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.
