Why Are Computational Neuroscience and Systems Biology So Separate?

Despite similar computational approaches, there is surprisingly little interaction between the computational neuroscience and the systems biology research communities. In this review I reconstruct the history of the two disciplines and show that this may explain why they grew up apart. The separation is a pity, as both fields can learn quite a bit from each other. Several examples are given, covering sociological, software technical, and methodological aspects. Systems biology is a better organized community which is very effective at sharing resources, while computational neuroscience has more experience in multiscale modeling and the analysis of information processing by biological systems. Finally, I speculate about how the relationship between the two fields may evolve in the near future

Modeling Signal Transduction Leading to Synaptic Plasticity: Evaluation and Comparison of Five Models

An essential phenomenon of the functional brain is synaptic plasticity which is associated with changes in the strength of synapses between neurons. These changes are affected by both extracellular and intracellular mechanisms. For example, intracellular phosphorylation-dephosphorylation cycles have been shown to possess a special role in synaptic plasticity. We, here, provide the first computational comparison of models for synaptic plasticity by evaluating five models describing postsynaptic signal transduction networks. Our simulation results show that some of the models change their behavior completely due to varying total concentrations of protein kinase and phosphatase. Furthermore, the responses of the models vary when models are compared to each other. Based on our study, we conclude that there is a need for a general setup to objectively compare the models and an urgent demand for the minimum criteria that a computational model for synaptic plasticity needs to meet.Peer reviewe

Gestion et visualisation de données hétérogènes multidimensionnelles : application PLM à la neuroimagerie

Neuroimaging domain is confronted with issues in analyzing and reusing the growing amount of heterogeneous data produced. Data provenance is complex – multi-subjects, multi-methods, multi-temporalities – and the data are only partially stored, restricting multimodal and longitudinal studies. Especially, functional brain connectivity is studied to understand how areas of the brain work together. Raw and derived imaging data must be properly managed according to several dimensions, such as acquisition time, time between two acquisitions or subjects and their characteristics. The objective of the thesis is to allow exploration of complex relationships between heterogeneous data, which is resolved in two parts : (1) how to manage data and provenance, (2) how to visualize structures of multidimensional data. The contribution follow a logical sequence of three propositions which are presented after a research survey in heterogeneous data management and graph visualization.The BMI-LM (Bio-Medical Imaging – Lifecycle Management) data model organizes the management of neuroimaging data according to the phases of a study and takes into account the scalability of research thanks to specific classes associated to generic objects. The application of this model into a PLM (Product Lifecycle Management) system shows that concepts developed twenty years ago for manufacturing industry can be reused to manage neuroimaging data. GMDs (Dynamic Multidimensional Graphs) are introduced to represent complex dynamic relationships of data, as well as JGEX (Json Graph EXchange) format that was created to store and exchange GMDs between software applications. OCL (Overview Constraint Layout) method allows interactive and visual exploration of GMDs. It is based on user’s mental map preservation and alternating of complete and reduced views of data. OCL method is applied to the study of functional brain connectivity at rest of 231 subjects that are represented by a GMD – the areas of the brain are the nodes and connectivity measures the edges – according to age, gender and laterality : GMDs are computed through processing workflow on MRI acquisitions into the PLM system. Results show two main benefits of using OCL method : (1) identification of global trends on one or many dimensions, and (2) highlights of local changes between GMD states.La neuroimagerie est confrontée à des difficultés pour analyser et réutiliser la masse croissante de données hétérogènes qu’elle produit. La provenance des données est complexe – multi-sujets, multi-analyses, multi-temporalités – et ces données ne sont stockées que partiellement, limitant les possibilités d’études multimodales et longitudinales. En particulier, la connectivité fonctionnelle cérébrale est analysée pour comprendre comment les différentes zones du cerveau travaillent ensemble. Il est nécessaire de gérer les données acquises et traitées suivant plusieurs dimensions, telles que le temps d’acquisition, le temps entre les acquisitions ou encore les sujets et leurs caractéristiques. Cette thèse a pour objectif de permettre l’exploration de relations complexes entre données hétérogènes, ce qui se décline selon deux axes : (1) comment gérer les données et leur provenance, (2) comment visualiser les structures de données multidimensionnelles. L’apport de nos travaux s’articule autour de trois propositions qui sont présentées à l’issue d’un état de l’art sur les domaines de la gestion de données hétérogènes et de la visualisation de graphes.Le modèle de données BMI-LM (Bio-Medical Imaging – Lifecycle Management) structure la gestion des données de neuroimagerie en fonction des étapes d’une étude et prend en compte le caractère évolutif de la recherche grâce à l’association de classes spécifiques à des objets génériques. L’implémentation de ce modèle au sein d’un système PLM (Product Lifecycle Management) montre que les concepts développés depuis vingt ans par l’industrie manufacturière peuvent être réutilisés pour la gestion des données en neuroimagerie. Les GMD (Graphes MultidimensionnelsDynamiques) sont introduits pour représenter des relations complexes entre données qui évoluent suivant plusieurs dimensions, et le format JGEX (Json Graph EXchange) a été créé pour permettre le stockage et l’échange de GMD entre applications. La méthode OCL (Overview Constraint Layout) permet l’exploration visuelle et interactive de GMD. Elle repose sur la préservation partielle de la carte mentale de l’utilisateur et l’alternance de vues complètes et réduites des données. La méthode OCL est appliquée à l’étude de la connectivité fonctionnelle cérébrale au repos de 231 sujets représentées sous forme de GMD – les zones du cerveau sont représentées par les noeuds et les mesures de connectivité par les arêtes – en fonction de l’âge, du genre et de la latéralité : les GMD sont obtenus par l’application de chaînes de traitement sur des acquisitions IRM dans le système PLM. Les résultats montrent deux intérêts principaux à l’utilisation de la méthode OCL : (1) l’identification des tendances globales sur une ou plusieurs dimensions et (2) la mise en exergue des changements locaux entre états du GMD

