rhythm.

The mechanisms underlying the mammalian ultradian sleep rhythm-the alternation of rapid-eye-movement (REM) and slow-wave (SW) states-are not well understood but probably depend, at least in part, on circuits in the brainstem1-6. Here, we use perturbation experiments to probe this ultradian rhythm in sleeping lizards (Pogona vitticeps)7-9 and test the hypothesis that it originates in a central pattern generator10,11-circuits that are typically susceptible to phase-dependent reset and entrainment by external stimuli12. Using light pulses, we find that Pogona's ultradian rhythm8 can be reset in a phase-dependent manner, with a critical transition from phase delay to phase advance in the middle of SW. The ultradian rhythm frequency can be decreased or increased, within limits, by entrainment with light pulses. During entrainment, Pogona REM (REMP)can be shortened but not lengthened, whereas SW can be dilated more flexibly. In awake animals, a few alternating light/dark epochs matching natural REMP and SW durations entrain a sleep-like brain rhythm, suggesting the transient activation of an ultradian rhythm generator. In sleeping animals, a light pulse delivered to a single eye causes an immediate ultradian rhythm reset, but only of the contralateral hemisphere; both sides resynchronize spontaneously, indicating that sleep is controlled by paired rhythm-generating circuits linked by functional excitation. Our results indicate that central pattern generators of a type usually known to control motor rhythms may also organize the ultradian sleep rhythm in a vertebrate.

Diminished circadian and ultradian rhythms of human brain activity in pathological tissue in vivo

Chronobiological rhythms, such as the circadian rhythm, have long been linked to neurological disorders, but it is currently unknown how pathological processes affect the expression of biological rhythms in the brain. Here, we use the unique opportunity of long-term, continuous intracranially recorded EEG from 38 patients (totalling 6338 hours) to delineate circadian (daily) and ultradian (minute to hourly) rhythms in different brain regions. We show that functional circadian and ultradian rhythms are diminished in pathological tissue, independent of regional variations. We further demonstrate that these diminished rhythms are persistent in time, regardless of load or occurrence of pathological events. These findings provide evidence that brain pathology is functionally associated with persistently diminished chronobiological rhythms in vivo in humans, independent of regional variations or pathological events. Future work interacting with, and restoring, these modulatory chronobiological rhythms may allow for novel therapies.

Ultradian rhythms of activity in a wild subterranean rodent.

Many animals adapt their activity patterns to the best environmental conditions using daily rhythms. African mole-rats are among the mammals that have become models for studying how these rhythms can be entrained by light or temperature in experimental laboratory studies. However, it is unclear whether they exhibit similar circadian rhythms in their natural lightless, subterranean environment. In this study, we used biologging to investigate the activity rhythms of wild, highveld mole-rats. We show that their activity cycle exhibited an ultradian rhythm with a length between 4 and 8 h. On an individual level, mole-rats displayed about five activity bouts per day, occurring at various times during the day and night. On a population level, activity peaked in the afternoon, coinciding with the peak in ambient temperature. Our research suggests that wild subterranean mammals, which experience reduced environmental variation, are unlikely to show clear circadian rhythmicity in activity patterns. Instead, activity periods are distributed over several bouts throughout the day and night, and activity coincides with the peak in daily temperature. We propose that ultradian rhythms in activity may be more common than previously thought and discuss how physiological processes may generate differences in periodicity between laboratory and wild populations.

Dynamics of a pituitary–adrenal model with distributed time delays

This paper investigates the effects of distributed time delays on the dynamics of the pituitary–adrenal axis. Our two-dimensional model incorporates distributed time delays with general delay kernels, specifically illustrating interactions between adrenocorticotropic hormone (ACTH) and cortisol (CORT). We derive general theoretical results for general delay kernels, exemplified by Dirac and weak Gamma kernels, revealing stability transitions characterized by Hopf bifurcations. We establish conditions for the local asymptotic stability of the unique equilibrium and discuss the existence of periodic solutions. Numerical simulations demonstrate that periodic oscillations appear for appropriate values of the average time delays. Including an external input results in both ultradian and circadian rhythms, highlighting the system’s dynamic responsiveness to external stimuli.

