Tinnitus remains one of the major reasons for patient visits to the otolaryngology clinic, but effective pharmacological therapies have yet to be developed for this disorder. The recent development of animal models of experimentally induced tinnitus offers promising new avenues for understanding the mechanisms of tinnitus and for the development of effective treatments. In this project we will seek further insights into the mechanisms underlying tinnitus using noise-induced hyperactivity in the dorsal cochlear nucleus as a model of tinnitus producing signals. First, we will investigate the roles of outer hair cell loss and excitotoxicity as triggers of hyperactivity in the DON. The goal will be to test the hypothesis that noise-induced hyperactivity consists of two components, one of which correlates strongly with the amount of outer hair cell loss, the other of which involves excitotoxic injury via NMDA receptors. Second, we will use quantitative PCR and related methods to identify the molecular correlates of noise-induced hyperactivity. We will test the prediction that hyperactivity is associated with changes in gene expression for one or more of the key neurotransmitter receptors, ion channel conductance channels, or regulatory proteins that control the level of excitability of DCN neurons. Third, pharmacological studies will be conducted in the DCN to dissect out the principal circuit elements involved in the generation of hyperactivity. These studies will determine whether the fusiform cells are the major generators of hyperactivity and whether that hyperactivity can be modulated by activating the granule cell-cartwheel cell pathway. Fourth, further insight into the identity of hyperactive cells will be sought by juxtacellular labeling of cells from which recordings of spontaneous activity have been obtained. Cells displaying hyperactivity will be distinguished from those with normal activity based on their morphological characteristics. And fifth, we will examine the role of changes in ion channel conductances as a possible mechanism contributing to the generation of hyperactivity. This role will be tested by determining whether neurons in the DCN of exposed animals show altered sensitivity to agents that block selected ion channels. Our focus will be on channels which have a strong influence on the level of spontaneous activity and which have been found in other systems to be up- or down-regulated following loss of afferent input.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Study Section
Auditory System Study Section (AUD)
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Miller, Roger
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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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
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