Date of Degree
PhD (Doctor of Philosophy)
Steven H. Green
Hair cells, the auditory sensory cells, are the sole afferent input to the spiral ganglion neurons (SGNs). HCs and adjacent organ of Corti supporting cells provide neurotrophic factors that prevent SGN degeneration. Following loss of hair cells, SGNs degenerate and gradually die. Most deafness, whether congenital, age-related, or due to noise, disease, trauma, or ototoxin, is a consequence of hair cell loss. Cochlear implants, the only means of restoring hearing to deaf people, electrically stimulate the SGNs, replacing the sensory function of hair cells. SGN degeneration compromises the efficacy of cochlear implants. For example, degeneration of the peripheral process raises the threshold for electrical stimulation, necessitating higher currents that reduce battery life and, by stimulating SGNs in a larger volume, reduce the precision of frequency representation. The goal of my research is to determine why SGNs degenerate or die so that therapies can be developed to prevent it. My approach to this goal focuses on answering two significant questions.
First, because the death of SGNs does not occur immediately after hair cell loss implies that hair cells are not the sole source of neurotrophic support for SGNs. Some neurotrophic support must be available even after hair cells are gone. What are the sources of neurotrophic factors for SGNs after hair cells are lost and why are they ultimately insufficient to prevent SGN death? In Chapter II I answer this question by quantifying neurotrophic factor expression in regions accessible to the SGNs: the organ of Corti and the cochlear nucleus. Answering this question will identify the key endogenous factors that support SGNs, which will facilitate development of optimal therapies.
Second, the fact that SGNs die over a long period of time raises the possibility that there is a difference between SGNs that die early and those that die weeks or months later. Is the time a cell dies purely stochastic or is there something distinctive about cells that die at different times? In Chapter III, I use microarray-based gene expression profiling to compare the initial population of SGNs at the onset of SGN death to a population of SGNs still surviving at a time when about half of the SGNs have already died. Identifying distinctive molecular features in the population of cells that can survive longer in the absence of hair cells may suggest therapeutic approaches to preventing SGN degeneration or death. Finally, Chapter IV addresses some of the molecular features identified by the microarray-based profiling by examining their role in SGN degeneration.
xi, 162 pages
Includes bibliographical references (pages 146-162).
Copyright 2014 Erin Bailey