The 70 years since the discovery of rapid eye movement sleep: history, electroencephalographic features and unsolved issues.

This article aims at providing a comprehensive review of the historical discovery and following research on rapid eye movement (REM) sleep, highlighting its manifold nature as a behavioural, electrophysiological and dreaming state. Pioneering works conducted by Aserinsky, Kleitman, Dement and Jouvet established the foundational understanding of REM sleep recurrence, brainstem mechanisms, and the paradoxical coexistence of electroencephalographic activation and muscle atonia. We focus on REM sleep homeostasis, emphasising its role in emotional recovery and the consequences of REM deprivation, such as the REM rebound effect. We also analyse the periodicity of REM sleep, its ultradian rhythm, and the physiological mechanisms underlying its regulation. Additionally, the article discusses the entangled relationship between arousals, sleep, and consciousness, pointing out the distinction between non-REM and REM sleep-related arousals, and the similarities between REM sleep and wakefulness.

Epigenetic regulation of global proteostasis dynamics by RBBP5 ensures mammalian organismal health.

Proteostasis is vital for cellular health, with disruptions leading to pathologies including aging, neurodegeneration and metabolic disorders. Traditionally, proteotoxic stress responses were studied as acute reactions to various noxious factors; however, recent evidence reveals that many proteostasis stress-response genes exhibit ~12-hour ultradian rhythms under physiological conditions in mammals. These rhythms, driven by an XBP1s-dependent 12h oscillator, are crucial for managing proteostasis. By exploring the chromatin landscape of the murine 12h hepatic oscillator, we identified RBBP5, a key subunit of the COMPASS complex writing H3K4me3, as an essential epigenetic regulator of proteostasis. RBBP5 is indispensable for regulating both the hepatic 12h oscillator and transcriptional response to acute proteotoxic stress, acting as a co-activator for proteostasis transcription factor XBP1s. RBBP5 ablation leads to increased sensitivity to proteotoxic stress, chronic inflammation, and hepatic steatosis in mice, along with impaired autophagy and reduced cell survival in vitro. In humans, lower RBBP5 expression is associated with reduced adaptive stress-response gene expression and hepatic steatosis. Our findings establish RBBP5 as a central regulator of proteostasis, essential for maintaining mammalian organismal health.

A Method for Predicting Ultradian Body Temperature Rhythms in Small Animals.

It has been found that the intraday dynamics of body temperature in small mammal and bird species on the adjacent day are similar. Therefore, by focusing on the body temperature dynamics of the previous day, it is possible to predict with a high degree of accuracy the periods of increase and decrease in body temperature for the current day. This phenomenon was observed when animals were kept under natural illumination and under artificial illumination when the phase of the intrinsic circadian rhythm shifted by 1-2 h every day. When analyzing this phenomenon in birds, it has been shown that the best match for body temperature dynamics occurs when comparing adjacent days based on sidereal days (a period of 23 h and 56 min). Over time, after several days, the daily patterns of body temperature fluctuation take on a completely different form and frequency. These facts suggest a connection between ultradian rhythms and the rotation of the Earth around its axis, and consequently, the position of animals on the surface of the planet relative to space objects.

