Robert A. McDougal

Reaction-diffusion in the NEURON simulator.

In order to support research on the role of cell biological principles (genomics, proteomics, signaling cascades and reaction dynamics) on the dynamics of neuronal response in health and disease, NEURONs Reaction-Diffusion (rxd) module in Python provides specification and simulation for these dynamics, coupled with the electrophysiological dynamics of the cell membrane. Arithmetic operations on species and parameters are overloaded, allowing arbitrary reaction formulas to be specified using Python syntax. These expressions are then transparently compiled into bytecode that uses NumPy for fast vectorized calculations. At each time step, rxd combines NEURONs integrators with SciPys sparse linear algebra library.

Twenty years of ModelDB and beyond: building essential modeling tools for the future of neuroscience

Neuron modeling may be said to have originated with the Hodgkin and Huxley action potential model in 1952 and Rall’s models of integrative activity of dendrites in 1964. Over the ensuing decades, these approaches have led to a massive development of increasingly accurate and complex data-based models of neurons and neuronal circuits. ModelDB was founded in 1996 to support this new field and enhance the scientific credibility and utility of computational neuroscience models by providing a convenient venue for sharing them. It has grown to include over 1100 published models covering more than 130 research topics. It is actively curated and developed to help researchers discover and understand models of interest. ModelDB also provides mechanisms to assist running models both locally and remotely, and has a graphical tool that enables users to explore the anatomical and biophysical properties that are represented in a model. Each of its capabilities is undergoing continued refinement and improvement in response to user experience. Large research groups (Allen Brain Institute, EU Human Brain Project, etc.) are emerging that collect data across multiple scales and integrate that data into many complex models, presenting new challenges of scale. We end by predicting a future for neuroscience increasingly fueled by new technology and high performance computation, and increasingly in need of comprehensive user-friendly databases such as ModelDB to provide the means to integrate the data for deeper insights into brain function in health and disease.

Calcium regulation of HCN channels supports persistent activity in a multiscale model of neocortex

Neuronal persistent activity has been primarily assessed in terms of electrical mechanisms, without attention to the complex array of molecular events that also control cell excitability. We developed a multiscale neocortical model proceeding from the molecular to the network level to assess the contributions of calcium (Ca(2+)) regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in providing additional and complementary support of continuing activation in the network. The network contained 776 compartmental neurons arranged in the cortical layers, connected using synapses containing AMPA/NMDA/GABAA/GABAB receptors. Metabotropic glutamate receptors (mGluR) produced inositol triphosphate (IP3) which caused the release of Ca(2+) from endoplasmic reticulum (ER) stores, with reuptake by sarco/ER Ca(2+)-ATP-ase pumps (SERCA), and influence on HCN channels. Stimulus-induced depolarization led to Ca(2+) influx via NMDA and voltage-gated Ca(2+) channels (VGCCs). After a delay, mGluR activation led to ER Ca(2+) release via IP3 receptors. These factors increased HCN channel conductance and produced firing lasting for ∼1min. The model displayed inter-scale synergies among synaptic weights, excitation/inhibition balance, firing rates, membrane depolarization, Ca(2+) levels, regulation of HCN channels, and induction of persistent activity. The interaction between inhibition and Ca(2+) at the HCN channel nexus determined a limited range of inhibition strengths for which intracellular Ca(2+) could prepare population-specific persistent activity. Interactions between metabotropic and ionotropic inputs to the neuron demonstrated how multiple pathways could contribute in a complementary manner to persistent activity. Such redundancy and complementarity via multiple pathways is a critical feature of biological systems. Mediation of activation at different time scales, and through different pathways, would be expected to protect against disruption, in this case providing stability for persistent activity.

Reproducibility in Computational Neuroscience Models and Simulations

Objective: Like all scientific research, computational neuroscience research must be reproducible. Big data science, including simulation research, cannot depend exclusively on journal articles as the method to provide the sharing and transparency required for reproducibility. Methods: Ensuring model reproducibility requires the use of multiple standard software practices and tools, including version control, strong commenting and documentation, and code modularity. Results: Building on these standard practices, model-sharing sites and tools have been developed that fit into several categories: 1) standardized neural simulators; 2) shared computational resources; 3) declarative model descriptors, ontologies, and standardized annotations; and 4) model-sharing repositories and sharing standards. Conclusion: A number of complementary innovations have been proposed to enhance sharing, transparency, and reproducibility. The individual user can be encouraged to make use of version control, commenting, documentation, and modularity in development of models. The community can help by requiring model sharing as a condition of publication and funding. Significance: Model management will become increasingly important as multiscale models become larger, more detailed, and correspondingly more difficult to manage by any single investigator or single laboratory. Additional big data management complexity will come as the models become more useful in interpreting experiments, thus increasing the need to ensure clear alignment between modeling data, both parameters and results, and experiment.

