Date of Award

1-1-2008

Degree Name

Doctor of Philosophy

Department

Pharmacology

First Advisor

Caspary, Donald

Abstract

FFifteen to thirty-five percent of the population in the United States experience tinnitus, a subjective "ringing in the ears". Up to 10% of tinnitus patients report their symptoms are severe and disabling. Tinnitus was induced in FBN rats using 116 dB (SPL) unilateral octave-band sound exposures centered at 16 kHz for one hour in an anesthetized preparation. Rats were assessed behaviorally by an operant conditioning paradigm as well as a gap detection method to verify the development of tinnitus. Both young (7 mos.) and aged (30 mos.) sound exposed rats showed significant elevated auditory brainstem-evoked response (ABR) thresholds for clix and all tested frequencies immediately after the sound exposure. Eighty days post-exposure, ABR thresholds for the young exposed rats were significantly close to the initial young control values while aged exposed rats showed residual thresholds shifts relative to aged controls. Sixteen weeks following sound exposure, young exposed rats showed significantly reduced gap detection at 24 and 32 kHz, suggestive of high frequency tinnitus. Aged exposed animals showed significant tinnitus-related behavioral changes near 10 kHz by both behavior methods. Message and protein levels of &alpha1-3 glycine receptor subunits (GlyRs), gephyrin, BDNF and its receptor TrkB were assessed in dorsal cochlear nucleus (DCN) fusiform cells 4 months post exposure utilizing quantitative in situ hybridization and immunocytochemistry. Young exposed rats showed significant decreases of GlyR &alpha1 protein at middle and high frequency regions in DCN unlike the contrasting increase of their message levels. Aged exposed rats showed higher &alpha1 subunit protein levels in the same high and middle DCN frequency regions. The GlyR anchoring protein, gephyrin, was significantly increased in both young and aged exposed rats, suggesting an intracellular receptor trafficking change following acoustic trauma. BDNF and TrkB were also increased over fusiform cells in both young and aged exposed rats. [3H] strychnine binding was used to evaluate DCN GlyR pharmacology and function following sound exposure. The age-related decrease in GlyR α1 protein was reflected in the significant age-related down-regulation of GlyR (Bmax). Tinnitus-related changes in GlyR &alpha1 protein level was reflected in the decline of the GlyR (Bmax) in young exposed rats and up-regulated GlyRs in aged exposed animals. The GlyRs in DCN of young exposed animals also demonstrated an increase in affinity, further suggesting a post-exposure receptor composition change. These findings suggest that both aging and/or sound exposure/tinnitus are associated with GlyR changes capable of altering alter the output of the DCN. Detailed characterization of these GlyR modifications could advance the development of novel selective drugs for tinnitus and age-related hearing loss.

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