Journal of Biological Rhythms最新文献

Sex hormones are well known to modulate circadian timekeeping as well as the behavioral and physiological responses to circadian disruption. Gonadectomy, reducing the amount of circulating gonadal hormones, in males and females produces alterations to the free-running rhythm and the responses to light exposure by the central oscillator of the suprachiasmatic nucleus (SCN). In this study, we tested whether estradiol plays a role in regulating the circadian responses to acute (light pulses) and chronic light exposure (constant light [LL] vs standard light:dark [LD] cycle) in female C57BL6/NJ mice. Mice were either ovariectomized or given sham surgery and given a placebo (P) or estradiol (E) pellet for hormone replacement so that there were 6 groups: (1) LD/Sham, (2) LL/Sham, (3) LD/OVX + P, (4) LL/OVX + P, (5) LD/OVX + E, and (6) LL/OVX + E. After 65 days of light cycle exposure, blood and SCNs were removed and serum estradiol plus SCN estradiol receptor alpha (ERα) and estradiol receptor beta (ERβ) were measured via ELISA. The OVX + P mice exhibited shorter circadian periods and were more likely to become arrhythmic in LL compared with mice with intact estradiol (sham or E replacement mice). The OVX + P mice exhibited reduced circadian robustness (power) and reduced circadian locomotor activity in both LD and LL compared with sham controls or OVX + E mice. The OVX + P mice also exhibited later activity onsets in LD and attenuated phase delays, but not advances, when given a 15-min light pulse compared with estradiol intact mice. LL led to reductions in ERβ, but not ERα, regardless of the surgery type. These results indicate that estradiol can modulate the effects of light on the circadian timing system and that estradiol can enhance responses to light exposure and provide protection against a loss of circadian robustness.

Under conditions of prolonged durations of warmth, flies counter potential temperature stress by shifting their locomotor activity from day into night when the conditions are likely to be less harsh. Modulation of a rhythmic behavior such as this in response to the environment would require interaction between at least 2 neuronal systems: (1) a sensory system to receive input from the environment, and (2) the internal clock to correctly time rhythmic activity in response to this thermosensory input. Our previous studies found that a thermosensory mutant of the ion channel Drosophila Transient Receptor Potential-A1 (dTRPA1) failed to shift activity into the dark like control flies do and also identified the role of a specific cluster of the dTRPA1-expressing neurons, the dTRPA1^sh+neurons necessary for this. In this study, we extended our previous findings and characterized the identity of these dTRPA1^sh+ neurons based on their overlap with circadian neurons. Utilizing various genetic manipulations, we asked whether the overlapping neurons could be potential points of intersection between the 2 circuits that modulate behavior under warm temperature, meaning whether they function as both-sensory and clock neurons. We found that the molecular clock within the dTRPA1^sh+ cluster was not necessary, but the expression of dTRPA1 in a subset of circadian neurons, the small ventrolateral neurons (sLNvs), was necessary in modulating phasing of behavior under warm temperature. Furthermore, attempting to identify the neuronal circuit, we were able to uncover the potential roles of serotonin and acetylcholine in modulating this temperature-dependent behavior. Finally, we also discuss possible parallel neuronal pathways that may exist to give rise to this modulation of behavior under warm temperature, thereby supporting and expanding the knowledge of the field about circuits that control temperature-mediated behavioral outcomes.

Key differences exist between individuals in terms of certain circadian-related parameters, such as intrinsic period and sensitivity to light. These variations can differentially impact circadian timing, leading to challenges in accurately implementing time-sensitive interventions. In this work, we parse out these effects by investigating the impact of parameters from a macroscopic model of human circadian rhythms on phase and amplitude outputs. Using in silico light data designed to mimic commonly studied schedules, we assess the impact of parameter variations on model outputs to gain insight into the different effects of these schedules. We show that parameter sensitivity is heavily modulated by the lighting routine that a person follows, with darkness and shift work schedules being the most sensitive. We develop a framework to measure overall sensitivity levels of the given light schedule and furthermore decompose the overall sensitivity into individual parameter contributions. Finally, we measure the ability of the model to extract parameters given light schedules with noise and show that key parameters like the circadian period can typically be recovered given known light history. This can inform future work on determining the key parameters to consider when personalizing a model and the lighting protocols to use when assessing interindividual variability.