Computational Modeling of IP3 Receptor Function and Intracellular Mechanisms in Synaptic Plasticity

Learning and memory in the brain have been shown to involve complex molecular interactions. In the field of computational neuroscience, mathematical modeling and computer simulations are combined with laboratory experiments to better understand the dynamics of these interactions. A vast number of computational models related to intracellular molecular mechanisms calls for means to compare them to each other. In this thesis, computational models and methods for understanding specific molecular mechanisms in synaptic plasticity, a phenomenon involved in learning, are studied and compared both quantitatively and qualitatively. The focus is set on the IP3 receptor kinetics and the intracellular molecular mechanisms including processing of calcium ions in the postsynaptic neuron. Calcium has been shown to play an important role in different types of synaptic plasticity, only the mechanisms and dynamics for elevation of cytosolic calcium concentration vary. The IP3 receptor, an intracellular calcium releasing channel, is one of the major factors responsible for the calcium elevation in neurons. Firstly, the applicability of deterministic and stochastic approaches in modeling the IP3 receptor kinetics, involving small number of molecules, is studied. In this case, the study shows that stochastic approach, especially Gillespie stochastic simulation algorithm, should be favored. Secondly, since a well-established model for IP3 receptor function in neurons is lacking, this thesis provides not only tools for model comparison but also an insight to which model of the tens of models to choose. Using stochastic simulations, four IP3 models are compared to experimental data to clarify how well they model the measured features in neurons. The results show that there are major differences in the statistical properties of the IP3 receptor models although the models have originally been developed to describe the same phenomenon. Thirdly, this study shows that the models for postsynaptic signaling in synaptic plasticity are becoming more sophisticated by involving stochastic properties, incorporating electrophysiolocial properties of the entire neuron, or having diffusion of signaling molecules. Computational comparison of these models reveals that when using the same input, models describing the phenomenon in the same neuron type produce different results. One of the future goals of computational neuroscience is to find predictive computational models for biochemical and biophysical mechanisms of synaptic plasticity in different brain areas and cells of mammals. When describing a system of molecular events, the selection of modeling and simulation approach should be done carefully by keeping the properties of the modeled biological system in mind. Not only do theoreticians and modelers need to consider experimental findings, but the experimental progress could also be enhanced by using simulations to select the most promising experiments. As discussed in this thesis, attention paid to these issues should improve the utility of modeling approaches for investigating molecular mechanisms of synaptic plasticity. Only then is it possible to use the models to learn something new about the mammalian brain function