The diagnosis and protection of the auditory peripheral system

Sammanfattning: The main focus of this thesis is on the diagnosis and prevention of peripheral hearing loss. An auditory evoked response measure (forward masking) was developed that specifically tests the function of the inner hair cells, independently of the outer hair cells. Specifically, the glutamate receptor, AMPA was found to play an important role in forward masking. The other issue of this thesis was that hearing loss induced by either noise trauma or ototoxic drugs can be protected by the use of neurotrophic factors and/or glutamate receptor antagonists. Several models of peripheral hearing loss were used which induced outer or inner hair cell dysfunction, inner hair cell degeneration, or post-synaptic pathology of the inner hair cell. It was found that the outer hair cell, is not involved in short-term adaptation of forward masking, rather the inner hair cell and its post-synaptic receptors play an important role in adaptation. In addition, while the AMPA receptor is essential whereas the NMDA receptor plays a lesser role in short-term adaptation. When hearing loss was induced by noise exposure it was found that the slope of the forward masking curve could be used to predict whether the threshold shift would develop into a temporary or a permanent hearing loss. If the difference in slope between pre-noise exposure and immediate-post noise expo- sure was more than 2 it suggested that the hearing loss would be permanent. In contrast, if the difference was less than 2, the noise-induced hearing loss would be temporary. The second part of the thesis was focused on finding a means of protecting against hearing loss. By infusing the cochlea with the neurotrophic factor, NT-3, we found that aminoglycoside-induced degeneration of the spiral ganglion neurons could be nearly completely prevented. The potency of NT-3 in protecting against spiral ganglion loss suggests that this neurotrophin may be useful for the treatment of hearing disorders. However, in this study, the neurotrophic factor, NT-3 did not afford protection against the loss of hair cells which suggest a limitation in its protective ability. When the combined treatment with MK801, a NMDA antagonist, and NT-3 were applied, it was found that hearing loss was attenuated and spiral ganglion neuron loss was nearly totally protected. This study indicates that the importance of the combined treatment of NT-3 and NMDA antagonists in the treatment of hearing disorders.