Morphogen-directed cell fate boundaries: slow passage through bifurcation and the role of folded saddles.

One of the fundamental mechanisms in embryogenesis is the process by which cells differentiate and create tissues and structures important for functioning as a multicellular organism. Morphogenesis involves diffusive process of chemical signalling involving morphogens that pre-pattern the tissue. These morphogens influence cell fate through a highly nonlinear process of transcriptional signalling. In this paper, we consider this multiscale process in an idealised model for a growing domain. We focus on intracellular processes that lead to robust differentiation into two cell lineages through interaction of a single morphogen species with a cell fate variable that undergoes a bifurcation from monostability to bistability. In particular, we investigate conditions that result in successful and robust pattern formation into two well-separated domains, as well as conditions where this fails and produces a pinned boundary wave where only one part of the domain grows. We show that successful and unsuccessful patterning scenarios can be characterised in terms of presence or absence of a folded saddle singularity for a system with two slow variables and one fast variable; this models the interaction of slow morphogen diffusion, slow parameter drift through bifurcation and fast transcription dynamics. We illustrate how this approach can successfully model acquisition of three cell fates to produce three-domain "French flag" patterning, as well as for a more realistic model of the cell fate dynamics in terms of two mutually inhibiting transcription factors.

Modelling the motion of organelles in an elongated cell via the coordination of heterogeneous drift-diffusion and long-range transport.

 Cellular distribution of organelles in living cells is achieved via a variety of transport mechanisms, including directed motion, mediated by molecular motors along microtubules (MTs), and diffusion which is predominantly heterogeneous in space. In this paper, we introduce a model for particle transport in elongated cells that couples poleward drift, long-range bidirectional transport and diffusion with spatial heterogeneity in a three-dimensional space. Using stochastic simulations and analysis of a related population model, we find parameter regions where the three-dimensional model can be reduced to a coupled one-dimensional model or even a one-dimensional scalar model. We explore the efficiency with which individual model components can overcome drift towards one of the cell poles to reach an approximately even distribution. In particular, we find that if lateral movement is well mixed, then increasing the binding ability of particles to MTs is an efficient way to overcome a poleward drift, whereas if lateral motion is not well mixed, then increasing the axial diffusivity away from MTs becomes an efficient way to overcome the poleward drift. Our three-dimensional model provides a new tool that will help to understand the mechanisms by which eukaryotic cells organize their organelles in an elongated cell, and in particular when the one-dimensional models are applicable.

Excitable networks for finite state computation with continuous time recurrent neural networks.

Continuous time recurrent neural networks (CTRNN) are systems of coupled ordinary differential equations that are simple enough to be insightful for describing learning and computation, from both biological and machine learning viewpoints. We describe a direct constructive method of realising finite state input-dependent computations on an arbitrary directed graph. The constructed system has an excitable network attractor whose dynamics we illustrate with a number of examples. The resulting CTRNN has intermittent dynamics: trajectories spend long periods of time close to steady-state, with rapid transitions between states. Depending on parameters, transitions between states can either be excitable (inputs or noise needs to exceed a threshold to induce the transition), or spontaneous (transitions occur without input or noise). In the excitable case, we show the threshold for excitability can be made arbitrarily sensitive.

Dead zones and phase reduction of coupled oscillators.

A dead zone in the interaction between two dynamical systems is a region of their joint phase space where one system is insensitive to the changes in the other. These can arise in a number of contexts, and their presence in phase interaction functions has interesting dynamical consequences for the emergent dynamics. In this paper, we consider dead zones in the interaction of general coupled dynamical systems. For weakly coupled limit cycle oscillators, we investigate criteria that give rise to dead zones in the phase interaction functions. We give applications to coupled multiscale oscillators where coupling on only one branch of a relaxation oscillation can lead to the appearance of dead zones in a phase description of their interaction.

State-dependent effective interactions in oscillator networks through coupling functions with dead zones.

The dynamics of networks of interacting dynamical systems depend on the nature of the coupling between individual units. We explore networks of oscillatory units with coupling functions that have 'dead zones', that is the coupling functions are zero on sets with interior. For such networks, it is convenient to look at the effective interactions between units rather than the (fixed) structural connectivity to understand the network dynamics. For example, oscillators may effectively decouple in particular phase configurations. Along trajectories, the effective interactions are not necessarily static, but the effective coupling may evolve in time. Here, we formalize the concepts of dead zones and effective interactions. We elucidate how the coupling function shapes the possible effective interaction schemes and how they evolve in time. This article is part of the theme issue 'Coupling functions: dynamical interaction mechanisms in the physical, biological and social sciences'.

