Journal of Biological Rhythms最新文献

The role of the hierarchical organization of the suprachiasmatic nucleus (SCN) in its functioning, jet lag, and the light treatment of jet lag remains poorly understood. Using the core-shell model, we mimic collective behavior of the core and shell populations of the SCN oscillators in transient states after rapid traveling east and west. The existence of a special region of slow dynamical states of the SCN oscillators can explain phenomena such as the east-west asymmetry of jet lag, instances when entrainment to an advance is via delay shifts, and the dynamics of jet lag recovery time. If jet lag brings the SCN state into this region, it will take a long time to leave it and restore synchronization among oscillators. We show that the population of oscillators in the core responds quickly to a rapid phase shift of the light-dark cycle, in contrast to the shell, which responds slowly. A slow recovery of the synchronization among the shell oscillators in transient states may strongly affect reentrainment in peripheral tissues and behavioral rhythms. We discuss the relationship between molecular, electrical, and behavioral rhythms. We also describe how light pulses affect the SCN and analyze the efficiency of the light treatment in facilitating the adaptation of the SCN to a new time zone. Light pulses of a moderate duration and intensity reduce the recovery time after traveling east, but not west. However, long duration and high intensity of light pulses are more detrimental than beneficial for speeding up reentrainment. The results of the core-shell model are compared with experimental data and other biologically motivated models of the SCN.

Circadian disruption is pervasive in modern society and associated with increased risk of disease. Chronic jet lag paradigms are popular experimental tools aiming to emulate human circadian disruption experienced during rotating and night shift work. Chronic jet lag induces metabolic phenotypes tied to liver and systemic functions, yet lack of a clear definition for how rhythmic physiology is impaired under these conditions hinders the ability to identify the underlying molecular mechanisms. Here, we compared 2 common chronic jet lag paradigms and found that neither induced arrythmicity of the liver and each had distinct effects on rhythmicity. Instead, more frequent 8-h forward shifts of the light schedule induced more severe misalignment and non-fasted hyperglycemia. Every other day shifts eventually uncoupled behavioral and hepatic rhythms from the light cycle, reminiscent of free-running conditions. These results point to misalignment, not arrhythmicity, as the initial disturbance tied to metabolic dysfunction in environmental circadian disruption and highlight considerations for the interpretation and design of chronic jet lag studies.

Although the sensitivity of the circadian system to the characteristics of light (e.g., biological timing, intensity, duration, spectrum) has been well studied in adults, data in early childhood remain limited. Utilizing a crossover, within-subjects design, we examined differences in the circadian response to evening light exposure at two different correlated color temperatures (CCT) in preschool-aged children. Healthy, good sleeping children (n = 10, 3.0-5.9 years) completed two 10-day protocols. In each protocol, after maintaining a stable sleep schedule for 7 days, a 3-day in-home dim-light circadian assessment was performed. On the first and third evenings of the in-home protocol, dim-light melatonin onset (DLMO) was assessed. On the second evening, children received a 1-h light exposure of 20 lux from either 2700 K (low CCT) or 5000 K (high CCT) (~9 and ~16 melanopic equivalent daylight illuminance (mEDI lux), respectively) centered around their habitual bedtime. Children received the remaining light condition during their second protocol, with the order counterbalanced across participants. Salivary melatonin was collected to compute melatonin suppression and circadian phase shift resulting from each experimental light condition. Melatonin suppression across the 1-h light stimulus was significantly greater during exposure to the high CCT light (M = 56.3%, SD = 19.25%) than during the low CCT light (M = 23.90%, SD = 41.06%). Both light conditions resulted in marked delays of circadian timing, but only a small difference (d = -0.25) was observed in the delay between the 5000 K (M = 35.3 min, SD = 34.3 min) and 2700 K (M = 26.7 min, SD = 15.9 min) conditions. Together, these findings add to a growing literature demonstrating high responsivity of the circadian clock to evening light exposure in early childhood and provide preliminary evidence of melatonin suppression sensitivity to differences in light spectrum in preschool-aged children.

Cardiovascular health requires the orchestration of the daily rhythm of blood pressure (BP), which responds to changes in light exposure and dietary patterns. Whether rhythmic light and feeding can modulate daily BP rhythm directly or via modulating intrinsic core clock gene Bmal1 is unknown. Using inducible global Bmal1 knockout mice (iBmal1KO), we explored the impact of rhythmic light, rhythmic feeding, or their combination on various physiological parameters. Daily rhythms of BP, heart rate, and locomotor activity were monitored via radiotelemetry, while food intake patterns were tracked using the BioDAQ system. Respiratory exchange ratio (RER) and energy expenditure (EE) were assessed through indirect calorimetry. In addition, spectrum analysis was employed to analyze spontaneous baroreflex sensitivity and heart rate variability, and urinary norepinephrine excretion was quantified using high-performance liquid chromatography (HPLC). Neither rhythmic feeding nor rhythmic light alone was sufficient to reinstate the daily BP rhythm in arrhythmic iBmal1KO mice. However, combining the light and feeding cues in synchrony partially restored the daily BP rhythm. Interestingly, rhythmic feeding alone robustly reinstated RER and EE rhythms, even without rhythmic light. Similar to BP, the partial reinstatement of the daily rhythms in heart rate and locomotor activity was observed only when rhythmic light and feeding were applied in tandem. Rhythmic light by itself did not restore the light-dark phase difference in baroreflex sensitivity, urinary norepinephrine excretion, or the daily rhythm of heart rate variability. However, rhythmic feeding, alone or in combination with rhythmic light, successfully reinstated the light-dark phase differences in these parameters. In the absence of Bmal1, the synergy between rhythmic light and feeding can partially restore daily BP rhythm.