Silencing of ultradian rhythms and metabolic depression during spontaneous daily torpor in Djungarian hamsters

Ultradian rhythms of metabolism, body temperature and activity are attenuated or disappear completely during torpor in Djungarian hamsters, for all three ultradian periodicities (URsmall, URmedium and URlarge). URsmall and URmedium disappear during entrance into torpor, whereas URlarge disappear later or continue with a low amplitude. This suggests a tight functional link between torpor and the expression of ultradian rhythms, i.e. torpor is achieved by suppression of metabolic rate as well as silencing of ultradian rhythms. Spontaneous torpor is often initiated after an ultradian burst of activity and metabolic rate, beginning with a period of motionless rest and accompanied by a decrease of metabolic rate and body temperature. To extend previous findings on the potential role of the adrenergic system on torpor induction we analysed the influence of the ß3-adrenergic agonist Mirabegron on torpor in Djungarian hamsters, as compared to the influence of the ß-adrenergic antagonist Propranolol. Hamsters were implanted with 10 day release pellets of Mirabegron (0.06 mg day−1) or Propranolol (0.3 mg day−1). Mirabegron transiently supressed and accelerated ultradian rhythms but had no effect on torpor behaviour. Propranolol did not affect torpor behaviour nor the expression of ultradian rhythms with the dosage applied during this study.

Multiple ultradian rhythms of metabolism, body temperature and activity in Djungarian hamsters

Djungarian hamsters (Phodopus sungorus) living at constant 15 °C Ta in short photoperiod (8:16 h L:D) showed pronounced ultradian rhythms (URs) of metabolic rate (MR), body temperature (Tb) and locomotor activity. The ultradian patterns differed between individuals and varied over time. The period length of URs for MR, Tb and activity was similar although not identical. Wavelet analysis showed that three different URs are existing in parallel, URs of small amplitude and short duration (URsmall), URs of medium amplitude and medium duration (URmedium) and URs of large amplitude (URlarge), superimposed on each other. URlarge were accompanied by an increase in locomotor activity, whereas URsmall and URmedium were of metabolic origin with lacking or delayed responses of activity. An energetic challenge to cold which raised total energy requirements by about 50% did not accelerate the period length of URs, but extended the amplitude of URsmall and URmedium. URlarge corresponds with the URs of activity, feeding and drinking, sleep and arousal as described in previous studies, which are related to midbrain dopaminergic signalling and hypothalamic ultradian signalling. The cause and control of URmedium and URsmall is unknown. Their periods are similar to periods of central and peripheral endocrine ultradian signalling, suggesting a link with URs of metabolism.

Simultaneous plasma and interstitial profiles of hormones and metabolites using URHYTHM: a novel ambulatory collection device

Increasing the sampling resolution when examining plasma hormone and metabolite profiles will more accurately describe diurnal/circadian rhythms and expose previously undiscovered ultradian rhythms that underpin metabolic physiology(1). In human research studies this must be tempered by the practical, ethical and safety concerns of repeated cannulation/blood draws. Here we examine the correlation between hormone and metabolite profiles present in interstitial fluid microdialysate(2), and plasma to help solve this dilemma.Hormonal markers of circadian phase (melatonin, cortisol) and metabolites will show similar profiles in plasma and interstitial fluid.Compare time-series hormone and metabolite profiles collected in interstitial fluid using a novel ambulatory microdialysis collection device (U-RHYTHM) with simultaneously drawn plasma samples.All study protocols were reviewed by Health Sciences Faculty Research Ethics Committee, University of Bristol. Fasted healthy male volunteers aged 18-35 (n=3) were fed a standardised breakfast (08:00), lunch (13:00), dinner (19:00) and snack (22:00) (2225kCal [83g protein, 273g carbohydrate, 83g fat, 27g fibre]). Participants remained on the study bed, lights off/sleep occurred between 23:00-07:00 (<4 lux).A 20kDa cutoff 30 mm linear microdialysis membrane was placed in periumbilical subcutaneous tissue, perpendicular to the midline. The membrane was perfused at 1µl/min and the microdialysate collected every 20 minutes for 25 hours into discrete samples using a portable fraction collector (URHYTHM) worn around the waist. Time-matched blood samples were obtained from an antecubital fossa canula.All samples were stored at -80°C prior to analysis. Hormones and metabolites were measured via targeted UPLC-MS/MS metabolomics, for the metabolites the AbsoluteIDQ® p180 kit (Biocrates Life Sciences AG)) was used with 10µL of plasma(3) and 15µL of microdialysate.Simultaneous time-courses of n = 24 metabolites were detected in plasma and interstitial microdialysate: alanine, arginine, asparagine, citrulline, glutamine, glutamate, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, trans-4-Hydroxyproline, taurine, carnitine and acetylcarnitine.Spearman rank cross correlation identified the time shift that was required to reach highest correlation between the plasma and microdialysate profiles. Excluding taurine, microdialysate profiles were delayed by 32.3 minutes (range 0-130) and 12.9 minutes (range 0-50) for participant 1 and 2, respectively (p <0.05), only 3/20 metabolite profiles were correlated for participant 3. Trans4-hydroxyproline had the strongest correlation (rs 0.890, 0.814 and 0.808), with only participant 3 displaying a time shift (50 minutes). Taurine had the weakest correlation in all 3 participants. (rs 0.096, 0.182, 0.325).These data demonstrate that our novel approach can be used to comprehensively detect hormone and metabolite profiles in interstitial fluid. Thus, the U-RHYTHM would serve as a useful tool, not only to increase sampling resolution in controlled laboratory studies but would prove particularly useful for examining circadian/ultradian profiles for chronobiology and nutrition studies in free-living individuals.

