Author Correction: The choroid plexus is an important circadian clock component.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Co-existing feedback loops generate tissue-specific circadian rhythms.

Gene regulatory feedback loops generate autonomous circadian rhythms in mammalian tissues. The well-studied core clock network contains many negative and positive regulations. Multiple feedback loops have been discussed as primary rhythm generators but the design principles of the core clock and differences between tissues are still under debate. Here we use global optimization techniques to fit mathematical models to circadian gene expression profiles for different mammalian tissues. It turns out that for every investigated tissue multiple model parameter sets reproduce the experimental data. We extract for all model versions the most essential feedback loops and find auto-inhibitions of period and cryptochrome genes, Bmal1-Rev-erb-α loops, and repressilator motifs as possible rhythm generators. Interestingly, the essential feedback loops differ between tissues, pointing to specific design principles within the hierarchy of mammalian tissue clocks. Self-inhibitions of Per and Cry genes are characteristic for models of suprachiasmatic nucleus clocks, whereas in liver models many loops act in synergy and are connected by a repressilator motif. Tissue-specific use of a network of co-existing synergistic feedback loops could account for functional differences between organs.

The choroid plexus is an important circadian clock component.

Mammalian circadian clocks have a hierarchical organization, governed by the suprachiasmatic nucleus (SCN) in the hypothalamus. The brain itself contains multiple loci that maintain autonomous circadian rhythmicity, but the contribution of the non-SCN clocks to this hierarchy remains unclear. We examine circadian oscillations of clock gene expression in various brain loci and discovered that in mouse, robust, higher amplitude, relatively faster oscillations occur in the choroid plexus (CP) compared to the SCN. Our computational analysis and modeling show that the CP achieves these properties by synchronization of "twist" circadian oscillators via gap-junctional connections. Using an in vitro tissue coculture model and in vivo targeted deletion of the Bmal1 gene to silence the CP circadian clock, we demonstrate that the CP clock adjusts the SCN clock likely via circulation of cerebrospinal fluid, thus finely tuning behavioral circadian rhythms.

Moran's I quantifies spatio-temporal pattern formation in neural imaging data.

MOTIVATION: Neural activities of the brain occur through the formation of spatio-temporal patterns. In recent years, macroscopic neural imaging techniques have produced a large body of data on these patterned activities, yet a numerical measure of spatio-temporal coherence has often been reduced to the global order parameter, which does not uncover the degree of spatial correlation. Here, we propose to use the spatial autocorrelation measure Moran's I, which can be applied to capture dynamic signatures of spatial organization. We demonstrate the application of this technique to collective cellular circadian clock activities measured in the small network of the suprachiasmatic nucleus (SCN) in the hypothalamus. RESULTS: We found that Moran's I is a practical quantitative measure of the degree of spatial coherence in neural imaging data. Initially developed with a geographical context in mind, Moran's I accounts for the spatial organization of any interacting units. Moran's I can be modified in accordance with the characteristic length scale of a neural activity pattern. It allows a quantification of statistical significance levels for the observed patterns. We describe the technique applied to synthetic datasets and various experimental imaging time-series from cultured SCN explants. It is demonstrated that major characteristics of the collective state can be described by Moran's I and the traditional Kuramoto order parameter R in a complementary fashion. AVAILABILITY AND IMPLEMENTATION: Python 2.7 code of illustrative examples can be found in the Supplementary Material. CONTACT: christoph.schmal@charite.de or grigory.bordyugov@hu-berlin.de. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Corrigendum: A Theoretical Study on Seasonality.

[This corrects the article on p. 94 in vol. 6, PMID: 25999912.].

Tuning the phase of circadian entrainment.

