Computational modeling of neuronal dynamics for systems analysis: application to neurons of the cardiorespiratory NTS in the rat.

Abstract The study constructs computational models of neurons in order to examine the contribution that their response dynamics may make to functional properties at the system level. As described in the accompanying study, neurons in the cardiorespiratory nucleus tractus solitarii (NTS) of the rat were recorded in vitro. When these cells were intracellularly injected with a constant current pulse, spike discharge patterns and subthreshold voltage trajectories were observed that were time- and voltage-dependent. The accompanying manuscript describes these dynamic responses in 4 classes of putative second-order cells that appear to receive direct primary afferent input, and a previous paper described two populations of rhythmically firing interneurons, one of which is intrinsically auto-active. In the present manuscript experimental neuronal voltage response data was collected across a current injection series for the S3 neuron type described in the accompanying study and for the auto-active neuron described previously. Using this data, computational model neurons have been constructed for these two neurons by using membrane ion channels to produce and match the observed neuronal voltage behavior. The channels were those implicated in the dynamic responses observed in the companion study, and include gNafast, gKdr, gKA, gKCa, gKAHP, gKM, gCaT and gCaL. The description of channel kinetics follows the Hodgkin-Huxley form. Different neuronal sources from the literature of channel kinetics were investigated and assembled into a ‘channel kinetics library’ from which both neuron models were tuned, primarily by adjusting the maximum channel densities, g¯, and time-dependence of kinetics. Methods are described for tuning the channel kinetics library to match various physiological responses. This approach created neuron models that were able to closely replicate the observed complex voltage and spiking responses of the two very different cardiorespiratory NTS neurons. The interaction of voltage- and calcium-dependent conductances were analyzed for their functional contributions by tuning their kinetics. Specific parameters are given that account for the behavior of each model. Sensitivity analyses by perturbing KCa and KA are are shown for both neurons, and I/F curves are presented for the auto-active neuron's simulated and recorded responses. The potential systems-level functional implications resulting from the different kinetics is demonstrated by driving the S3 model neuron in simulation with the pattern of input produced by model primary baroreceptor afferents. The limitations and significance of this approach are discussed. The present study of model neurons are being extended to the larger family of neurons found in the cardiorespiratory NTS (e.g. S1, S2 and S4), are being related to the baroreceptor vagal reflex by in vivo studies, and are being used to explore systems level computation, for example by creating networks reflecting baroreceptor reflex organization. The present kinetics library in principle could be used in this way for other neuronal systems.