NTW-MT: a Multi-threaded Simulator for Reaction Diffusion Simulations in NEURON

This paper describes a parallel discrete event simulator, Neuron Time Warp-Multi Thread (NTW-MT), developed for the simulation of reaction diffusion models of neurons. The simulator was developed as part of the NEURON project and is intended to be included in NEURON. It relies upon a stochastic discrete event model developed for chemical reactions. NTW-MT is optimistic and thread-based, in which communication latency among threads within the same process is minimized by pointers. We investigate the performance of NTW-MT on a reaction-diffusion model for the transmission of calcium waves in a neuron. Calcium plays a fundamental role in the second messenger system of a neuron. However, the mechanism by which calcium waves are transmitted is not entirely understood. Stochastic models are more realistic than deterministic models for small populations of ions such as those found in apical dendrites. To be more precise, we simulate a stochastic discrete event model for calcium wave propagation on an unbranched apical dendrite of a hippocampal pyramidal neuron. We examine the performance of NTW-MT on this calcium wave model and compare it to the performance of (1) a process based optimistic simulator and (2) a threaded simulator which uses a single priority (SQ) queue for each thread. Our multi-threaded simulator is shown to achieve superior performance to these simulators.

3D-printer visualization of neuron models.

Neurons come in a wide variety of shapes and sizes. In a quest to understand this neuronal diversity, researchers have three-dimensionally traced tens of thousands of neurons; many of these tracings are freely available through online repositories like NeuroMorpho.Org and ModelDB. Tracings can be visualized on the computer screen, used for statistical analysis of the properties of different cell types, used to simulate neuronal behavior, and more. We introduce the use of 3D printing as a technique for visualizing traced morphologies. Our method for generating printable versions of a cell or group of cells is to expand dendrite and axon diameters and then to transform the tracing into a 3D object with a neuronal surface generating algorithm like Constructive Tessellated Neuronal Geometry (CTNG). We show that 3D printed cells can be readily examined, manipulated, and compared with other neurons to gain insight into both the biology and the reconstruction process. We share our printable models in a new database, 3DModelDB, and encourage others to do the same with cells that they generate using our code or other methods. To provide additional context, 3DModelDB provides a simulatable version of each cell, links to papers that use or describe it, and links to associated entries in other databases.

Simulation neurotechnologies for advancing brain research: Parallelizing large networks in neuron

Large multiscale neuronal network simulations are of increasing value as more big data are gathered about brain wiring and organization under the auspices of a current major research initiative, such as Brain Research through Advancing Innovative Neurotechnologies. The development of these models requires new simulation technologies. We describe here the current use of the NEURON simulator with message passing interface (MPI) for simulation in the domain of moderately large networks on commonly available high-performance computers (HPCs). We discuss the basic layout of such simulations, including the methods of simulation setup, the run-time spike-passing paradigm, and postsimulation data storage and data management approaches. Using the Neuroscience Gateway, a portal for computational neuroscience that provides access to large HPCs, we benchmark simulations of neuronal networks of different sizes (500–100,000 cells), and using different numbers of nodes (1–256). We compare three types of networks, composed of either Izhikevich integrate-and-fire neurons (I&F), single-compartment Hodgkin-Huxley (HH) cells, or a hybrid network with half of each. Results show simulation run time increased approximately linearly with network size and decreased almost linearly with the number of nodes. Networks with I&F neurons were faster than HH networks, although differences were small since all tested cells were point neurons with a single compartment.

ModelView for ModelDB: Online Presentation of Model Structure

ModelDB (modeldb.yale.edu), a searchable repository of source code of more than 950 published computational neuroscience models, seeks to promote model reuse and reproducibility. Code sharing is a first step; however, model source code is often large and not easily understood. To aid users, we have developed ModelView, a web application for ModelDB that presents a graphical view of model structure augmented with contextual information for NEURON and NEURON-runnable (e.g. NeuroML, PyNN) models. Web presentation provides a rich, simulator-independent environment for interacting with graphs. The necessary data is generated by combining manual curation, text-mining the source code, querying ModelDB, and simulator introspection. Key features of the user interface along with the data analysis, storage, and visualization algorithms are explained. With this tool, researchers can examine and assess the structure of hundreds of models in ModelDB in a standardized presentation without installing any software, downloading the model, or reading model source code.

Neuron time warp

Detailed simulation of chemical reactions and the diffusion of ions through a neuronal membrane presents challenges due to the multiple scales at which this occurs, scales that require development and consolidation of a number of different simulation methodologies. In this paper, we describe Neuron Time Warp (NTW), a part of the NEURON project for development of multi-scale tools for simulations of brain parts and brains. NTW relies upon the Next Subvolume Method, a stochastic Monte Carlo algorithm used to simulate chemical reactions within the membrane of a neuron. We make use of a model of a dendrite branch on which to evaluate NTWs performance using MPI and shared memory on a multi-core machine. This work is a first step towards the development of multi-scale simulation models which are capable of portraying the behavior of a neuron with greater fidelity then is possible with differential equation based models alone.

Open Source Brain: a collaborative resource for visualizing, analyzing, simulating and developing standardized models of neurons and circuits

Computational models are powerful tools for investigating brain function in health and disease. However, biologically detailed neuronal and circuit models are complex and implemented in a range of specialized languages, making them inaccessible and opaque to many neuroscientists. This has limited critical evaluation of models by the scientific community and impeded their refinement and widespread adoption. To address this, we have combined advances in standardizing models, open source software development and web technologies to develop Open Source Brain, a platform for visualizing, simulating, disseminating and collaboratively developing standardized models of neurons and circuits from a range of brain regions. Model structure and parameters can be visualized and their dynamical properties explored through browser-controlled simulations, without writing code. Open Source Brain makes neural models transparent and accessible and facilitates testing, critical evaluation and refinement, thereby helping to improve the accuracy and reproducibility of models, and their dissemination to the wider community.