Date of Award

2019

Embargo Period

8-1-2024

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

Edward L. Krug

Third Advisor

Kelly C. Harris

Fourth Advisor

Judy R. Dubno

Fifth Advisor

Bärbel Rohrer

Sixth Advisor

Bradley A. Schulte

Abstract

The auditory nerve (AN) is an integral part of the auditory system and without it, we cannot hear sound. Glial cells insulate type I spiral ganglion neurons (SGNs) with myelin sheaths, which are protective and constrain electrical signal within SGNs, facilitating propagation. Formation of excitable nodal domains containing clusters of voltage-gated ion channels in unmyelinated gaps along axons also allow for rapid saltatory conduction. Sensorineural hearing loss is commonly attributed to loss of synaptic connections between the AN fibers and hair cells, hair cell loss, or SGN death. Primary glial dysfunction in the AN is not as well-studied. Demyelinating diseases such as Guillain-Barre and Charcot-Marie-Tooth, characterized by myelin and nodal abnormalities, result in reduced nerve function manifesting into muscle weakness, sensational changes, and neuropathy. In this dissertation, we identified for the first time three types of excitable nodal domains in the AN and how these nodal structures form/refine during postnatal cochlear development. Our results reveal that maturation of the nodal domains contributes to gain in hearing function. In addition, our data demonstrate that dysregulation of glial function and dysmyelination after noise in young adult AN is partly responsible for noise-induced hearing loss. Lastly, we determined that primary glial dysfunction in AN development via knockout of myelination-regulator Quaking results in chronic dysmyelination and abnormal nodal structure formation leading to slower conduction, dyssynchronous AN firing, and hearing loss.

Rights

All rights reserved. Copyright is held by the author.

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