Adam JH Newton, Craig Kelley, Michael L Hines, William W Lytton, Robert A McDougal
Meeting: https://yale.zoom.us/j/5299709870 Telephone: 646 568 7788
Meeting ID: 529 970 9870
Poster: http://adamnewton.org/CNS2020.pdf
Workshop: W4 S6: The NEURON Simulator
Recent improvements and performance enhancements in the NEURON (neuron.yale.edu) reaction-diffusion module (rxd) allow us to model multiple relevant concentrations in the intracellular and extracellular space. The extracellular space is a coarse-grained macroscopic model based on a volume averaging approach, allowing the user to specify both the free volume fraction (the proportion of space in which species are able to diffuse) and the tortuosity (the average multiplicative increase in path length due to obstacles). These tissue characteristics can be spatially dependent to account for regional or pathological differences.
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Using a multiscale modeling approach we have developed a pair of models for spreading depolarization at spatial scales from microns to mm, and time scales from ms to minutes. The cellular/subcellular-scale model adapted existing mechanisms for a morphologically detailed CA1 pyramidal neuron together with a simple astrocyte model. This model included reaction-diffusion of K+ , Na+, Cl− and glutamate, with detailed cytosolic and endoplasmic reticulum Ca2+ regulation. Homeostatic mechanisms were added to the model, including; Na-K- ATPase pumps, Ca2+ pumps, SERCA, NKCC1, KCC2 and glutamate transporters. We use BluePyOpt to perform a parameter search, constrained by the requirements of realistic electrophysiological responses while maintaining ionic homeostasis. This detailed model was used to explore the hypothesis that individual dendrites have distinct vulnerability to damage due to area-volume ratios leading to different intracellular Ca2+ levels.
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At the tissue-scale we adapted a simpler point neurons model, and densely packed them in a coarse-grained macroscopic 3D volume. The models include a simple model for oxygen and dynamic changes in volume fraction. This allows us to model the effect of changes in tissue diffusion characteristics on the wave propagation during spreading depolarization.
Acknowledgments: Research supported by NIH grant R01MH086638