Late chronotype, which often leads to higher social jetlag (SJL), is strongly associated with the prevalence of smoking. Any circadian disruption, strain, or misalignment, results in people not being able to live according to their biological time as is described by SJL, which we will therefore use as umbrella term. We hypothesized two scenarios potentially explaining the association between smoking and SJL: (A) If smoking delays the clock, circadian phase should advance upon quitting. (B) If people smoke more to compensate the consequences of SJL, circadian phase should not change upon quitting. To distinguish between these two hypotheses, we accompanied participants of a smoking cessation program (not involving nicotine replacement products) across the cessation intervention (3 weeks prior and 6 weeks after) by monitoring their circadian behavior, sleep quality, and daytime sleepiness via questionnaires and actimetry. Our results show no effects of cessation on SJL, chronotype, sleep quality, or daytime sleepiness, thereby favoring scenario (B). Thus, smoking may be a consequence of rather than a cause for SJL. Daytime sleepiness was a significant predictor for the outcome in our model but did not improve with cessation.

Temperature influences animal physiology and behavior. Animals must set an appropriate body temperature to maintain homeostasis and maximize survival. Mammals set their body temperatures using metabolic and behavioral strategies. The daily fluctuation in body temperature is called the body temperature rhythm (BTR). For example, human body temperature increases during wakefulness and decreases during sleep. BTR is controlled by the circadian clock, is closely linked with metabolism and sleep, and entrains peripheral clocks located in the liver and lungs. However, the underlying mechanisms of BTR are largely unclear. In contrast to mammals, small ectotherms, such as Drosophila, control their body temperatures by choosing appropriate environmental temperatures. The preferred temperature of Drosophila increases during the day and decreases at night; this pattern is referred to as the temperature preference rhythm (TPR). As flies are small ectotherms, their body temperature is close to that of the surrounding environment. Thus, Drosophila TPR produces BTR, which exhibits a pattern similar to that of human BTR. In this review, we summarize the regulatory mechanisms of TPR, including recent studies that describe neuronal circuits relaying ambient temperature information to dorsal neurons (DNs). The neuropeptide diuretic hormone 31 (DH31) and its receptor (DH31R) regulate TPR, and a mammalian homolog of DH31R, the calcitonin receptor (CALCR), also plays an important role in mouse BTR regulation. In addition, both fly TPR and mammalian BTR are separately regulated from another clock output, locomotor activity rhythms. These findings suggest that the fundamental mechanisms of BTR regulation may be conserved between mammals and flies. Furthermore, we discuss the relationships between TPR and other physiological functions, such as sleep. The dissection of the regulatory mechanisms of Drosophila TPR could facilitate an understanding of mammalian BTR and the interaction between BTR and sleep regulation.

Beyond visual perception, light has non-image-forming effects mediated by melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). The present study first used multielectrode array recordings to show that in a diurnal rodent, Nile grass rats (Arvicanthis niloticus), ipRGCs generate rod/cone-driven and melanopsin-based photoresponses that stably encode irradiance. Subsequently, two ipRGC-mediated non-image-forming effects, namely entrainment of daily rhythms and light-induced arousal, were examined. Animals were first housed under a 12:12 h light/dark cycle (lights-on at 0600 h) with the light phase generated by a low-irradiance fluorescent light (F12), a daylight spectrum (D65) stimulating all photoreceptors, or a narrowband 480 nm spectrum (480) that maximized melanopsin stimulation and minimized S-cone stimulation (λ_max 360 nm) compared to D65. Daily rhythms of locomotor activities showed onset and offset closer to lights-on and lights-off, respectively, in D65 and 480 than in F12, and higher day/night activity ratio under D65 versus 480 and F12, suggesting the importance of S-cone stimulation. To assess light-induced arousal, 3-h light exposures using 4 spectra that stimulated melanopsin equally but S-cones differentially were superimposed on F12 background lighting: D65, 480, 480 + 365 (narrowband 365 nm), and D65 - 365. Compared to the F12-only condition, all four pulses increased in-cage activity and promoted wakefulness, with 480 + 365 having the greatest and longest-lasting wakefulness-promoting effects, again indicating the importance of stimulating S-cones as well as melanopsin. These findings provide insights into the temporal dynamics of photoreceptor contributions to non-image-forming photoresponses in a diurnal rodent that may help guide future studies of lighting environments and phototherapy protocols that promote human health and productivity.

