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Multiscale Computer Modeling of Spreading Depolarization in Brain Slices
Craig Kelley1, Adam J H Newton2, Sabina Hrabetova3,4
1Program in Biomedical Engineering, SUNY Downstate Health Sciences University & NYU Tandon School of Engineering, Brooklyn, NY, 11203 craig.kelley@downstate.edu.
Eneuro
|August 4, 2022
Summary
Spreading depolarization (SD) computer models reveal that extracellular space volume and hypoxia significantly impact its speed. Enlarging the extracellular space can inhibit SD, offering potential therapeutic insights.
Area of Science:
- Computational neuroscience
- Neurophysiology
- Biophysics
Background:
- Spreading depolarization (SD) involves neuronal depolarization and ion homeostasis disruption, linked to neurological disorders.
- SD is characterized by a slow wave of neuronal activity followed by silence.
Purpose of the Study:
- To develop multiscale computer models of spreading depolarization (SD) in brain slices.
- To investigate the factors influencing SD propagation speed and characteristics.
Main Methods:
- Utilized the NEURON simulator to model 36,000 neurons with detailed ion channel and transporter dynamics.
- Incorporated ion and oxygen diffusion, extracellular space (ECS) dynamics, and glial/neuronal ion clearance mechanisms.
- Simulated SD propagation in brain slices of varying thicknesses under different conditions, including hypoxia and propionate exposure.
Main Results:
- SD propagated at realistic speeds (2-4 mm/min), with speeds increasing up to 50% under hypoxia or propionate.
- Extracellular space shrinkage was identified as the primary mechanism for speed increase in these conditions.
- Model predictions indicated that SD velocity correlates with neuronal density and dendritic structure.
Conclusions:
- Model simulations suggest that increasing ECS volume could inhibit SD.
- Slice thickness impacts SD due to core hypoxia, creating a pathological cycle.
- SD exhibits all-or-none behavior, with initiating conditions having minimal effect on propagation speed.
