A dynamical model of the distributed interaction of intracellular signals

A major goal of modern cell biology is to understand the regulation of cell behavior in the reductive terms of all the molecular interactions. This aim is made explicit by the assertion that understanding a cell\u27s response to stimuli requires a full inventory of details. Currently, no satisfactory explanation exists to explain why cells exhibit only a relatively small number of different behavioral modes. In this thesis, a discrete dynamical model is developed to study interactions between certain types of signaling proteins. The model is generic and connectionist in nature and incorporates important concepts from the biology. The emphasis is on examining dynamic properties that occur on short-term time scales and are independent of gene expression. A number of modeling assumptions are made. However, the framework is flexible enough to be extended in future studies. The dynamical states of the system are explored both computationally and analytically. Monte Carlo methods are used to study the state space of simulated networks over selected parameter regimes. Networks show a tendency to settle into fixed points or oscillations over a wide range of initial conditions. A genetic algorithm (GA) is also designed to explore properties of networks. It evolves a population of modeled cells, selecting and ranking them according to a fitness function, which is designed to mimic features of real biological evolution. An analogue of protein domain shuffling is used as the crossover operator and cells are reproduced asexually. The effects of changing the parameters of the GA are explored. A clustering algorithm is developed to test the effectiveness of the GA search at generating cells, which display a limited number of different behavioral modes. Stability properties of equilibrium states in small networks are analyzed. The ability to generalize these techniques to larger networks is discussed. Topological properties of networks generated by the GA are examined. Structural properties of networks are used to provide insight into their dynamic properties. The dynamic attractors exhibited by such signaling networks may provide a framework for understanding why cells persist in only a small number of stable behavioral modes

Mammalian Brain As a Network of Networks

Acknowledgements AZ, SG and AL acknowledge support from the Russian Science Foundation (16-12-00077). Authors thank T. Kuznetsova for Fig. 6.Peer reviewedPublisher PD

Robot control with biological cells

At present there exists a large gap in size, performance, adaptability and robustness between natural and artificial information processors for performing coherent perception-action tasks under real-time constraints. Even the simplest organisms have an enviable capability of coping with an unknown dynamic environment. Robots, in contrast, are still clumsy if confronted with such complexity. This paper presents a bio-hybrid architecture developed for exploring an alternate approach to the control of autonomous robots. Circuits prepared from amoeboid plasmodia of the slime mold Physarum polycephalum are interfaced with an omnidirectional hexapod robot. Sensory signals from the macro-physical environment of the robot are transduced to cellular scale and processed using the unique micro-physical features of intracellular information processing. Conversely, the response form the cellular computation is amplified to yield a macroscopic output action in the environment mediated through the robot’s actuators

Modeling Cell-to-Cell Communication Networks Using Response-Time Distributions.

Cell-to-cell communication networks have critical roles in coordinating diverse organismal processes, such as tissue development or immune cell response. However, compared with intracellular signal transduction networks, the function and engineering principles of cell-to-cell communication networks are far less understood. Major complications include: cells are themselves regulated by complex intracellular signaling networks; individual cells are heterogeneous; and output of any one cell can recursively become an additional input signal to other cells. Here, we make use of a framework that treats intracellular signal transduction networks as "black boxes" with characterized input-to-output response relationships. We study simple cell-to-cell communication circuit motifs and find conditions that generate bimodal responses in time, as well as mechanisms for independently controlling synchronization and delay of cell-population responses. We apply our modeling approach to explain otherwise puzzling data on cytokine secretion onset times in T cells. Our approach can be used to predict communication network structure using experimentally accessible input-to-output measurements and without detailed knowledge of intermediate steps

Data-driven modelling of biological multi-scale processes

Biological processes involve a variety of spatial and temporal scales. A holistic understanding of many biological processes therefore requires multi-scale models which capture the relevant properties on all these scales. In this manuscript we review mathematical modelling approaches used to describe the individual spatial scales and how they are integrated into holistic models. We discuss the relation between spatial and temporal scales and the implication of that on multi-scale modelling. Based upon this overview over state-of-the-art modelling approaches, we formulate key challenges in mathematical and computational modelling of biological multi-scale and multi-physics processes. In particular, we considered the availability of analysis tools for multi-scale models and model-based multi-scale data integration. We provide a compact review of methods for model-based data integration and model-based hypothesis testing. Furthermore, novel approaches and recent trends are discussed, including computation time reduction using reduced order and surrogate models, which contribute to the solution of inference problems. We conclude the manuscript by providing a few ideas for the development of tailored multi-scale inference methods.Comment: This manuscript will appear in the Journal of Coupled Systems and Multiscale Dynamics (American Scientific Publishers

The role of inhibitory feedback for information processing in thalamocortical circuits

The information transfer in the thalamus is blocked dynamically during sleep, in conjunction with the occurence of spindle waves. As the theoretical understanding of the mechanism remains incomplete, we analyze two modeling approaches for a recent experiment by Le Masson {\sl et al}. on the thalamocortical loop. In a first step, we use a conductance-based neuron model to reproduce the experiment computationally. In a second step, we model the same system by using an extended Hindmarsh-Rose model, and compare the results with the conductance-based model. In the framework of both models, we investigate the influence of inhibitory feedback on the information transfer in a typical thalamocortical oscillator. We find that our extended Hindmarsh-Rose neuron model, which is computationally less costly and thus siutable for large-scale simulations, reproduces the experiment better than the conductance-based model. Further, in agreement with the experiment of Le Masson {\sl et al}., inhibitory feedback leads to stable self-sustained oscillations which mask the incoming input, and thereby reduce the information transfer significantly.Comment: 16 pages, 15eps figures included. To appear in Physical Review

Perspectives on the Neuroscience of Cognition and Consciousness

The origin and current use of the concepts of computation, representation and information in Neuroscience are examined and conceptual flaws are identified which vitiate their usefulness for addressing problems of the neural basis of Cognition and Consciousness. In contrast, a convergence of views is presented to support the characterization of the Nervous System as a complex dynamical system operating in the metastable regime, and capable of evolving to configurations and transitions in phase space with potential relevance for Cognition and Consciousness