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.

Peroxiredoxins couple metabolism and cell division in an ultradian cycle.

Redox cycles have been reported in ultradian, circadian and cell cycle-synchronized systems. Redox cycles persist in the absence of transcription and cyclin-CDK activity, indicating that cells harbor multiple coupled oscillators. Nonetheless, the causal relationships and molecular mechanisms by which redox cycles are embedded within ultradian, circadian or cell division cycles remain largely elusive. Yeast harbor an ultradian oscillator, the yeast metabolic cycle (YMC), which comprises metabolic/redox cycles, transcriptional cycles and synchronized cell division. Here, we reveal the existence of robust cycling of H2O2 and peroxiredoxin oxidation during the YMC and show that peroxiredoxin inactivation disrupts metabolic cycling and abolishes coupling with cell division. We find that thiol-disulfide oxidants and reductants predictably modulate the switching between different YMC metabolic states, which in turn predictably perturbs cell cycle entry and exit. We propose that oscillatory H2O2-dependent protein thiol oxidation is a key regulator of metabolic cycling and its coordination with cell division.

Budgerigars have complex sleep structure similar to that of mammals.

Birds and mammals share specialized forms of sleep including slow wave sleep (SWS) and rapid eye movement sleep (REM), raising the question of why and how specialized sleep evolved. Extensive prior studies concluded that avian sleep lacked many features characteristic of mammalian sleep, and therefore that specialized sleep must have evolved independently in birds and mammals. This has been challenged by evidence of more complex sleep in multiple songbird species. To extend this analysis beyond songbirds, we examined a species of parrot, the sister taxon to songbirds. We implanted adult budgerigars (Melopsittacus undulatus) with electroencephalogram (EEG) and electrooculogram (EOG) electrodes to evaluate sleep architecture, and video monitored birds during sleep. Sleep was scored with manual and automated techniques, including automated detection of slow waves and eye movements. This can help define a new standard for how to score sleep in birds. Budgerigars exhibited consolidated sleep, a pattern also observed in songbirds, and many mammalian species, including humans. We found that REM constituted 26.5% of total sleep, comparable to humans and an order of magnitude greater than previously reported. Although we observed no spindles, we found a clear state of intermediate sleep (IS) similar to non-REM (NREM) stage 2. Across the night, SWS decreased and REM increased, as observed in mammals and songbirds. Slow wave activity (SWA) fluctuated with a 29-min ultradian rhythm, indicating a tendency to move systematically through sleep states as observed in other species with consolidated sleep. These results are at variance with numerous older sleep studies, including for budgerigars. Here, we demonstrated that lighting conditions used in the prior budgerigar study-and commonly used in older bird studies-dramatically disrupted budgerigar sleep structure, explaining the prior results. Thus, it is likely that more complex sleep has been overlooked in a broad range of bird species. The similarities in sleep architecture observed in mammals, songbirds, and now budgerigars, alongside recent work in reptiles and basal birds, provide support for the hypothesis that a common amniote ancestor possessed the precursors that gave rise to REM and SWS at one or more loci in the parallel evolution of sleep in higher vertebrates. We discuss this hypothesis in terms of the common plan of forebrain organization shared by reptiles, birds, and mammals.

Amplitude of One-Minute Fluctuations of Secondary Cosmic Rays as a Marker of Environmental Factor Determining Ultradian Rhythms in Body Temperature of Laboratory Rats.

The study examined association between oscillations of body temperature of laboratory Wistar rats maintained under constant illumination with the amplitude of fluctuations of secondary cosmic rays reported by neutron count rate provided by neutron monitors and geomagnetic undulations. In contrast to geomagnetic undulations, neutron count rate variations and body temperature oscillations in rats assessed by spectrum analysis of the corresponding step functions at 1-min intervals demonstrated almost permanent variations with the periods ranging from 100 to 400 min. Under conditions of constant illumination inducing changes in the period of circadian rhythm and predominance of the ultradian rhythms, an association between neutron count rate fluctuations and body temperature oscillations was observed perpetually during the day- and nighttime.

Possible External Factors Determining Ultradian (4-20-min) Rhythms of Body Temperature.