Existence and stability of chimera states in a minimal system of phase oscillators.

We examine partial frequency locked weak chimera states in a network of six identical and indistinguishable phase oscillators with neighbour and next-neighbour coupling and two harmonic coupling of the form g ( ϕ ) = - sin ⁡ ( ϕ - α ) + r sin ⁡ 2 ϕ . We limit to a specific partial cluster subspace, reduce to a two dimensional system in terms of phase differences, and show that this has an integral of motion for α = π / 2 and r = 0 . By careful analysis of the phase space, we show that there is a continuum of neutrally stable weak chimera states in this case. We approximate the Poincaré return map for these weak chimera solutions and demonstrate several results about the stability and bifurcation of weak chimeras for small ß = π / 2 - α and r that agree with numerical path-following of the solutions.

Rate-induced tipping from periodic attractors: Partial tipping and connecting orbits.

We consider how breakdown of the quasistatic approximation for attractors can lead to rate-induced tipping, where a qualitative change in tracking/tipping behaviour of trajectories can be characterised in terms of a critical rate. Associated with rate-induced tipping (where tracking of a branch of quasistatic attractors breaks down), we find a new phenomenon for attractors that are not simply equilibria: partial tipping of the pullback attractor where certain phases of the periodic attractor tip and others track the quasistatic attractor. For a specific model system with a parameter shift between two asymptotically autonomous systems with periodic attractors, we characterise thresholds of rate-induced tipping to partial and total tipping. We show these thresholds can be found in terms of certain periodic-to-periodic and periodic-to-equilibrium connections that we determine using Lin's method for an augmented system.

Modeling Endoplasmic Reticulum Network Maintenance in a Plant Cell.

The endoplasmic reticulum (ER) in plant cells forms a highly dynamic network of complex geometry. ER network morphology and dynamics are influenced by a number of biophysical processes, including filament/tubule tension, viscous forces, Brownian diffusion, and interactions with many other organelles and cytoskeletal elements. Previous studies have indicated that ER networks can be thought of as constrained minimal-length networks acted on by a variety of forces that perturb and/or remodel the network. Here, we study two specific biophysical processes involved in remodeling. One is the dynamic relaxation process involving a combination of tubule tension and viscous forces. The other is the rapid creation of cross-connection tubules by direct or indirect interactions with cytoskeletal elements. These processes are able to remodel the ER network: the first reduces network length and complexity whereas the second increases both. Using live cell imaging of ER network dynamics in tobacco leaf epidermal cells, we examine these processes on ER network dynamics. Away from regions of cytoplasmic streaming, we suggest that the dynamic network structure is a balance between the two processes, and we build an integrative model of the two processes for network remodeling. This model produces quantitatively similar ER networks to those observed in experiments. We use the model to explore the effect of parameter variation on statistical properties of the ER network.

Chaos in generically coupled phase oscillator networks with nonpairwise interactions.

The Kuramoto-Sakaguchi system of coupled phase oscillators, where interaction between oscillators is determined by a single harmonic of phase differences of pairs of oscillators, has very simple emergent dynamics in the case of identical oscillators that are globally coupled: there is a variational structure that means the only attractors are full synchrony (in-phase) or splay phase (rotating wave/full asynchrony) oscillations and the bifurcation between these states is highly degenerate. Here we show that nonpairwise coupling-including three and four-way interactions of the oscillator phases-that appears generically at the next order in normal-form based calculations can give rise to complex emergent dynamics in symmetric phase oscillator networks. In particular, we show that chaos can appear in the smallest possible dimension of four coupled phase oscillators for a range of parameter values.

Controlled and stochastic retention concentrates dynein at microtubule ends to keep endosomes on track.