A versatile recording device for the analysis of continuous daily external activity in colonies of highly eusocial bees.

As pollinators, bees are key to maintaining the biodiversity of angiosperm plants, and for agriculture they provide a billion-dollar ecosystem service. But they also compete for resources (primarily nectar and pollen), especially the highly social bees that live in perennial colonies. So, how do they organize their daily temporal activities? Here, we present a versatile, low-cost device for the continuous, automatic recording and data analysis of the locomotor activity in the colony-entrance tube of highly eusocial bees. Consisting of an in-house built block containing an infrared detector, the passage of bees in the colony entrance tunnel is registered and automatically recorded in an Arduino environment, together with concomitant recordings of temperature and relative humidity. With a focus on the highly diverse Neotropical stingless bees (Meliponini), we obtained 10-day consecutive recordings for two colonies each of the species Melipona quadrifasciata and Frieseomelitta varia, and also for the honey bee. The Lomb-Scargle periodogram analysis identified a predominant circadian rhythmicity for all three species, but also indications of ultradian rhythms. For M. quadrifasciata, which is comparable in size to the honey bee, we found evidence for a possibly anticipatory activity already before sunrise. As all three species also presented activity at night in the colony entrance tube, this also raises questions about sleep organization in social insects. The cost and versatility of the device and the open-source options for data analysis make this an attractive system for conducting studies on circadian rhythms in social bees under natural conditions, complementing studies on flower visits by these important pollinators.

Circadian and ultradian rhythms: Clinical implications.

The hypothalamic-pituitary-adrenal axis is an extremely dynamic system with a combination of both circadian and ultradian oscillations. This state of 'continuous dynamic equilibration' provides a platform that is able to anticipate events, is sensitive in its response to stressors, remains robust during perturbations of both the internal and external environments and shows plasticity to adapt to a changed environment. In this review, we describe these oscillations of glucocorticoid (GC) hormones and why they are so important for GC-dependent gene activation in the brain and liver, and their consequent effects on the regulation of synaptic and memory function as well as appetite control and metabolic regulation. Abnormalities of mood, appetite and metabolic regulation are well-known consequences of GC therapy, and we suggest that the pattern of GC treatment and hormone replacement should be a much higher priority for endocrinologists and the pharmaceutical industry. One of the major impediments to our research on the importance of these cortisol rhythms in our patients has been our inability to measure repeated levels of hormones across the day in patients in their home or work surroundings. We describe how new wearable methodologies now allow the measurement of 24-h cortisol profiles - including during sleep - and will enable us to define physiological normality and allow us both to develop better diagnostic tests and inform, at an individual patient level, how to improve replacement therapy.