The study examined the effect of passive magnetic shielding on the magnitude of rhythmic oscillations of body temperature (BT) with 4-20 min periods in mice and their correlation with similar oscillations in unshielded control group. A magnetic permalloy screen that 35-fold attenuates the total geomagnetic field and decreased the undulations of magnetic field with the periods of few minutes by 5 times, produced no effect on the mean amplitude of BT oscillations within the same period range, their spectral power, and the cross-spectral density of examined rhythms in comparison with the control (unshielded) mice. Thus, either the mice possess a very sensitive magnetic sensory system or there exists an external non-magnetic factor affecting rhythmicity of BT. The study advanced intensity of thermal neutron radiation near the Earth's surface known to reflect the flow of accelerated particles generated by the secondary cosmic rays as the external factor, which strongly correlates with BT rhythms revealed by cross-spectrum analysis.

Changes in Body Temperature of Small Mammals and Birds in a Few Minutes Range as Reflection of Environmental Influences.

The study examined the changes in intraperitoneal body temperature of laboratory mice, Jungar hamsters, European greenfinch Chloris chloris, and starlings. In a few minutes range, these changes significantly correlated not only between the animals of the same species, but also between the different classes such as birds and mammals, which were isolated from each other and maintained under different illumination regimen. This phenomenon indicates some external influence(s) on the central mechanisms of the thermal control system not related to illumination regiment. In 80% cases, the phases of most pronounced rhythms of body temperature oscillating with the periods of 8-9 and 12-13 min coincided with those of geomagnetic field within the accuracy of ±1 min. However, the amplitude of body temperature oscillations did not depend on the amplitude of geomagnetic field (GMF) oscillations. Synchronicity of the changes in body temperature and GMF was observed at the amplitude of GMF oscillation of 0.4 nT, which is extremely low value. In contrast, there was no reaction of body temperature to greater (6-10 nT) but irregular and abrupt perturbations of GMF.

Phase Analysis of Ultradian Rhythms of Body Temperature in Laboratory Mice Maintained under Constant Illumination at Different Longitudinal Locations.

The study examined the rhythmic oscillations of body temperature with the period ranging 100-400 min in three groups of laboratory mice maintained under persistent artificial illumination in Moscow and Ulyanovsk. The difference in the moments of sunrise or sunset in these towns is about 1 h. The greatest rhythmic oscillations of body temperature in examined mice had the periods of 100-400 min. The phase analysis of 100-200-min rhythms revealed their synchronicity with local but not universal time despite the mice had no photic signs indicating alternation of day and night. Of them, the most pronounced were the rhythms with the periods of 121, 143, 151, and 186 min. The present data suggest existence of an external environmental synchronizer of body temperature ultradian rhythms related to local solar time.

The Origin of GnRH Pulse Generation: An Integrative Mathematical-Experimental Approach.

Fertility critically depends on the gonadotropin-releasing hormone (GnRH) pulse generator, a neural construct comprised of hypothalamic neurons coexpressing kisspeptin, neurokoinin-B and dynorphin. Here, using mathematical modeling and in vivo optogenetics we reveal for the first time how this neural construct initiates and sustains the appropriate ultradian frequency essential for reproduction. Prompted by mathematical modeling, we show experimentally using female estrous mice that robust pulsatile release of luteinizing hormone, a proxy for GnRH, emerges abruptly as we increase the basal activity of the neuronal network using continuous low-frequency optogenetic stimulation. Further increase in basal activity markedly increases pulse frequency and eventually leads to pulse termination. Additional model predictions that pulsatile dynamics emerge from nonlinear positive and negative feedback interactions mediated through neurokinin-B and dynorphin signaling respectively are confirmed neuropharmacologically. Our results shed light on the long-elusive GnRH pulse generator offering new horizons for reproductive health and wellbeing.SIGNIFICANCE STATEMENT The gonadotropin-releasing hormone (GnRH) pulse generator controls the pulsatile secretion of the gonadotropic hormones LH and FSH and is critical for fertility. The hypothalamic arcuate kisspeptin neurons are thought to represent the GnRH pulse generator, since their oscillatory activity is coincident with LH pulses in the blood; a proxy for GnRH pulses. However, the mechanisms underlying GnRH pulse generation remain elusive. We developed a mathematical model of the kisspeptin neuronal network and confirmed its predictions experimentally, showing how LH secretion is frequency-modulated as we increase the basal activity of the arcuate kisspeptin neurons in vivo using continuous optogenetic stimulation. Our model provides a quantitative framework for understanding the reproductive neuroendocrine system and opens new horizons for fertility regulation.

PSK1 coordinates glucose metabolism and utilization and regulates energy-metabolism oscillation in Saccharomyces cerevisiae.

