Theoretical, Computational, and Experimental Topics in Anterior Pituitary Cell Signaling
Fletcher, Patrick Allen (author)
Bertram, R. (Richard) (professor co-directing dissertation)
Tabak-Sznajder, Joel (professor co-directing dissertation)
Yang, Wei (university representative)
Cogan, Nicholas G. (committee member)
Mascagni, Michael V. (committee member)
Mio, Washington (committee member)
Florida State University (degree granting institution)
College of Arts and Sciences (degree granting college)
Department of Mathematics (degree granting department)
The neuroendocrine system presents a diversity of patterns in hormone secretion across a large range of temporal scales. These patterns of secretion are crucial to many aspects of animal survival and behavior. This offers a wealth of important and interesting topics of study amenable to theoretical, experimental, and computational approaches. The pituitary gland plays a large role in neuroendocrine physiology by decoding signals from the brain, translating those signals and relaying them to the glands and tissues of the body via the circulatory system. The cells of the anterior pituitary gland use a diverse set of biochemical processes to accomplish this task. The first step is the activation of a hormone receptor, which convert an extracellular signal to an intracellular one. These receptors in turn trigger cascades of chemical reactions involving enzymes and intracellular messengers, as well as changes in membrane potential dynamics and intracellular Ca2+ ion concentrations, all of which are important in controlling the production and secretion of hormones at appropriate levels. The first portion of this dissertation studies how such biochemical systems respond to patterned inputs, such as pulsatile patterns that are characteristic of hormones in the reproductive system, growth hormone, and stress-responsive hormones. We examine how models of some common intracellular signaling components such as receptor binding and protein phosphorylation respond to pulsed inputs. We then study how a preference for a specific input pulse frequency may arise from the interactions between transcription factors, which are molecules regulating the expression of genes and in this case responsible for production of a hormone. The next portion of this work describes experiments performed to demonstrate the direct actions of a hormone, oxytocin, on three pituitary cell types. Intracellular Ca2+ ion concentration was measured in primary cultured female rat pituitary cells in vitro using video microscopy and a fluorescent \ca-sensitive dye. Oxytocin triggered increases in intracellular Ca2+ concentration as well as secretion of hormone from gonadotrophs, somatotrophs, and lactotrophs in a manner consistent with a direct action via the oxytocin receptor. Finally, computational tools are presented for harnessing the computational power of graphics processing units to rapidly compute numerical solutions to initial value problems such as those that arise in the study of pituitary cell electrophysiology. This provides tools for more rapid model exploration by computing the ensembles of parameter combinations required in parameter sweep and parameter space sampling computations in parallel. This allows rapid computations to be performed on inexpensive modern desktop or laptop computers. As a case study, we use a model of membrane potential dynamics of pituitary lactotroph cells, which is produces spiking and bursting patterns. We compare the actions of three K+ channel conductances known to be increased by the action of the hormone dopamine in lactotrophs. Paradoxically, low levels of dopamine stimulate Ca2+ increases despite only increasing these typically inhibitory conductances, a result previously hypothesized to be due to a transition from spiking to bursting. We compare the mechanisms by which one of the K+ channels is able to promote this stimulatory effect while the other two are not, and we find that this effect is robust in a population of model cells with randomized background parameters.
Anterior pituitary, Electrophysiology modeling, Mathematical modeling, Mathematical neuroendocrinology, Parallel computing, Singaling pathways
June 2, 2015.
A Dissertation submitted to the Department of Mathematics in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Includes bibliographical references.
Richard Bertram, Professor Co-Directing Dissertation; Joel Tabak, Professor Co-Directing Dissertation; Wei Yang, University Representative; Nick Cogan, Committee Member; Michael Mascagni, Committee Member; Washington Mio, Committee Member.
Florida State University
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