P216 Modeling spreading depolarization in control and ischemic neocortical microcircuits using immunostained identify capillaries
Adam JH Newton*1,Craig Kelley2,Siyan Guo3, Joy Wang3, Sydney Zink4, Marcello DiStasio4,5, Robert A McDougal3,5,6,7, William W Lytton1,8,9,10
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Department of Physiology and Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, New York
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Department of Biomedical Engineering, Columbia University, New York, NY.
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Department of Biostatistics, Yale University, New Haven, CT, United States
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Department of Pathology, Yale School of Medicine, New Haven, CT, United States
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Wu Tsai Institute, Yale University, New Haven, CT, United States
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Department of Biomedical Informatics and Data Science, Yale University, New Haven, CT, United States
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Program in Computational Biology and Biomedical Informatics, Yale University, New Haven, CT, United States
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Department of Neurology, SUNY Downstate Health Sciences University, Brooklyn, New York
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Department of Neurology, Kings County Hospital Center, Brooklyn, New York
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The Robert F. Furchgott Center for Neural and Behavioral Science, Brooklyn, New York
*Email: adam.newton@neurosim.downstate.edu
Introduction
Brain tissue requires a lot of energy to support the energy-intensive activity of neural information processing, particularly restoring ion homeostasis following action potentials. This high demand for energy leaves the system vulnerable to failures in homeostasis, such as spreading depolarization (SD). SDs are a wave of prolonged depolarizations preceded by a brief period of hyperexcitability that propagates through grey matter at 1-9mm/min [1]. Multiple neurological disorders can lead to SD, including migraine aura, epilepsy, traumatic brain injury, and ischemic stroke.
Methods
We modeled point neurons with Hodgkin-Huxley style channels augmented with homeostatic mechanisms, including Na+/K+-ATPase, NKCC1, KCC2, and dynamic volume changes. Astrocytic buffering was modeled as a field of oxygen-dependent and independent clearance of extracellular K+. Connectivity was based on prior models and the weights and the distribution of external drive were scaled to account for differences between conductance-based Integrate-and-Fire models[2,3]. A 2.0 x 2.3 cm cross-section of the human cortical plate in V1 with immunostaining for CD34, was used to determine the locations of 918 capillaries (mean capillary density: 199.6/cm2; mean±SD capillary cross-sectional area: 16.7±11.9μm2).
Results
We used NEURON/RxD/NetPyNE to simulate13,000 neurons representing ~1 mm3of mouse cortex (layers 2-6), monitoring the concentration of Na+, K+, Cl-, and oxygen, both intra- and extra-cellularly[4–7]. Spreading depolarization could be reliably triggered in each layer by elevating extracellular K+with differences in propagation speed between layers.
Discussion
We use this model to explore the hypotheses that vascular heterogeneity will lead to areas where neurons and astrocytes are well-supplied with oxygen and can better maintain normal activity following insult (increased extracellular K+or reduced perfusion). We also examined the mechanisms that could give rise to greater susceptibility and propagation speeds in the superficial layers compared with the deep cortical layers[8].
Acknowledgements
This research was funded by the National Institute of Mental Health, National Institutes of Health, grant number R01 MH086638, with HPC time fromNIH S10 award, 1S10OD032417-01, and the Yale Center for Research Computing McClearly cluster.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
References
1.https://doi.org/10.1007/s12028-021-01429-4
2.https://doi.org/10.1093/cercor/bhs3586
3.https://doi.org/10.1162/neco_a_01400
4.https://doi.org/10.3389/fninf.2022.884046
5.https://doi.org/10.3389/fninf.2018.00041
6.https://doi.org/10.7554/eLife.44494
7.https://doi.org/10.1523/ENEURO.0082-22.2022
8.https://doi.org/10.1177/0271678X16659496
