Effects of carboplatin-induced inner hair cell loss on auditory perception in chinchilla
MetadataShow full item record
The mammalian inner ear, the cochlea, contains two distinct sensory cell types, inner hair cells and outer hair cells. Previous studies have shown that outer hair cell damage leads to hearing impairments in which threshold to sound perception increases and frequency selectivity decreases. This type of hair cell damage is typically associated with aging, noise exposure or ototoxicity and has been extensively studied. However, little is known about the effects of selective inner hair cell loss on hearing. Since inner hair cells and type I afferent neurons provide the primary route for transmitting information to the central auditory system, it is important to understand their role in hearing. To address this important question, four measures of auditory performance were assessed in the chinchilla before and after selectively destroying the inner hair cells with carboplatin, a platinum based anti-tumor agent. In order to assess hearing sensitivity, thresholds to tones in quiet were tested across a broad range of frequencies in (250-11,300 Hz) before and after carboplatin treatment. After carboplatin treatment, there was no significant change in thresholds across frequencies 250-4000 Hz. Thresholds at 8000 and 11,300 Hz showed significant changes but the actual threshold shift was smaller than expected. Next, the same group of subjects was then tested across these frequencies (250-11,300 Hz) in the presence of a 50 dB SPL broad band noise masker. After carboplatin, there was a significant elevation in thresholds at all frequencies, suggesting that selective inner hair cell loss reduced the ability to resolve signals in noise. To obtain a more direct estimate of frequency selectivity, tuning was tested using three narrow band noise maskers (70 dB SPL) centered at 500, 2000, and 4000 Hz. A series of pure tone frequencies (250-11,300 Hz) were tested above and below the center frequency of each masker to obtain the shape of the auditory filters (an index of tuning) at the three masker frequencies. After carboplatin there was a significant elevation in thresholds across all of the frequencies tested under all three masking conditions. The most intriguing results were elevations at frequencies distant to the center frequency of the masker. The elevations in threshold below the center frequency of each masker were contrary to what is known about the spread of excitation in the cochlea. Both masking experiments showed a significant impairment in detecting signals in noise following selective inner hair cell loss. The fourth behavioral experiment evaluated temporal resolution as a function of selective inner hair cell loss. A gap detection paradigm, in which animals were required to detect brief silent intervals embedded in continuously running broadband noise, was used. After carboplatin treatment, a significant increase in gap detection threshold was found across the four intensities tested (75, 65, 50, and 40 dB SPL BBN). At the highest intensity (75 dB SPL) gap detection threshold on average doubled while at the lowest intensity tested there was a threefold increase in gap detection times. These results showed that selective inner hair cell loss significantly impaired auditory temporal resolution. At the end of the behavioral experiments, all animals were sacrificed, the cochleae were removed, and both inner and outer hair cells were counted. The relationship between the inner hair cell lesion size and threshold shift in quiet showed that thresholds increased at a rate of 3 dB for each additional 10% inner hair cell loss above 40% inner hair cell loss. The relationship of inner hair cell loss to thresholds in broad band noise showed that thresholds increased at a rate of 1.5 dB for each additional 10% inner hair cell loss above 25% inner hair cell loss. Moderate inner hair cell lesions were found to increase thresholds to narrow band noise at both the center frequency of each masker as well as the upper and lower frequency skirts of the narrow band noise masking patterns. Finally, the gap detection paradigm also proved to be sensitive to moderate inner hair cell lesions with elevations observed in all conditions tested and across all animals following carboplatin treatment. The overall results show that threshold in quiet was a relatively insensitive measure of moderate inner hair cell lesions. In contrast, threshold in noise and gap detection were much more sensitive to inner hair cell loss. The results presented in this study are the first to show the perceptual consequences of inner hair cell loss on hearing and may be useful in determining the etiology of clinical syndromes in which inner hair cell dysfunction is suspected, such as in Auditory Neuropathy.