The main objective of this study is to further develop our animal model of tinnitus with the goal of defining physiological and chemical correlates of this hearing disorder at the level of the cochlear nucleus. This project builds on our recent studies showing that intense sound exposure at levels sufficient to induce tinnitus in humans leads to increases in spontaneous neural activity (hyperactivity) in the dorsal cochlear nucleus.
The specific aims of this project are as follows: 1) Two-choice behavioral tests will be employed to characterize the pitch and loudness of sound-induced tinnitus in hamsters. The relationship of these measures to altered activity in the cochlear nucleus will be investigated by quantifying the magnitude and spatial distribution patterns of hyperactivity in the same animals. 2) The laminar distribution of the hyperactive cells will be determined by marking sites where activity is highest with horseraddish peroxidase,HRP. Further clarification of the cellular substrates underlying hyperactivity will be sought by immunolabeling hyperactive cells with antibodies to the c-fos gene product in cochlear nucleus sections. 3) The cochlear nuclei will then be analyzed chemically to determine whether increases in spontaneous activity are correlated with chemical changes. The concentrations of selected neurotransmitter candidates, neurotransmitter-associated enzymes, and neurotransmitter receptors will be assayed using high performance liquid chromatography and autoradiography. Changes in these elements will be mapped along the tonotopic axis. Chemically altered areas will be identified and correlated with regions showing hyperactivity. 4) The possible role of cochlear outer hair cell loss as a trigger of hyperactivity and tinnitus will be investigated by testing whether animals treated with cisplatin, an agent known to induce tinnitus in humans and to cause selective outer hair cell loss in humans and animals, show evidence of behavioral tinnitus and hyperactivity in the cochlear nucleus. Findings from these experiments are expected to contribute to an understanding of central mechanisms of tinnitus and pave the way toward the development of anti-tinnitus therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC003258-03A1
Application #
2903506
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Project Start
1997-01-01
Project End
2004-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Wayne State University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Heffner, Henry E (2011) A two-choice sound localization procedure for detecting lateralized tinnitus in animals. Behav Res Methods 43:577-89
Finlayson, Paul G; Kaltenbach, James A (2009) Alterations in the spontaneous discharge patterns of single units in the dorsal cochlear nucleus following intense sound exposure. Hear Res 256:104-17
Kaltenbach, James A (2007) The dorsal cochlear nucleus as a contributor to tinnitus: mechanisms underlying the induction of hyperactivity. Prog Brain Res 166:89-106
Kaltenbach, James A; Zhang, Jinsheng (2007) Intense sound-induced plasticity in the dorsal cochlear nucleus of rats: evidence for cholinergic receptor upregulation. Hear Res 226:232-43
Kaltenbach, James A (2006) Summary of evidence pointing to a role of the dorsal cochlear nucleus in the etiology of tinnitus. Acta Otolaryngol Suppl :20-6
Kaltenbach, James A (2006) The dorsal cochlear nucleus as a participant in the auditory, attentional and emotional components of tinnitus. Hear Res 216-217:224-34
Kaltenbach, James A; Zhang, Jinsheng; Finlayson, Paul (2005) Tinnitus as a plastic phenomenon and its possible neural underpinnings in the dorsal cochlear nucleus. Hear Res 206:200-26
Kaltenbach, James A; Zacharek, Mark A; Zhang, Jinsheng et al. (2004) Activity in the dorsal cochlear nucleus of hamsters previously tested for tinnitus following intense tone exposure. Neurosci Lett 355:121-5
Zacharek, Mark A; Kaltenbach, James A; Mathog, T Alecia et al. (2002) Effects of cochlear ablation on noise induced hyperactivity in the hamster dorsal cochlear nucleus: implications for the origin of noise induced tinnitus. Hear Res 172:137-43
Kaltenbach, J A (2000) Neurophysiologic mechanisms of tinnitus. J Am Acad Audiol 11:125-37