Date of Award

5-4-2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Gennady Cymbalyuk

Second Advisor

Ronald Calabrese

Third Advisor

Vadym Apalkov

Fourth Advisor

Vladimir Bondarenko

Fifth Advisor

Chun Jiang

Abstract

Membrane bound ion pumps have long been studied in a housekeeping role, and it is well known that they play a major part in creating the ionic gradients which determine the electrical excitability in a cell. Recent work has begun to highlight other, more direct roles for ion pumps in rhythm generation and information processing. As many pumps obtain energy for active ion transport from adenosine triphosphate (ATP) hydrolysis, they can exchange ions in an electrically asymmetric manner, generating an outward current, which along with ion channel currents, drives the membrane potential of the cell. Membrane potential is a major determining characteristic for how information is transferred between neurons, and so in persistently active excitable cells, pumps can provide a considerable contribution to neuron dynamics. Specialized networks of neurons and non-neural cells which drive rhythmic behaviors such as breathing and locomotion, must robustly produce useful patterns for the animal under dynamic behavioral goals in a highly variable environment. Here we will focus on two well-studied classes of ATPase pumps (the plasma membrane calcium ATPase pump (PMCA) and the sodium-potassium ATPase pump (Na+/K+ pump)) and investigate the role of these pumps in two rhythm generating biological subsystems with a combination of modeling and experimental approaches. In a model of a leech heartbeat central pattern generator, we demonstrate how the neuromodulator myomodulin can regulate the temporal properties of rhythm generation through effects on the hyperpolarization-activated current and the Na+/K+ pump current, and discuss the benefits of modulators which target multiple currents. With this model, we also show how synaptic inhibition can support a functional pattern when pump current is downregulated. Then, in a model of interstitial cells of Cajal (ICC) in the muscular syncytium of the intestinal walls, we demonstrate that due to the importance of complex intracellular calcium oscillations in the generation of ICC rhythms, the PMCA pump can play a major role in regulating the temporal properties of rhythm generation. We discuss rhythm generation mechanisms in both systems and predict parameter domains of multistability which correspond to both functional and pathological states of rhythm generation.

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