An official website of the United States government
The circadian clock in mammals regulates the sleep/wake cycle and many associated behavioral and physiological processes. The cellular clock mechanism involves a transcriptional negative feedback loop that gives rise to circadian rhythms in gene expression with an approximately 24-hour periodicity. To maintain system robustness, clocks throughout the body must be synchronized and their functions coordinated. In mammals, the master clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is entrained to the light/dark cycle through photic signal transduction and subsequent induction of core clock gene expression. The SCN in turn relays the time-of-day information to clocks in peripheral tissues. While the SCN is highly responsive to photic cues, peripheral clocks are more sensitive to non-photic resetting cues such as nutrients, body temperature, and neuroendocrine hormones. For example, feeding/fasting and physical activity can entrain peripheral clocks through signaling pathways and subsequent regulation of core clock genes and proteins. As such, timing of food intake and physical activity matters. In an ideal world, the sleep/wake and feeding/fasting cycles are synchronized to the light/dark cycle. However, asynchronous environmental cues, such as those experienced by shift workers and frequent travelers, often lead to misalignment between the master and peripheral clocks. Emerging evidence suggests that the resulting circadian disruption is associated with various diseases and chronic conditions that further circadian desynchrony and accelerate disease progression. In this review, we discuss how sleep, nutrition, and physical activity synchronize circadian clocks and how chronomedicine may offer novel strategies for disease intervention.
more »
« less
What is phase in cellular clocks
Four inter-related measures of phase are described to study the phase synchronization of cellular oscillators, and computation of these measures is described and illustrated on single cell fluorescence data from the model filamentous fungus, Neurospora crassa. One of these four measures is the phase shift ϕ in a sinusoid of the form x(t) = A(cos(ωt + ϕ), where t is time. The other measures arise by creating a replica of the periodic process x(t) called the Hilbert transform x̃(t), which is 90 degrees out of phase with the original process x(t). The second phase measure is the phase angle FH(t) between the replica x̃(t) and X(t), taking values between -π and π. At extreme values the Hilbert Phase is discontinuous, and a continuous form FC(t) of the Hilbert Phase is used, measuring time on the nonnegative real axis (t). The continuous Hilbert Phase FC(t) is used to define the phase MC(t1,t0) for an experiment beginning at time t0 and ending at time t1. In that phase differences at time t0 are often of ancillary interest, the Hilbert Phase FC(t0) is subtracted from FC(t1). This difference is divided by 2π to obtain the phase MC(t1,t0) in cycles. Both the Hilbert Phase FC(t) and the phase MC(t1,t0) are functions of time and useful in studying when oscillators phase-synchronize in time in signal processing and circadian rhythms in particular. The phase of cellular clocks is fundamentally different from circadian clocks at the macroscopic scale because there is an hourly cycle superimposed on the circadian cycle.
more »
« less
- Award ID(s):
- 1713746
- PAR ID:
- 10100618
- Date Published:
- Journal Name:
- The Yale journal of biology & medicine
- Volume:
- 92
- ISSN:
- 0044-0086
- Page Range / eLocation ID:
- 169-178
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Most eukaryotes and cyanobacterial species have a biological clock that allows adaptation to the daily light/dark cycle of the planet. A central problem in the study of the biological clock is understanding the synchro-nization of the stochastic oscillators in different cells and tissues, but this problem is largely unstudied, particularly in the context of circadian rhythms. We developed a novel microfluidic platform to make high-throughput and high-precision measurements of biological clocks on a controlled number of Neurospora crassa (N. crassa) cells. Single cell measurements in this platform enabled us to test whether clocks of individual cells are able to communicate.more » « less
-
Circadian rhythms are internal processes repeating approximately every 24 hours in living organisms. The dominant circadian pacemaker is synchronized to the environmental light-dark cycle. Other circadian pacemakers, which can have noncanonical circadian mechanisms, are revealed by arousing stimuli, such as scheduled feeding, palatable meals and running wheel access, or methamphetamine administration. Organisms also have ultradian rhythms, which have periods shorter than circadian rhythms. However, the biological mechanism, origin, and functional significance of ultradian rhythms are not well-elucidated. The dominant circadian rhythm often masks ultradian rhythms; therefore, we disabled the canonical circadian clock of mice by knocking out Per1/2/3 genes, where Per1 and Per2 are essential components of the mammalian light-sensitive circadian mechanism. Furthermore, we recorded wheel-running activity every minute under constant darkness for 272 days. We then investigated rhythmic components in the absence of external influences, applying unique multiscale time-resolved methods to analyze the oscillatory dynamics with time-varying frequencies. We found four rhythmic components with periods of ∼17 h, ∼8 h, ∼4 h, and ∼20 min. When the ∼17-h rhythm was prominent, the ∼8-h rhythm was of low amplitude. This phenomenon occurred periodically approximately every 2-3 weeks. We found that the ∼4-h and ∼20-min rhythms were harmonics of the ∼8-h rhythm. Coupling analysis of the ridge-extracted instantaneous frequencies revealed strong and stable phase coupling from the slower oscillations (∼17, ∼8, and ∼4 h) to the faster oscillations (∼20 min), and weak and less stable phase coupling in the reverse direction and between the slower oscillations. Together, this study elucidated the relationship between the oscillators in the absence of the canonical circadian clock, which is critical for understanding their functional significance. These studies are essential as disruption of circadian rhythms contributes to diseases, such as cancer and obesity, as well as mood disorders.more » « less
-
Abstract As the circadian clock regulates fundamental biological processes, disrupted clocks are often observed in patients and diseased tissues. Determining the circadian time of the patient or the tissue of focus is essential in circadian medicine and research. Here we present tauFisher, a computational pipeline that accurately predicts circadian time from a single transcriptomic sample by finding correlations between rhythmic genes within the sample. We demonstrate tauFisher’s performance in adding timestamps to both bulk and single-cell transcriptomic samples collected from multiple tissue types and experimental settings. Application of tauFisher at a cell-type level in a single-cell RNAseq dataset collected from mouse dermal skin implies that greater circadian phase heterogeneity may explain the dampened rhythm of collective core clock gene expression in dermal immune cells compared to dermal fibroblasts. Given its robustness and generalizability across assay platforms, experimental setups, and tissue types, as well as its potential application in single-cell RNAseq data analysis, tauFisher is a promising tool that facilitates circadian medicine and research.more » « less
-
Most aspects of physiology and behaviour fluctuate every 24 h in mammals. These circadian rhythms are orchestrated by an autonomous central clock located in the suprachiasmatic nuclei that coordinates the timing of cellular clocks in tissues throughout the body. The critical role of this circadian system is emphasized by increasing evidence associating disruption of circadian rhythms with diverse pathologies. Accordingly, mounting evidence suggests a bidirectional relationship where disruption of rhythms by circadian misalignment may contribute to liver diseases while liver diseases alter the central clock and circadian rhythms in other tissues. Therefore, liver pathophysiology may broadly impact the circadian system and may provide a mechanistic framework for understanding and targeting metabolic diseases and adjust metabolic setpoints.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- The DOI is not currently available.