The circadian clock coordinates daily physiological, metabolic and behavioural rhythms. These endogenous oscillations are synchronized with external cues ('zeitgebers'), such as daily light and temperature cycles. When the circadian clock is entrained by a zeitgeber, the phase difference ψ between the phase of a clock-controlled rhythm and the phase of the zeitgeber is of fundamental importance for the fitness of the organism. The phase of entrainment ψ depends on the mismatch between the intrinsic period τ and the zeitgeber period T and on the ratio of the zeitgeber strength to oscillator amplitude. Motivated by the intriguing complexity of empirical data and by our own experiments on temperature entrainment of mouse suprachiasmatic nucleus (SCN) slices, we present a theory on how clock and zeitgeber properties determine the phase of entrainment. The wide applicability of the theory is demonstrated using mathematical models of different complexity as well as by experimental data. Predictions of the theory are confirmed by published data on Neurospora crassa strains for different period mismatches τ - T and varying photoperiods. We apply a novel regression technique to analyse entrainment of SCN slices by temperature cycles. We find that mathematical models can explain not only the stable asymptotic phase of entrainment, but also transient phase dynamics. Our theory provides the potential to explore seasonal variations of circadian rhythms, jet lag and shift work in forthcoming studies.

A theoretical study on seasonality.

In addition to being endogenous, a circadian system must be able to communicate with the outside world and align its rhythmicity to the environment. As a result of such alignment, external Zeitgebers can entrain the circadian system. Entrainment expresses itself in coinciding periods of the circadian oscillator and the Zeitgeber and a stationary phase difference between them. The range of period mismatches between the circadian system and the Zeitgeber that Zeitgeber can overcome to entrain the oscillator is called an entrainment range. The width of the entrainment range usually increases with increasing Zeitgeber strength, resulting in a wedge-like Arnold tongue. This classical view of entrainment does not account for the effects of photoperiod on entrainment. Zeitgebers with extremely small or large photoperiods are intuitively closer to constant environments than equinoctial Zeitgebers and hence are expected to produce a narrower entrainment range. In this paper, we present theoretical results on entrainment under different photoperiods. We find that in the photoperiod-detuning parameter plane, the entrainment zone is shaped in the form of a skewed onion. The bottom and upper points of the onion are given by the free-running periods in DD and LL, respectively. The widest entrainment range is found near photoperiods of 50%. Within the onion, we calculated the entrainment phase that varies over a range of 12 h. The results of our theoretical study explain the experimentally observed behavior of the entrainment phase in dependence on the photoperiod.

Timing of circadian genes in mammalian tissues.

Circadian clocks are endogenous oscillators driving daily rhythms in physiology. The cell-autonomous clock is governed by an interlocked network of transcriptional feedback loops. Hundreds of clock-controlled genes (CCGs) regulate tissue specific functions. Transcriptome studies reveal that different organs (e.g. liver, heart, adrenal gland) feature substantially varying sets of CCGs with different peak phase distributions. To study the phase variability of CCGs in mammalian peripheral tissues, we develop a core clock model for mouse liver and adrenal gland based on expression profiles and known cis-regulatory sites. 'Modulation factors' associated with E-boxes, ROR-elements, and D-boxes can explain variable rhythms of CCGs, which is demonstrated for differential regulation of cytochromes P450 and 12 h harmonics. By varying model parameters we explore how tissue-specific peak phase distributions can be generated. The central role of E-boxes and ROR-elements is confirmed by analysing ChIP-seq data of BMAL1 and REV-ERB transcription factors.

Human chronotypes from a theoretical perspective.

The endogenous circadian timing system has evolved to synchronize an organism to periodically recurring environmental conditions. Those external time cues are called Zeitgebers. When entrained by a Zeitgeber, the intrinsic oscillator adopts a fixed phase relation ψ to the Zeitgeber. Here, we systematically study how the phase of entrainment depends on clock and Zeitgeber properties. We combine numerical simulations of amplitude-phase models with predictions from analytically tractable models. In this way we derive relations between the phase of entrainment ψ to the mismatch between the endogenous and Zeitgeber period, the Zeitgeber strength, and the range of entrainment. A core result is the "180° rule" asserting that the phase ψ varies over a range of about 180° within the entrainment range. The 180° rule implies that clocks with a narrow entrainment range ("strong oscillators") exhibit quite flexible entrainment phases. We argue that this high sensitivity of the entrainment phase contributes to the wide range of human chronotypes.

The interplay of cis-regulatory elements rules circadian rhythms in mouse liver.

