Sensitivity studies of models of voltage-dependent conductance in neurons

This thesis consists of two manuscripts: “Exploring voltage-dependent ion channels in silico by hysteretic conductance” by Tom Andersson, and “Statistical sensitivity analysis and remodeling of whole-cell conductances in nociceptors” by Tom Andersson, Joanna Tyrcha and Olivia Eriksson. The general approach to modeling neuronal excitability is to formalize and simulate systems of ordinary differential equations that describe voltage-dependent and ionic specific conductances of cell membranes. The systems are deterministic in nature, but rely on a large number of uncertain parameter estimations. The uncertainty is usually ignored and left out of account when analyzing neuronal excitability by means of conductance models. Here we present two sensitivity studies of voltage-dependent conductance models demonstrating the value of both systematic and random parameter variations in formalizing and evaluating model components of membrane excitability. In the first study, we put a specific sensitivity measure to use, i.e. hysteretic conductance (conductance loops), to explore the state space and kinetics of voltage-dependent ion channels. In the second study, we evaluate response effects of parameter variations in a conductance model of nociceptors, revealing critical regulatory parameters by statistical analysis. The studies show that designed sensitivity measures and statistical methods can reveal new conductance mechanisms and regulatory pathways in existing neuronal conductance models.