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Cannon R.C.,Textensor Ltd | O'Donnell C.,University of Edinburgh | Nolan M.F.,University of Edinburgh
PLoS Computational Biology | Year: 2010

Neuronal activity is mediated through changes in the probability of stochastic transitions between open and closed states of ion channels. While differences in morphology define neuronal cell types and may underlie neurological disorders, very little is known about influences of stochastic ion channel gating in neurons with complex morphology. We introduce and validate new computational tools that enable efficient generation and simulation of models containing stochastic ion channels distributed across dendritic and axonal membranes. Comparison of five morphologically distinct neuronal cell types reveals that when all simulated neurons contain identical densities of stochastic ion channels, the amplitude of stochastic membrane potential fluctuations differs between cell types and depends on sub-cellular location. For typical neurons, the amplitude of membrane potential fluctuations depends on channel kinetics as well as open probability. Using a detailed model of a hippocampal CA1 pyramidal neuron, we show that when intrinsic ion channels gate stochastically, the probability of initiation of dendritic or somatic spikes by dendritic synaptic input varies continuously between zero and one, whereas when ion channels gate deterministically, the probability is either zero or one. At physiological firing rates, stochastic gating of dendritic ion channels almost completely accounts for probabilistic somatic and dendritic spikes generated by the fully stochastic model. These results suggest that the consequences of stochastic ion channel gating differ globally between neuronal cell-types and locally between neuronal compartments. Whereas dendritic neurons are often assumed to behave deterministically, our simulations suggest that a direct consequence of stochastic gating of intrinsic ion channels is that spike output may instead be a probabilistic function of patterns of synaptic input to dendrites. © 2010 Cannon et al. Source


Gleeson P.,University College London | Crook S.,Arizona State University | Cannon R.C.,Textensor Ltd | Hines M.L.,Yale University | And 9 more authors.
PLoS Computational Biology | Year: 2010

Biologically detailed single neuron and network models are important for understanding how ion channels, synapses and anatomical connectivity underlie the complex electrical behavior of the brain. While neuronal simulators such as NEURON, GENESIS, MOOSE, NEST, and PSICS facilitate the development of these data-driven neuronal models, the specialized languages they employ are generally not interoperable, limiting model accessibility and preventing reuse of model components and cross-simulator validation. To overcome these problems we have used an Open Source software approach to develop NeuroML, a neuronal model description language based on XML (Extensible Markup Language). This enables these detailed models and their components to be defined in a standalone form, allowing them to be used across multiple simulators and archived in a standardized format. Here we describe the structure of NeuroML and demonstrate its scope by converting into NeuroML models of a number of different voltage- and ligand-gated conductances, models of electrical coupling, synaptic transmission and short-term plasticity, together with morphologically detailed models of individual neurons. We have also used these NeuroML-based components to develop an highly detailed cortical network model. NeuroML-based model descriptions were validated by demonstrating similar model behavior across five independently developed simulators. Although our results confirm that simulations run on different simulators converge, they reveal limits to model interoperability, by showing that for some models convergence only occurs at high levels of spatial and temporal discretisation, when the computational overhead is high. Our development of NeuroML as a common description language for biophysically detailed neuronal and network models enables interoperability across multiple simulation environments, thereby improving model transparency, accessibility and reuse in computational neuroscience. © 2010 Gleeson et al. Source


Gewaltig M.-O.,Ecole Polytechnique Federale de Lausanne | Cannon R.,Textensor Ltd
PLoS Computational Biology | Year: 2014