Current Challenges and Future Directions in the Assessment of Glucocorticoid Status.

Glucocorticoid hormones (GC) are secreted in a circadian and ultradian rhythm and play a critical role in maintaining physiological homeostasis, with both excess and insufficient GC associated with adverse effects on health. Current assessment of GC status is primarily clinical, often in conjunction with serum cortisol values, which may be stimulated or suppressed depending on the GC disturbance being assessed. In the setting of extreme perturbations in cortisol levels i.e. markedly low or high levels, symptoms and signs of GC dysfunction may be overt. However, when disturbances in cortisol GC status values are less extreme, such as when assessing optimization of a GC replacement regimen, signs and symptoms can be more subtle or non-specific. Current tools for assessing GC status, are best suited to identifying profound disturbances but may lack sensitivity for confirming optimal GC status. Moreover, single cortisol values do not necessarily reflect an individual's GC status, as they are subject to inter- and intra-individual variation, do not take into account the pulsatile nature of cortisol secretion, variation in binding proteins, or local tissue concentrations as dictated by 11βeta-hydroxysteroid dehydrogenase (11β-HSD) activity, as well as GC receptor sensitivity. In the present review, we evaluate possible alternative methods for the assessment of GC status that do not solely rely on measurement of circulating cortisol levels. We discuss the potential of changes in metabolomic profiles, miRNA, gene expression, epigenetic, and other novel biomarkers such as GDF-15 and osteocalcin, that could in future aid in the objective classification of GC status.

Sleep Stage Estimation by Introduction of Sleep Domain Knowledge to AI: Towards Personalized Sleep Counseling System with GenAI

As a first step towards realizing an AI sleep counselor capable of generating personalized advice, this paper proposes a method for monitoring daily sleep conditions with a mattress sensor. To improve the accuracy of sleep stage estimation and to get accurate sleep structure, this paper introduced sleep domain knowledge to machine learning for improving the accuracy of sleep stage estimation. Concretely, the proposed method estimates ultradian rhythm based on the body movement density, updates prediction probabilities of each sleep stage by ML model and applies WAKE/NR3 detection based on the large/small body movement. Through the human subject experiment, the following implications have been revealed: (1) the proposed method improved the percentage of Accuracy by 65.0% from 61.5% and the QWK score by 0.196 from 0.297 by the conventional machine learning method; (2) the proposed method prevents over-NR12 estimating and is useful for understanding sleep structure by estimating REM sleep and NR3 sleep correctly. (3) the correct estimation of ultradian rhythms significantly improved the sleep stage estimation, with an Accuracy of 77.6% and a QWK score of 0.52 when all subjects' ultradian rhythms were estimated correctly.

What Is a Correct Output by Generative AI From the Viewpoint of Well-Being? – Perspective From Sleep Stage Estimation –

This paper explores an answer to the question of “what is a correct output by generative AI from the viewpoint of well-being?” and discusses an effectiveness of taking account of a biological rhythm for this issue. Concretely, this paper focuses on an estimation of the REM sleep stage as one of sleep stages, and compared its estimations based on random forest as one of the machine learning methods and the ultradian rhythm as one of the biological rhythms. From the human subject experiment, the following implications have been revealed: (1) the REM sleep stage is wrongly estimated in many areas by random forest; and (2) the integration of the REM sleep stage estimation based on the biological rhythm with that based on random forest improves the F-score of the estimated REM sleep stage.

The translational aspects of glucocorticoid biorhythmicity in modern therapeutics

Glucocorticoids are a class of steroid hormones, vital for mammalian life. They have a plethora of biological effects, mainly supporting metabolic, cognitive, and immunological functions. The pharmacological use of glucocorticoids makes them one of the most frequently prescribed drugs across all continents, and in all types of forms. Nevertheless, a number of serious adverse effects accompany the prolonged treatment with high doses of glucocorticoids. Research developments over the last 20 years have gradually reshaped the way we think about glucocorticoid-based therapeu¬tics. Aside their circadian rhythm and their delayed regulatory influence over an extensive number of sensitive genes, glucocorticoids also possess an underlying, ultradian rhythm, and also exert rapid, non-genomic effects. The notion that chronicity of glucocorticoid stimulation may differentially modulate the type of biological effects of the hormone brings various chronopharmacological concepts on the table of modern glucocorticoid-based therapeutics.

