Multiscale modeling for computational systems biology is growing in importance for neuroscience as well as for other areas of biomedical research. Integration of recent findings in computational cell biology and synapse function, in the context of neurons and neuronal networks, will require simulations that can incorporate reaction-diffusion modeling down to the level of genomic and proteomic expression. This will allow simulation of the complex biochemical interactions occurring in cell bodies, dendrites and spines. To do this, the NEURON simulator, designed to simulate electrophysiology, will require major extensions. The primary extension will involve addition of 3-dimensional intracellular spatial integration with registration to the existing multicompartment voltage integration. Additional extensions at front and back- ends will also be needed to make the new tools fully useable. This work will be done in collaboration with the VCell team at University of Connecticut Health Center, who will provide us with code from their integration procedures and will consult on development of additional viewers that will be needed for these complex simulations. This procedure will also ensure interoperability with the VCell simulator, other existing cell biology simulators that read and write SBML (Systems Biology markup-language), and NeuroML. The extensions to NEURON will be effected through the following Specific Aims. 1. Kinetic translation from other kinetic markup languages. 2. Implementation of 3-D intracellular reaction diffusion modeling. 3. Development of two primary driving projects: a. model of ALS-related mitochondrial transport dysfunction;b. model of chemical fluxes between spine and dendrite. 4. Dissemination of the new tools. Dissemination is of critical importance to ensure that the new tool is used by some of the more than 650 active NEURON users. We will also make efforts to encourage cell neurobiologists to incorporate both NEURON and VCell into their technique repertoire. The ready translation of models between these two major platforms, using the several hundred peer-review published simulations available, will encourage simulation reuse and speed development of new applications.

Public Health Relevance

The enormous complexity of brain interactions makes understanding brain diseases such as Alzheimer disease, Parkinson disease and epilepsy more difficult than understanding diseases in other organs. Part of this complexity lies in the need to understand how the chemicals that underlie learning and memory and brain energy interact with the electrical signals that travel along nerve fibers. We will extend NEURON, one of the most widely used nerve and brain simulators, so that it simulates chemical reactions as well as electric signals and allow these two types of information to be combined to understand disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH086638-03
Application #
8260864
Study Section
Neurotechnology Study Section (NT)
Program Officer
Freund, Michelle
Project Start
2010-06-01
Project End
2016-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$397,856
Indirect Cost
$73,631
Name
Suny Downstate Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
040796328
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
McDougal, Robert A; Bulanova, Anna S; Lytton, William W (2016) Reproducibility in Computational Neuroscience Models and Simulations. IEEE Trans Biomed Eng 63:2021-35
Neymotin, S A; McDougal, R A; Bulanova, A S et al. (2016) Calcium regulation of HCN channels supports persistent activity in a multiscale model of neocortex. Neuroscience 316:344-66
Neymotin, Samuel A; Dura-Bernal, Salvador; Lakatos, Peter et al. (2016) Multitarget Multiscale Simulation for Pharmacological Treatment of Dystonia in Motor Cortex. Front Pharmacol 7:157
Neymotin, Samuel A; McDougal, Robert A; Sherif, Mohamed A et al. (2015) Neuronal calcium wave propagation varies with changes in endoplasmic reticulum parameters: a computer model. Neural Comput 27:898-924
Seidenstein, Alexandra H; Barone, Frank C; Lytton, William W (2015) Computer modeling of ischemic stroke. Scholarpedia J 10:
Dura-Bernal, Salvador; Chadderdon, George L; Neymotin, Samuel A et al. (2014) Towards a real-time interface between a biomimetic model of sensorimotor cortex and a robotic arm. Pattern Recognit Lett 36:204-212
Lytton, William W; Neymotin, Samuel A; Kerr, Cliff C (2014) Multiscale modeling for clinical translation in neuropsychiatric disease. J Comput Surg 1:
Taxin, Zachary H; Neymotin, Samuel A; Mohan, Ashutosh et al. (2014) Modeling molecular pathways of neuronal ischemia. Prog Mol Biol Transl Sci 123:249-75
Lee, Giljae; Matsunaga, Andréa; Dura-Bernal, Salvador et al. (2014) Towards real-time communication between in vivo neurophysiological data sources and simulator-based brain biomimetic models. J Comput Surg 3:1-23
McDougal, Robert A; Hines, Michael L; Lytton, William W (2013) Reaction-diffusion in the NEURON simulator. Front Neuroinform 7:28

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