Almost all research work in computational neuroscience involves software. As researchers try to understand ever more complex systems, there is a continual need for software with new capabilities. Because of the wide range of questions being investigated, new software is often developed rapidly by individuals or small groups. In these cases, it can be hard to demonstrate that the software gives the right results. Software developers are often open about the code they produce and willing to share it, but there is little appreciation among potential users of the great diversity of software development practices and end results, and how this affects the suitability of software tools for use in research projects. To help clarify these issues, we have reviewed a range of software tools and asked how the culture and practice of software development affects their validity and trustworthiness.We identified four key questions that can be used to categorize software projects and correlate them with the type of product that results. The first question addresses what is being produced. The other three concern why, how, and by whom the work is done. The answers to these questions show strong correlations with the nature of the software being produced, and its suitability for particular purposes. Based on our findings, we suggest ways in which current software development practice in computational neuroscience can be improved and propose checklists to help developers, reviewers, and scientists to assess the quality of software and whether particular pieces of software are ready for use in research. © 2014 Gewaltig, Cannon. Source


Oliveira R.F.,George Mason University | Terrin A.,University of Glasgow | di Benedetto G.,Venetian Institute of Molecular Medicine | Cannon R.C.,Textensor Ltd | And 4 more authors.
PLoS ONE | Year: 2010

Cyclic AMP (cAMP) and its main effector Protein Kinase A (PKA) are critical for several aspects of neuronal function including synaptic plasticity. Specificity of synaptic plasticity requires that cAMP activates PKA in a highly localized manner despite the speed with which cAMP diffuses. Two mechanisms have been proposed to produce localized elevations in cAMP, known as microdomains: impeded diffusion, and high phosphodiesterase (PDE) activity. This paper investigates the mechanism of localized cAMP signaling using a computational model of the biochemical network in the HEK293 cell, which is a subset of pathways involved in PKA-dependent synaptic plasticity. This biochemical network includes cAMP production, PKA activation, and cAMP degradation by PDE activity. The model is implemented in NeuroRD: novel, computationally efficient, stochastic reaction-diffusion software, and is constrained by intracellular cAMP dynamics that were determined experimentally by real-time imaging using an Epac-based FRET sensor (H30). The model reproduces the high concentration cAMP microdomain in the submembrane region, distinct from the lower concentration of cAMP in the cytosol. Simulations further demonstrate that generation of the cAMP microdomain requires a pool of PDE4D anchored in the cytosol and also requires PKA-mediated phosphorylation of PDE4D which increases its activity. The microdomain does not require impeded diffusion of cAMP, confirming that barriers are not required for microdomains. The simulations reported here further demonstrate the utility of the new stochastic reaction-diffusion algorithm for exploring signaling pathways in spatially complex structures such as neurons. © 2010 Oliveira et al. Source


Vella M.,University of Cambridge | Cannon R.C.,Textensor Ltd | Crook S.,Arizona State University | Davison A.P.,French National Center for Scientific Research | And 4 more authors.
Frontiers in Neuroinformatics | Year: 2014

NeuroML is an XML-based model description language, which provides a powerful common data format for defining and exchanging models of neurons and neuronal networks. In the latest version of NeuroML, the structure and behavior of ion channel, synapse, cell, and network model descriptions are based on underlying definitions provided in LEMS, a domain-independent language for expressing hierarchical mathematical models of physical entities. While declarative approaches for describing models have led to greater exchange of model elements among software tools in computational neuroscience, a frequent criticism of XML-based languages is that they are difficult to work with directly. Here we describe two Application Programming Interfaces (APIs) written in Python (http://www.python.org), which simplify the process of developing and modifying models expressed in NeuroML and LEMS. The libNeuroML API provides a Python object model with a direct mapping to all NeuroML concepts defined by the NeuroML Schema, which facilitates reading and writing the XML equivalents. In addition, it offers a memory-efficient, array-based internal representation, which is useful for handling large-scale connectomics data. The libNeuroML API also includes support for performing common operations that are required when working with NeuroML documents. Access to the LEMS data model is provided by the PyLEMS API, which provides a Python implementation of the LEMS language, including the ability to simulate most models expressed in LEMS. Together, libNeuroML and PyLEMS provide a comprehensive solution for interacting with NeuroML models in a Python environment. © 2014 Vella, Cannon, Crook, Davison, Ganapathy, Robinson, Silver and Gleeson. Source

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