Bidirectional transport of early endosomes (EEs) involves microtubules (MTs) and associated motors. In fungi, the dynein/dynactin motor complex concentrates in a comet-like accumulation at MT plus-ends to receive kinesin-3-delivered EEs for retrograde transport. Here, we analyse the loading of endosomes onto dynein by combining live imaging of photoactivated endosomes and fluorescent dynein with mathematical modelling. Using nuclear pores as an internal calibration standard, we show that the dynein comet consists of ∼55 dynein motors. About half of the motors are slowly turned over (T(1/2): ∼98 s) and they are kept at the plus-ends by an active retention mechanism involving an interaction between dynactin and EB1. The other half is more dynamic (T(1/2): ∼10 s) and mathematical modelling suggests that they concentrate at MT ends because of stochastic motor behaviour. When the active retention is impaired by inhibitory peptides, dynein numbers in the comet are reduced to half and ∼10% of the EEs fall off the MT plus-ends. Thus, a combination of stochastic accumulation and active retention forms the dynein comet to ensure capturing of arriving organelles by retrograde motors.

Weak chimeras in minimal networks of coupled phase oscillators.

We suggest a definition for a type of chimera state that appears in networks of indistinguishable phase oscillators. Defining a "weak chimera" as a type of invariant set showing partial frequency synchronization, we show that this means they cannot appear in phase oscillator networks that are either globally coupled or too small. We exhibit various networks of four, six, and ten indistinguishable oscillators, where weak chimeras exist with various dynamics and stabilities. We examine the role of Kuramoto-Sakaguchi coupling in giving degenerate (neutrally stable) families of weak chimera states in these example networks.

Structure and dynamics of ER: minimal networks and biophysical constraints.

The endoplasmic reticulum (ER) in live cells is a highly mobile network whose structure dynamically changes on a number of timescales. The role of such drastic changes in any system is unclear, although there are correlations with ER function. A better understanding of the fundamental biophysical constraints on the system will allow biologists to determine the effects of molecular factors on ER dynamics. Previous studies have identified potential static elements that the ER may remodel around. Here, we use these structural elements to assess biophysical principles behind the network dynamics. By analyzing imaging data of tobacco leaf epidermal cells under two different conditions, i.e., native state (control) and latrunculin B (treated), we show that the geometric structure and dynamics of ER networks can be understood in terms of minimal networks. Our results show that the ER network is well modeled as a locally minimal-length network between the static elements that potentially anchor the ER to the cell cortex over longer timescales; this network is perturbed by a mixture of random and deterministic forces. The network need not have globally minimum length; we observe cases where the local topology may change dynamically between different Euclidean Steiner network topologies. The networks in the treated cells are easier to quantify, because they are less dynamic (the treatment suppresses actin dynamics), but the same general features are found in control cells. Using a Langevin approach, we model the dynamics of the nonpersistent nodes and use this to show that the images can be used to estimate both local viscoelastic behavior of the cytoplasm and filament tension in the ER network. This means we can explain several aspects of the ER geometry in terms of biophysical principles.

Network attractors and nonlinear dynamics of neural computation.

The importance of understanding the nonlinear dynamics of neural systems, and the relation to cognitive systems more generally, has been recognised for a long time. Approaches that analyse neural systems in terms of attractors of autonomous networks can be successful in explaining system behaviours in the input-free case. Nonetheless, a computational system usually needs inputs from its environment to effectively solve problems, and this necessitates a non-autonomous framework where typically the effects of a changing environment can be studied. In this review, we highlight a variety of network attractors that can exist in autonomous systems and can be used to aid interpretation of the dynamics in the presence of inputs. Such network attractors (that consist of heteroclinic or excitable connections between invariant sets) lend themselves to modelling discrete-state computations with continuous inputs, and can sometimes be thought of as a hybrid model between classical discrete computation and continuous-time dynamical systems. Bibliographic info here.

A Continuous Time Dynamical Turing Machine.

Continuous time recurrent neural networks (CTRNNs) are systems of coupled ordinary differential equations (ODEs) inspired by the structure of neural networks in the brain. CTRNNs are known to be universal dynamical approximators: given a large enough system, the parameters of a CTRNN can be tuned to produce output that is arbitrarily close to that of any other dynamical system. However, in practice, both designing systems of CTRNN to have a certain output, and the reverse-understanding the dynamics of a given system of CTRNN-can be nontrivial. In this article, we describe a method for embedding any specified Turing machine in its entirety into a CTRNN. As such, we describe in detail a continuous time dynamical system that performs arbitrary discrete-state computations. We suggest that in acting as both a continuous time dynamical system and as a computer, the study of such systems can help refine and advance the debate concerning the Computational Hypothesis that cognition is a form of computation and the Dynamical Hypothesis that cognitive systems are dynamical systems.