Energy-metabolism oscillations (EMO) are ultradian biological rhythms observed in in aerobic chemostat cultures of Saccharomyces cerevisiae. EMO regulates energy metabolism such as glucose, carbohydrate storage, O2 uptake, and CO2 production. PSK1 is a nutrient responsive protein kinase involved in regulation of glucose metabolism, sensory response to light, oxygen, and redox state. The aim of this investigation was to assess the function of PSK1 in regulation of EMO. The mRNA levels of PSK1 fluctuated in concert with EMO, and deletion of PSK1 resulted in unstable EMO with disappearance of the fluctuations and reduced amplitude, compared with the wild type. Furthermore, the mutant PSK1Δ showed downregulation of the synthesis and breakdown of glycogen with resultant decrease in glucose concentrations. The redox state represented by NADH also decreased in PSK1Δ compared with the wild type. These data suggest that PSK1 plays an important role in the regulation of energy metabolism and stabilizes ultradian biological rhythms. These results enhance our understanding of the mechanisms of biorhythms in the budding yeast.

Kisspeptin Neuron-Specific and Self-Sustained Calcium Oscillation in the Hypothalamic Arcuate Nucleus of Neonatal Mice: Regulatory Factors of its Synchronization.

INTRODUCTION: Synchronous and pulsatile neural activation of kisspeptin neurons in the arcuate nucleus (ARN) are important components of the gonadotropin-releasing hormone pulse generator, the final common pathway for central regulation of mammalian reproduction. However, whether ARN kisspeptin neurons can intrinsically generate self-sustained synchronous oscillations from the early neonatal period and how they are regulated remain unclear. OBJECTIVE: This study aimed to examine the endogenous rhythmicity of ARN kisspeptin neurons and its neural regulation using a neonatal organotypic slice culture model. METHODS: We monitored calcium (Ca2+) dynamics in real-time from individual ARN kisspeptin neurons in neonatal organotypic explant cultures of Kiss1-IRES-Cre mice transduced with genetically encoded Ca2+ indicators. Pharmacological approaches were employed to determine the regulations of kisspeptin neuron-specific Ca2+ oscillations. A chemogenetic approach was utilized to assess the contribution of ARN kisspeptin neurons to the population dynamics. RESULTS: ARN kisspeptin neurons in neonatal organotypic cultures exhibited a robust synchronized Ca2+ oscillation with a period of approximately 3 min. Kisspeptin neuron-specific Ca2+ oscillations were dependent on voltage-gated sodium channels and regulated by endoplasmic reticulum-dependent Ca2+ homeostasis. Chemogenetic inhibition of kisspeptin neurons abolished synchronous Ca2+ oscillations, but the autocrine actions of the neuropeptides were marginally effective. Finally, neonatal ARN kisspeptin neurons were regulated by N-methyl-D-aspartate and gamma-aminobutyric acid receptor-mediated neurotransmission. CONCLUSION: These data demonstrate that ARN kisspeptin neurons in organotypic cultures can generate synchronized and self-sustained Ca2+ oscillations. These oscillations controlled by multiple regulators within the ARN are a novel ultradian rhythm generator that is active during the early neonatal period.

Multiple-scale neuroendocrine signals connect brain and pituitary hormone rhythms.

Small assemblies of hypothalamic "parvocellular" neurons release their neuroendocrine signals at the median eminence (ME) to control long-lasting pituitary hormone rhythms essential for homeostasis. How such rapid hypothalamic neurotransmission leads to slowly evolving hormonal signals remains unknown. Here, we show that the temporal organization of dopamine (DA) release events in freely behaving animals relies on a set of characteristic features that are adapted to the dynamic dopaminergic control of pituitary prolactin secretion, a key reproductive hormone. First, locally generated DA release signals are organized over more than four orders of magnitude (0.001 Hz-10 Hz). Second, these DA events are finely tuned within and between frequency domains as building blocks that recur over days to weeks. Third, an integration time window is detected across the ME and consists of high-frequency DA discharges that are coordinated within the minutes range. Thus, a hierarchical combination of time-scaled neuroendocrine signals displays local-global integration to connect brain-pituitary rhythms and pace hormone secretion.

Effect of Surgical Removal of Testicles and Adrenal Glands on Ultradian Rhythms of Body Temperature in Male Wistar Rats under Conditions of Constant Illumination.