A mathematical model for the role of dopamine-D2 self-regulation in the production of ultradian rhythms.

Many self-motivated and goal-directed behaviours display highly flexible, approximately 4 hour ultradian (shorter than a day) oscillations. Despite lacking direct correspondence to physical cycles in the environment, these ultradian rhythms may be involved in optimizing functional interactions with the environment and reflect intrinsic neural dynamics. Current evidence supports a role of mesostriatal dopamine (DA) in the expression and propagation of ultradian rhythmicity, however, the biochemical processes underpinning these oscillations remain to be identified. Here, we use a mathematical model to investigate D2 autoreceptor-dependent DA self-regulation as the source of ultradian behavioural rhythms. DA concentration at the midbrain-striatal synapses is governed through a dual-negative feedback-loop structure, which naturally gives rise to rhythmicity. This model shows the propensity of striatal DA to produce an ultradian oscillation characterized by a flexible period that is highly sensitive to parameter variations. Circadian (approximately 24 hour) regulation consolidates the ultradian oscillations and alters their response to the phase-dependent, rapid-resetting effect of a transient excitatory stimulus. Within a circadian framework, the ultradian rhythm orchestrates behavioural activity and enhances responsiveness to an external stimulus. This suggests a role for the circadian-ultradian timekeeping hierarchy in governing organized behaviour and shaping daily experience through coordinating the motivation to engage in recurring, albeit not highly predictable events, such as social interactions.

Association between Ultradian Rhythms of Body Temperature in Small Mammals and Earth's Crust Stress.

Association was assessed between the data harvested by a long-baseline laser interference deformograph and the dynamics of body temperature (BT) in hamsters deprived of natural daily light-darkness changes. The power spectral data revealed the positive correlation between simultaneous time series of hamster BT and the Earth's crust deformation (ECD). The superposed epoch analysis established an association between abrupt upstrokes of hamster BT and ECD increments. Thus, the direct relationships between BT dynamics (reflecting predominance of sympathetic part of autonomic nervous system) and ECD (according to long-baseline laser interference deformography) were established. The study observed synchronization of the free-running circadian rhythm of hamster BT with the tidal stress in Earth's lithosphere. Further studies are needed to find the physical factor underlying the revealed relationships.

Stress-free blood sampling in minipigs: A novel method for assessing 24-h cortisol profiles and drug effects on diurnal and ultradian rhythms

We developed a novel, stress-free blood sampling method for minipigs, allowing continuous cortisol monitoring over 24 h. Baseline cortisol levels exhibited both ultradian and diurnal rhythms. During nighttime, smaller ultradian rhythms overlaid a lower baseline cortisol, which increased in sleeping pigs before lights were turned on. Additionally, we developed an analytical tool based on the R package “pracma” to quantify ultradian peak and circadian components of the cortisol profiles.To validate our model, we investigated the effects of Verucerfont, a CRH receptor antagonist, and Venlafaxine, a serotonin-norepinephrine reuptake inhibitor. Verucerfont reduced cortisol levels during the first 9 h without affecting diurnal rhythm. Cortisol peak parameters decreased, with a 31% reduction in overall area under the curve (AUC) and a 38% reduction in ultradian average AUC. Ultradian peaks decreased from 7 to 4.5, with 34% lower amplitude. Venlafaxine maintained plasma concentrations within the targeted human effective range.This method enables us to enhance our understanding of cortisol regulation and provide valuable insights for the impact of investigation drugs on the diurnal and ultradian rhythms of cortisol.