Quasipotentials for coupled escape problems and the gate-height bifurcation.

The escape statistics of a gradient dynamical system perturbed by noise can be estimated using properties of the associated potential landscape. More generally, the Freidlin and Wentzell quasipotential (QP) can be used for similar purposes, but computing this is nontrivial and it is only defined relative to some starting point. In this paper we focus on computing quasipotentials for coupled bistable units, numerically solving a Hamilton- Jacobi-Bellman type problem. We analyze noise induced transitions using the QP in cases where there is no potential for the coupled system. Gates (points on the boundary of basin of attraction that have minimal QP relative to that attractor) are used to understand the escape rates from the basin, but these gates can undergo a global change as coupling strength is changed. Such a global gate-height bifurcation is a generic qualitative transition in the escape properties of parametrized nongradient dynamical systems for small noise.

Chaos in symmetric phase oscillator networks.

Phase-coupled oscillators serve as paradigmatic models of networks of weakly interacting oscillatory units in physics and biology. The order parameter which quantifies synchronization so far has been found to be chaotic only in systems with inhomogeneities. Here we show that even symmetric systems of identical oscillators may not only exhibit chaotic dynamics, but also chaotically fluctuating order parameters. Our findings imply that neither inhomogeneities nor amplitude variations are necessary to obtain chaos; i.e., nonlinear interactions of phases give rise to the necessary instabilities.

Noisy network attractor models for transitions between EEG microstates.

The brain is intrinsically organized into large-scale networks that constantly re-organize on multiple timescales, even when the brain is at rest. The timing of these dynamics is crucial for sensation, perception, cognition, and ultimately consciousness, but the underlying dynamics governing the constant reorganization and switching between networks are not yet well understood. Electroencephalogram (EEG) microstates are brief periods of stable scalp topography that have been identified as the electrophysiological correlate of functional magnetic resonance imaging defined resting-state networks. Spatiotemporal microstate sequences maintain high temporal resolution and have been shown to be scale-free with long-range temporal correlations. Previous attempts to model EEG microstate sequences have failed to capture this crucial property and so cannot fully capture the dynamics; this paper answers the call for more sophisticated modeling approaches. We present a dynamical model that exhibits a noisy network attractor between nodes that represent the microstates. Using an excitable network between four nodes, we can reproduce the transition probabilities between microstates but not the heavy tailed residence time distributions. We present two extensions to this model: first, an additional hidden node at each state; second, an additional layer that controls the switching frequency in the original network. Introducing either extension to the network gives the flexibility to capture these heavy tails. We compare the model generated sequences to microstate sequences from EEG data collected from healthy subjects at rest. For the first extension, we show that the hidden nodes 'trap' the trajectories allowing the control of residence times at each node. For the second extension, we show that two nodes in the controlling layer are sufficient to model the long residence times. Finally, we show that in addition to capturing the residence time distributions and transition probabilities of the sequences, these two models capture additional properties of the sequences including having interspersed long and short residence times and long range temporal correlations in line with the data as measured by the Hurst exponent.

Harmonic cross-correlation decomposition for multivariate time series.

We introduce harmonic cross-correlation decomposition (HCD) as a tool to detect and visualize features in the frequency structure of multivariate time series. HCD decomposes multivariate time series into spatiotemporal harmonic modes with the leading modes representing dominant oscillatory patterns in the data. HCD is closely related to data-adaptive harmonic decomposition (DAHD) [Chekroun and Kondrashov, Chaos 27, 093110 (2017)10.1063/1.4989400] in that it performs an eigendecomposition of a grand matrix containing lagged cross-correlations. As for DAHD, each HCD mode is uniquely associated with a Fourier frequency, which allows for the definition of multidimensional power and phase spectra. Unlike in DAHD, however, HCD does not exhibit a systematic dependency on the ordering of the channels within the grand matrix. Further, HCD phase spectra can be related to the phase relations in the data in an intuitive way. We compare HCD with DAHD and multivariate singular spectrum analysis, a third related correlation-based decomposition, and we give illustrative applications to a simple traveling wave, as well as to simulations of three coupled Stuart-Landau oscillators and to human EEG recordings.