We have studied body temperature dynamics of mature male Wistar rats maintained under constant illumination after surgical removal of the testicles and adrenal glands. In gonadectomized animals, pronounced increases in body temperature (>0.9°C) were observed every 4-6 h; during the periods 03.35-04.30, 07.35-08.30, 11.35-12.30, 15.35-16.30, 19.35-20.30, and 23.35-00.30, they were recorded 1.5-fold more often than during the rest periods. These results do not significantly differ from the parameters of the control group. Combined removal of the testicles and adrenal glands led to shortening of main period of temperature oscillations to 4-4.5 h and a decrease in its amplitude; pronounced increase in body temperature (>0.5°C) was observed 2.1 times more often during the periods 03.35-04.30, 07.35-08.30, 11.35-12.30, 15.35-16.30, 19.35-20.30, and 23.35-00.30 than in other time intervals. Thus, the removal of the testicles and adrenal glands does not violate the 4-h intraday rhythm of body temperature.

Body Temperature Dynamics in Small Mammals and Birds in 10-120-min Period Range.

The dynamics of intraperitoneal body temperature was analyzed in males of C57BL/6 mice and common greenfinches (Chloris chloris). Despite the membership in different classes, these mammals demonstrated the identical set of harmonics in body temperature spectra. The study revealed synchronicity of body temperature oscillations in distantly isolated animals. The data suggest that body temperature oscillations in 10-120-min (circahoralian) period range reflect the effect of an external environmental biotropic factor on temperature control in small mammals and birds.

Ultradian Rhythms of Body Temperatures in Male Wistar Rats Maintained under Conditions of Constant Illumination.

We studied the dynamics of the body temperature in mature male Wistar rats maintained under condition of constant illumination. It was shown that body temperature under these conditions varied with a 3-5-h period. The daily dynamics of body temperature summed up over 20-23-day intervals showed a 4-h ultradian rhythm with maxima at 3.35-4.30, 7.35-8.30, 11.35-12.30, 15.35-16.30, 19.35-20.30, and 23.35-00.30 h. During these hours, pronounced (>0.9°C) increase in body temperature was observed by 1.6 times more often than in other eriods. Thus, there are periods during the day when the increase in body temperature in rats in the absence of light cues occurs more often than in other periods of the day. Hence, about 4-h ultradian rhythm of body temperature has an external synchronizer that differs from lighting conditions.

Infradian and Ultradian Rhythms of Body Temperature Resumption during Hibernation.

The rhythms of short-term arousal episodes, associated with normalization of low body temperature, were studied in hibernating Erinaceus roumanicus. The episodes of body temperature recovery during hibernation were 1.7 times more incident during the acrophase of 4.058-day rhythm of glucocorticoid hormones, detected previously, than during the batiphase of this rhythm. Ultradian rhythm of arousal episodes conformed to a 4-h biorhythm: the maximum number of body temperature resumption episodes was recorded at 00.00-01.00, 04.00-05.00, 08.00-09.00, 12.00-13.00, 16.00-17.00, and 20.00-21.00. These data indicated that in mammals the mechanisms of infradian and ultradian rhythm maintenance were stable and did not depend on body temperature or were determined by external factors with periods of 4.058 days and 4 h.

Circadian and ultradian glucocorticoid rhythmicity: Implications for the effects of glucocorticoids on neural stem cells and adult hippocampal neurogenesis.

Psychosocial stress, and within the neuroendocrine reaction to stress specifically the glucocorticoid hormones, are well-characterized inhibitors of neural stem/progenitor cell proliferation in the adult hippocampus, resulting in a marked reduction in the production of new neurons in this brain area relevant for learning and memory. However, the mechanisms by which stress, and particularly glucocorticoids, inhibit neural stem/progenitor cell proliferation remain unclear and under debate. Here we review the literature on the topic and discuss the evidence for direct and indirect effects of glucocorticoids on neural stem/progenitor cell proliferation and adult neurogenesis. Further, we discuss the hypothesis that glucocorticoid rhythmicity and oscillations originating from the activity of the hypothalamus-pituitary-adrenal axis, may be crucial for the regulation of neural stem/progenitor cells in the hippocampus, as well as the implications of this hypothesis for pathophysiological conditions in which glucocorticoid oscillations are affected.

Impact of time-of-day on brain morphometric measures derived from T1-weighted magnetic resonance imaging.

