Date of Award

1-1-2018

Embargo Period

1-1-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pathology and Laboratory Medicine

College

College of Graduate Studies

First Advisor

Hainan Lang

Second Advisor

Carl Atkinson

Third Advisor

Jeremy L. Barth

Fourth Advisor

Judy R. Dubno

Fifth Advisor

Edward L. Krug

Sixth Advisor

Stephen P. Ethier

Abstract

Hearing relies on the transmission of auditory information from sensory hair cells to the brain through the auditory nerve. This relay of information requires hair cells to be innervated by spiral ganglion neurons (SGNs) in an exclusive manner and for SGNs and their axons to be ensheathed by myelinating and non-myelinating glial cells. In the developing auditory nerve, mistargeted SGN axons undergo retraction or pruning, and excessive neural cells are eliminated to obtain the characteristic innervation pattern seen in the mature cochlea. The mechanisms governing auditory nerve maturation remain unclear. However, in peripheral nerves, key contributors to the establishment of mature nerve circuitry are immune cells, such as macrophages. The major goal of this dissertation was to determine if macrophages are beneficial for the structure and function of the developing auditory nerve. Using postnatal mice, we examined macrophage distribution and activation in the developing auditory nerve and explored the relationship between macrophages and glial cells. In the developing auditory nerve, the number of macrophages and glial cells peaked during the first postnatal week, concurrent with the period of SGN refinement. Macrophage and glial cell numbers were significantly reduced by the second postnatal week, when SGN pruning is complete. Macrophages also phagocytosed glial cells, suggesting a role for macrophages in regulating glial cell numbers. Transient depletion of macrophages in postnatal mice resulted in cochlear pathologies, including increased glial cell numbers, temporary cochlear lateral wall alterations and diminished auditory function. Another goal of this dissertation was to investigate the role of immune-related pathways in the auditory nerve. Complement proteins localize to the surface of nerves during developmental refinement and injury-related regeneration. Using adult complement fB-/- mice, we examined the role of alternative complement signaling in the auditory nerve. Similar with our findings in macrophage-depleted mice, factor B deficient mice demonstrated diminished auditory function and exhibited increased glial cell numbers and myelin dysfunction. These common pathologies indicate that macrophages and the alternative complement signaling pathway regulate glial cell numbers and function, demonstrating that macrophages and specified immune signals are beneficial and required for auditory nerve development by supporting glial cell function.

Rights

All rights reserved. Copyright is held by the author.

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