In both diurnal and nocturnal species, the neurons in the suprachiasmatic nucleus (SCN) generate a daily pattern in which the impulse frequency peaks at midday and is lowest during the night. This pattern, common to both day-active and night-active species, has led to the long-standing notion that their functional difference relies merely on a sign reversal in SCN output. However, recent evidence shows that the response of the SCN to the animal's physical activity is opposite in nocturnal and diurnal animals. This finding suggests the presence of additional differences in the circadian system between nocturnal and diurnal species. We therefore attempted to identify these differences in neuronal network organization using the A-B two-oscillator model, which is comprised of Poincaré like oscillators. Based on this model, we infer that in diurnal animals the feedback from physical activity acts on neuronal subpopulations in the SCN that do not receive light input; in contrast, in nocturnal animals, physical activity acts on light-receptive neurons in the SCN in order to produce high-amplitude circadian rhythms.

Environmental light conditions during development can have long-lasting effects on the physiology and behavior of an animal. Photoperiod, a clear example of environmental light conditions, is detected by and coded in the suprachiasmatic nucleus. It is therefore possible that differences observed in behavior in adulthood after exposure to different perinatal photoperiods are caused by lasting changes in the suprachiasmatic nucleus or alternatively, in other nuclei affected by perinatal photoperiod. It can then be expected that behavior with strong circadian aspects, like rest-activity and sleep, are affected by difference in photoperiod during development as well. To investigate this further, we exposed mice to different photoperiods during their development in the womb until weaning (long: 16 h of light, 8 h of darkness; short: 8 h of light, 16 h of darkness). After weaning, the animals were exposed to a 12 h:12 h light:dark cycle for at least 3 more weeks and some animals were subsequently exposed to constant darkness. We assessed their rest-activity patterns by recording voluntary locomotor activity and used EEG recordings to determine sleep architecture and electroencephalographic spectral density. Perinatal long photoperiod animals showed a shorter duration of locomotor activity than short photoperiod-developed mice in a 12:12 light-dark cycle. This difference disappeared in constant darkness. In the light phase, that is, during the day, perinatal long photoperiod mice spent less time awake and more time in NREM sleep than short photoperiod-developed mice. No effects of perinatal photoperiod were observed in the EEG spectral density or in response to sleep deprivation. We see lasting differences in behavioral locomotor activity and sleep in female and male mice after exposure to different perinatal photoperiods. We conclude that perinatal photoperiod programs a developing mammal for different external conditions and changes brain physiology, which in turn results in long-lasting, possibly even permanent, changes in the sleep and locomotor activity.

An autonomous, environmentally synchronizable circadian rhythm is a ubiquitous feature of life on Earth. In multicellular organisms, this rhythm is generated by a transcription-translation feedback loop present in nearly every cell that drives daily expression of thousands of genes in a tissue-dependent manner. Identifying the genes that are under circadian control can elucidate the mechanisms by which physiological processes are coordinated in multicellular organisms. Today, transcriptomic profiling at the single-cell level provides an unprecedented opportunity to understand the function of cell-level clocks. However, while many cycling detection algorithms have been developed to identify genes under circadian control in bulk transcriptomic data, it is not known how best to adapt these algorithms to single-cell RNA seq data. Here, we benchmark commonly used circadian detection methods on their reliability and efficiency when applied to single-cell RNA seq data. Our results provide guidance on adapting existing cycling detection methods to the single-cell domain and elucidate opportunities for more robust and efficient rhythm detection in single-cell data. We also propose a subsampling procedure combined with harmonic regression as an efficient strategy to detect circadian genes in the single-cell setting.

Mammalian circadian biologists commonly characterize the relation between circadian clocks as hierarchical, with the clock in the suprachiasmatic nucleus at the top of the hierarchy. The lineage of research since the suprachiasmatic nucleus (SCN) was first identified as the clock in mammals has challenged this perspective, revealing clocks in peripheral tissues, showing that they respond to their own zeitgebers, coordinate oscillations among themselves, and in some cases modify the behavior of the SCN. Increasingly circadian timekeepers appear to constitute a heterarchical network, with control distributed and operating along multiple pathways. One reason for the continued invocation of hierarchy in mammalian circadian biology is that it is difficult to understand how a heterarchical system could operate effectively so as to maintain the organism. Evolved mechanisms, however, need not respect hierarchy and those that have survived have demonstrated the ability of heterarchical organizaton to maintain organisms.