Measures of brain morphometry derived from T1-weighted (T1W) magnetic resonance imaging (MRI) are widely used to elucidate the relation between brain structure and function. However, the computation of T1W morphometric measures can be confounded by subject-related factors such as head motion and level of hydration. A recent study reported subtle yet significant changes in brain volume from morning to evening in a large group of patient populations as well as in healthy elderly individuals. In addition, there is a growing recognition that factors such as circadian rhythm can impact MRI measures of brain function and structure. Here, we provide a comprehensive assessment of the impact of time-of-day (TOD) on widely used measures of brain morphometry in a group of 19 healthy young adults. Our results show that (a) even in a small group of healthy adult volunteers, a highly significant reduction in apparent brain volume, from morning to evening, could be detected; (b) the apparent volume of all three major tissue compartments - gray matter, white matter, and cerebrospinal fluid - were influenced by TOD, and the magnitude of the TOD effect varied across the tissue compartments; (c) measures of cortical thickness, cortical surface area, and gray matter density computed with widely used neuroimaging software suites (i.e., FreeSurfer, FSL-VBM) were all affected by TOD, while other measures, such as curvature indices and sulcal depth, were not; and (d) the effect of TOD appeared to have a greater impact on morphometric measures of the frontal and temporal lobe than on other major lobes of the brain. Our results suggest that the TOD effect is a physiological phenomenon and that controlling for the effect of TOD is crucial for proper interpretation of apparent structural differences measured with T1W morphometry.

Immediate effects of phototherapy on sleep in very preterm neonates: an observational study.

Process C (internal clock) and Process S (sleep-wake homeostasis) are the basis of sleep-wake regulation. In the last trimester of pregnancy, foetal heart rate is synchronized with the maternal circadian rhythm. At birth, this interaction fails and an ultradian rhythm appears. Light exposure is a strong factor influencing the synchronization of sleep-wake processes. However, little is known about the effects of phototherapy on the sleep rhythm of premature babies. It was hypothesized that sleep in preterm infants would not differ during phototherapy, but that a maturation effect would be seen. Sleep states were studied in 38 infants born < 32 weeks gestational age and/or < 1 500 g birth weight. Videos of 3 h were taken over the first 5 days of life. Based on breathing and movement patterns, behavioural states were defined as: awake; active sleep; or quiet sleep. Videos with and without phototherapy were compared for amounts of quiet sleep and active states (awake + active sleep). No significant association between phototherapy and amount of quiet sleep was found (P = 0.083). Analysis of videos in infants not under phototherapy revealed an increase in time spent awake with increasing gestational age. The current data suggest that the ultradian rhythm of preterm infants seems to be independent of phototherapy, supporting the notion that sleep rhythm in this population is mainly driven by their internal clock.

Circadian and ultradian cardiovascular rhythmicity in obese children.

UNLABELLED: Altered circadian and ultradian blood pressure (BP) and heart rate (HR) rhythmicity have been described in diseases with increased cardiovascular risk. We analyzed cardiovascular rhythmicity in obese children. BP and HR rhythmicity was assessed with Fourier analysis from 24-h ambulatory BP measurements in 75 obese children and compared with an age- and gender-matched, lean healthy reference group of 150 subjects. Multivariate regression analysis was applied to identify significant independent factors explaining variability of rhythmicity. Prevalence of 24- and 6-h BP rhythmicity in the obese group was lower (p = 0.03 and p = 0.02), whereas the prevalence of HR rhythmicity was comparable in both groups. Excluding hypertensive participants, the results remained similar. Twenty-four-hour BP and HR acrophase were delayed in obese children (p = 0.004, p < 0.0001), 24-h BP amplitude did not differ (p = 0.07), and 24-h HR amplitude was blunted (p = < 0.0001). BP Mesor in the obese group was higher (p = 0.02); HR Mesor did not differ (p = 0.1). Multivariate regression analysis failed to identify a single anthropometric or blood pressure parameter explaining the variability of BP and HR rhythmicity. CONCLUSION: Prevalence and parameters of circadian and ultradian BP and HR rhythmicity in obese children are altered compared to a healthy reference group, independent of preexisting hypertension. WHAT IS KNOWN: • Altered cardiovascular rhythmicity has been described in children with different diseases such as primary hypertension or chronic renal failure. What is New: • This study reveals altered cardiovascular rhythmicity in obese children compared to an age and gender-matched healthy reference group independent from preexisting hypertension.