The mammalian circadian clock is driven by cell-autonomous transcriptional feedback loops that involve E-boxes, D-boxes, and ROR-elements. In peripheral organs, circadian rhythms are additionally affected by systemic factors. We show that intrinsic combinatorial gene regulation governs the liver clock. With a temporal resolution of 2 h, we measured the expression of 21 clock genes in mouse liver under constant darkness and equinoctial light-dark cycles. Based on these data and known transcription factor binding sites, we develop a six-variable gene regulatory network. The transcriptional feedback loops are represented by equations with time-delayed variables, which substantially simplifies modelling of intermediate protein dynamics. Our model accurately reproduces measured phases, amplitudes, and waveforms of clock genes. Analysis of the network reveals properties of the clock: overcritical delays generate oscillations; synergy of inhibition and activation enhances amplitudes; and combinatorial modulation of transcription controls the phases. The agreement of measurements and simulations suggests that the intrinsic gene regulatory network primarily determines the circadian clock in liver, whereas systemic cues such as light-dark cycles serve to fine-tune the rhythms.

Self-emerging and turbulent chimeras in oscillator chains.

We report on a self-emerging chimera state in a homogeneous chain of nonlocally and nonlinearly coupled oscillators. This chimera, i.e., a state with coexisting regions of complete and partial synchrony, emerges via a supercritical bifurcation from a homogeneous state. We develop a theory of chimera based on the Ott-Antonsen equations for the local complex order parameter. Applying a numerical linear stability analysis, we also describe the instability of the chimera and transition to phase turbulence with persistent patches of synchrony.

Anomalous pulse interaction in dissipative media.

We review a number of phenomena occurring in one-dimensional excitable media due to modified decay behind propagating pulses. Those phenomena can be grouped in two categories depending on whether the wake of a solitary pulse is oscillatory or not. Oscillatory decay leads to nonannihilative head-on collision of pulses and oscillatory dispersion relation of periodic pulse trains. Stronger wake oscillations can even result in a bistable dispersion relation. Those effects are illustrated with the help of the Oregonator and FitzHugh-Nagumo models for excitable media. For a monotonic wake, we show that it is possible to induce bound states of solitary pulses and anomalous dispersion of periodic pulse trains by introducing nonlocal spatial coupling to the excitable medium.

Wave trains in an excitable FitzHugh-Nagumo model: bistable dispersion relation and formation of isolas.

We investigate the dispersion relations of nonlinear periodic wave trains in excitable systems which describe the dependence of the propagation velocity on the wavelength. Pulse interaction by oscillating pulse tails within a wave train leads to bistable wavelength bands, in which two stable and one unstable wave train coexist for the same wavelength. The essential spectra of the unstable wave trains exhibit a circle of eigenvalues with positive real parts which is detached from the imaginary axis. We describe the destruction of the bistable dispersion curve and the formation of isolas of wave trains in a sequence of transcritical bifurcations unfolding into pairs of saddle-node bifurcations. It turns out that additional dispersion curves of unstable wave trains play an important role in the destruction of the bistable dispersion curve.

Creating bound states in excitable media by means of nonlocal coupling.

We consider pulses of excitation in reaction-diffusion systems subjected to nonlocal coupling. This coupling represents long-range connections between the elements of the medium; the connection strength decays exponentially with the distance. Without coupling, pulses interact only repulsively and bound states with two or more pulses propagating at the same velocity are impossible. Upon switching on nonlocal coupling, pulses begin to interact attractively and form bound states. First we present numerical results on the emergence of bound states in the excitable Oregonator model for the photosensitive Belousov-Zhabotinsky reaction with nonlocal coupling. Then we show that the appearance of bound states is provided solely by the exponential decay of nonlocal coupling and thus can be found in a wide class of excitable systems, regardless of the particular kinetics. The theoretical explanation of the emergence of bound states is based on the bifurcation analysis of the profile equations that describe the spatial shape of pulses. The central object is a codimension-4 homoclinic orbit which exists for zero coupling strength. The emergence of bound states is described by the bifurcation to 2-homoclinic solutions from the codimension-4 homoclinic orbit upon switching on nonlocal coupling. We stress that the high codimension of the bifurcation to bound states is generic, provided that the coupling range is sufficiently large.