Cochlear synaptopathy, neural pathophysiology and suprathreshold processing in animal models of sensorineural hearing loss

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Project 1 Summary - Abstract Animal studies of acquired sensorineural hearing loss (SNHL) have shown that loss of synapses between auditory nerve fibers (ANFs) and inner hair cells (IHCs) often occurs before permanent hair cell damage. This primary cochlear nerve degeneration (CND) has little effect on thresholds, but decreases discriminability of sounds, especially in noisy environments, and may trigger tinnitus and hyperacusis due to changes in excitation/inhibition in central auditory circuits. In prior work, Project 1 showed that several suprathreshold electrophysiological metrics can predict synaptic loss in animals when thresholds are normal, and Project 3 showed that these metrics correlate with word-identification performance in challenging listening environments among subjects with normal audiometric thresholds, consistent with a role for CND in hearing impairment that hides behind the audiogram. Over the next 5 years, all Center Projects shift focus to the study of CND in cases where thresholds are elevated. Consistent with the intent of the P50 mechanism, the primary role of Project 1 animal work is in support of the human studies. To that end, we have developed a set of animal models with complementary patterns of neural and hair cell damage. In Aim 1 we use these models to: 1) clarify the cellular generators of the summating potential, the biomarker best correlated with word scores in human subjects, 2) validate the utility of a novel electrophysiologic metric, the envelope following response to rectangular-wave amplitude modulation, in detecting CND in the presence of outer hair cell damage, and 3) determine whether the different CND-eliciting lesions all selectively target cochlear neurons with high thresholds and low spontaneous rates. For Aim 2, we have developed a novel electrophysiological assay of central auditory hyperactivity (that will also be used in human subjects) and a set of behavioral assays to detect changes in loudness perception and the presence of phantom sounds. By applying these assays to animals with different lesion patterns, we can test key hypotheses about the interactions between peripheral CND, central gain control adjustments, and the disabling perceptual anomalies of tinnitus and hyperacusis.