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Multiscale computer modeling of spreading depolarization in brain slices

View ORCID ProfileCraig Kelley, Adam JH Newton, Sabina Hrabetova, View ORCID ProfileRobert A. McDougal, William W Lytton
doi: https://doi.org/10.1101/2022.01.20.477118
Craig Kelley
1Program in Biomedical Engineering, SUNY Downstate Health Sciences University & NYU Tandon School of Engineering, Brooklyn, NY, USA, 11203
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  • For correspondence: craig.kelley@downstate.edu
Adam JH Newton
2Department of Physiology & Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA, 11203
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Sabina Hrabetova
3Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA, 11203
4The Robert F. Furchgott Center for Neural and Behavioral Science, Brooklyn, NY, USA, 11203
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Robert A. McDougal
5Department of Biostatistics, Yale University, New Haven, CT, USA, 06513
6Yale Center for Medical Informatics, Yale University, New Haven, CT, USA, 06513
7Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA, 06513
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William W Lytton
2Department of Physiology & Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA, 11203
4The Robert F. Furchgott Center for Neural and Behavioral Science, Brooklyn, NY, USA, 11203
8Department of Neurology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA, 11203
9Department of Neurology, Kings County Hospital Center, Brooklyn, NY, USA, 11203
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Abstract

Spreading depolarization (SD) is a slow-moving wave of neuronal depolarization accompanied by a breakdown of ion concentration homeostasis, followed by long periods of neuronal silence (spreading depression), and associated with several neurological conditions. We developed multiscale (ions to tissue slice) computer models of SD in brain slices using the NEURON simulator: 36,000 neurons (2 voltage-gated ion channels; 3 leak channels; 3 ion exchangers/pumps) in the extracellular space (ECS) of a slice (1 mm sides, varying thickness) with ion (K+, Cl−, Na+) and O2 diffusion and equilibration with a surrounding bath. Glia and neurons cleared K+ from the ECS via Na+/K+pumps. SD propagated through the slices at realistic speeds of 2–5 mm/min, which was augmented by 25–30% in models incorporating the effects of hypoxia or of propionate. In both cases, the speedup was mediated principally by ECS shrinkage. Our model allows us to make the following testable predictions: 1. SD can be inhibited by enlarging ECS volume; 2. SD velocity will be greater in areas with greater neuronal density, total neuronal volume, or larger/more dendrites; 3. SD is all-or-none: initiating K+ bolus properties have little impact on SD speed; 4. Slice thickness influences SD due to relative hypoxia in the slice core, exacerbated by SD in a pathological cycle; 5. Higher neuronal spike rates and faster spread will be observed in the core than the periphery of perfused slice during SD.

Significance Spreading depolarization (SD) is a slow moving wave of electrical and ionic imbalances in brain tissue and is a hallmark of several neurological disorders. We developed a multiscale computer model of brain slices with realistic neuronal densities, ions, and oxygenation. Our model shows that SD is exacerbated by and causes hypoxia, resulting in strong SD dependence on slice thickness. Our model also predicts that the velocity of SD propagation is not dependent on its initiation, but instead on tissue properties, including the amount of extracellular space and the total area of neuronal membrane, suggesting faster SD following ischemic stroke or traumatic brain injury.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Conflict of interest statement: The authors declare no competing financial interests.

  • https://github.com/suny-downstate-medical-center/SDinSlice

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted January 22, 2022.
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Multiscale computer modeling of spreading depolarization in brain slices
Craig Kelley, Adam JH Newton, Sabina Hrabetova, Robert A. McDougal, William W Lytton
bioRxiv 2022.01.20.477118; doi: https://doi.org/10.1101/2022.01.20.477118
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Multiscale computer modeling of spreading depolarization in brain slices
Craig Kelley, Adam JH Newton, Sabina Hrabetova, Robert A. McDougal, William W Lytton
bioRxiv 2022.01.20.477118; doi: https://doi.org/10.1101/2022.01.20.477118

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