The ability of flatworms to regenerate entire brain structures, and indeed much of their body from mere fragments of the whole animal, presents the unique opportunity to observe the development of day-night rhythms in adult animals. In many animals, young are arrhythmic, and their species-specific timing of activity develops as the animal matures. In this study, we created two flatworm cohorts, housed in isolation, that were regenerating either (1) the brain in a decapitated animal, or (2) major body structures in a bisected, tailless animal. In this way, we observed how bisection influenced the level of activity and diel rhythmicity, and how these developed as each flatworm regenerated. Here, we demonstrate that intact flatworms were predominantly active at night, with peaks in activity seen in the hours after lights-off and before lights-on. While decapitated and tailless flatworms could still move, both were less active than the original animal, and both segments retained a nocturnal lifestyle. Furthermore, decapitated flatworms, once regenerated, again showed a U-shaped pattern of nocturnal activity reminiscent of the two night-time peaks seen in the original animal. These results could be used to further investigate how regeneration may affect motor control and motor output, or to further investigate the presence of a clock in the flatworm brain.

Circadian misalignment occurs with age, jet lag, and shift work, leading to maladaptive health outcomes including cardiovascular diseases. Despite the strong link between circadian disruption and heart disease, the cardiac circadian clock is poorly understood, prohibiting identification of therapies to restore the broken clock. Exercise is the most cardioprotective intervention identified to date and has been suggested to reset the circadian clock in other peripheral tissues. Here, we tested the hypothesis that conditional deletion of core circadian gene Bmal1 would disrupt cardiac circadian rhythm and function and that this disruption would be ameliorated by exercise. To test this hypothesis, we generated a transgenic mouse with spatial and temporal deletion of Bmal1 only in adult cardiac myocytes (Bmal1 cardiac knockout [cKO]). Bmal1 cKO mice demonstrated cardiac hypertrophy and fibrosis concomitant with impaired systolic function. This pathological cardiac remodeling was not rescued by wheel running. While the molecular mechanisms responsible for the profound cardiac remodeling are unclear, it does not appear to involve activation of the mammalian target of rapamycin (mTOR) signaling or changes in metabolic gene expression. Interestingly, cardiac deletion of Bmal1 disrupted systemic rhythms as evidenced by changes in the onset and phasing of activity in relationship to the light/dark cycle and by decreased periodogram power as measured by core temperature, suggesting cardiac clocks can regulate systemic circadian output. Together, we suggest a critical role for cardiac Bmal1 in regulating both cardiac and systemic circadian rhythm and function. Ongoing experiments will determine how disruption of the circadian clock causes cardiac remodeling in an effort to identify therapeutics to attenuate the maladaptive outcomes of a broken cardiac circadian clock.

The circadian clock of Neurospora crassa is based on a negative transcriptional/translational feedback loops. The frequency (frq) gene controls the morning-specific rhythmic transcription of a sense RNA encoding FRQ, the negative element of the core circadian feedback loop. In addition, a long noncoding antisense RNA, qrf, is rhythmically transcribed in an evening-specific manner. It has been reported that the qrf rhythm relies on transcriptional interference with frq transcription and that complete suppression of qrf transcription impairs the circadian clock. We show here that qrf transcription is dispensable for circadian clock function. Rather, the evening-specific transcriptional rhythm of qrf is mediated by the morning-specific repressor CSP-1. Since CSP-1 expression is induced by light and glucose, this suggests a rhythmic coordination of qrf transcription with metabolism. However, a possible physiological significance for the circadian clock remains unclear, as suitable assays are not available.