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Multiscale computer modeling of brain excitability: applications to spreading depression and neuronal impedance
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Lytton, William
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Spring 2023
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2023-06-26
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Kelley_thesis_062823.pdf
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Multiscale modeling of biological systems integrates disparate experimental results into unified
theoretical frameworks. We used multiscale modeling to investigate excitability in neural systems at
the scales of dendrites, single neurons, and tissue-scale activation patterns. We employed impedance
analysis to study subthreshold excitability in morphologically and biophysically detailed models of
neocortical layer 5b pyramidal neurons, which predicted that the interaction of hyperpolarizationactivated
cyclic nucleotide-gated (HCN) and Twik-associated acid-sensitive K+ (TASK) channels
are integral to producing their observed impedance profiles. Impedance analysis is properly limited
to studying neuronal responses to small, subthreshold stimuli, but this excludes a great deal of
neuronal function. To overcome the limitations of impedance analysis, we developed an analog to
impedance phase to characterize high amplitude signals, both sub- and suprathreshold. For high
amplitude stimuli, we found different phase shifts during hyperpolarizing and depolarizing halfcycles.
We also found two nonstationary phase relationships between spiking and stimulus: phase
retreat, where action potentials occurred progressively later in cycles of the input stimulus resulting
from adaptation, and phase advance, where action potentials occurred progressively earlier. In a
separate study, we developed a computer model of spreading depolarization (SD) in brain slices
using the NEURON simulator: 36,000+ neurons in the extracellular space (ECS) of a slice with ion
and O2 diffusion and equilibration with a surrounding bath. Simulations reproduced key features
of SD, including its speed moving across the tissue and firing properties of individual neurons,
and led to a number of experimentally-testable predictions. We have also developed a model of
neocortex in vivo with realistic distributions of O2 sources based on histology from human subjects.
This model can be used to investigate the role of connectivity in SD propagation and how ischemic
insults lead to SD initiation.
Citation
Kelley, C (2023). Multiscale computer modeling of brain excitability: applications to spreading depression and neuronal impedance [doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/14766