Recent work suggests that hair cells are not the most vulnerable elements in the inner ear; rather, it is the synapses between hair cells and cochlear nerve terminals that degenerate first in the aging or noise-exposed ear. This primary neural degeneration does not affect hearing thresholds, but likely contributes to problems understanding speech in difficult listening environments, and may be important in the generation of tinnitus and/or hyperacusis. To look for signs of cochlear synaptopathy in humans, we recruited college students and divided them into low-risk and high-risk groups based on self-report of noise exposure and use of hearing protection. Cochlear function was assessed by otoacoustic emissions and click-evoked electrocochleography; hearing was assessed by behavioral audiometry and word recognition with or without noise or time compression and reverberation. Both groups had normal thresholds at standard audiometric frequencies, however, the high-risk group showed significant threshold elevation at high frequencies (10–16 kHz), consistent with early stages of noise damage. Electrocochleography showed a significant difference in the ratio between the waveform peaks generated by hair cells (Summating Potential; SP) vs. cochlear neurons (Action Potential; AP), i.e. the SP/AP ratio, consistent with selective neural loss. The high-risk group also showed significantly poorer performance on word recognition in noise or with time compression and reverberation, and reported heightened reactions to sound consistent with hyperacusis. These results suggest that the SP/AP ratio may be useful in the diagnosis of “hidden hearing loss” and that, as suggested by animal models, the noise-induced loss of cochlear nerve synapses leads to deficits in hearing abilities in difficult listening situations, despite the presence of normal thresholds at standard audiometric frequencies.

Although protective effects of the cochlea’s efferent feedback pathways have been well documented, prior work has focused on hair cell damage and cochlear threshold elevation and, correspondingly, on the high sound pressure levels (> 100 dB SPL) necessary to produce them. Here we explore the noise-induced loss of cochlear neurons that occurs with lower intensity exposures and in the absence of permanent threshold shifts. Using confocal microscopy to count synapses between hair cells and cochlear nerve fibers, and using measurement of auditory brainstem responses and otoacoustic emissions to assess cochlear pre- and post-synaptic function, we compare the damage from a weeklong exposure to moderate-level noise (84 dB SPL) in mice with varying degrees of cochlear de-efferentation induced by surgical lesion to the olivocochlear pathway. Such exposure causes minimal acute threshold shift and no chronic shifts in mice with normal efferent feedback. In de-efferented animals, there was up to 40% loss of cochlear nerve synapses and a corresponding decline in the amplitude of the auditory brainstem response. Quantitative analysis of the de-efferentation in inner vs. outer hair cell areas suggested that outer hair cell efferents are most important in minimizing this neuropathy, presumably by virtue of their sound-evoked feedback reduction of cochlear amplification. The moderate nature of this acoustic overexposure suggests that cochlear neurons are at risk even in everyday acoustic environments, and, thus, that the need for cochlear protection is plausible as a driving force in the design of this feedback pathway.

To further understand the roles and origins of gamma-aminobutyric acid (GABA) and calcitonin gene-related peptide (CGRP) in the efferent innervation of the cochlea, we first produced in the mouse an immunocytochemical map of the efferent terminals that contain acetylcholine (ACh), CGRP, and GABA. Olivocochlear (OC) terminals in inner and outer hair cell (IHC and OHC) regions were analyzed quantitatively along the cochlear spiral via light-microscopic observation of cochlear wholemounts immunostained with antibodies to glutamic acid decarboxylase (GAD), vesicular acetylcholine transporter (VAT), or the peptide CGRP. Further immunochemical characterization was performed in mice with chronic OC transection at the floor of the fourth ventricle to distinguish crossed from uncrossed contributions and, indirectly, the contributions of lateral versus medial components of the OC system. The results in mouse showed that (1) there are prominent GABAergic, cholinergic, and CGRPergic innervations in the OHC and IHC regions, (2) GABA and CGRP are extensively colocalized with ACh in all OC terminals in the IHC and OHC areas, (3) the longitudinal gradient of OC innervation peaks roughly at the 10-kHz region in the OHC area and is more uniform along the cochlear spiral in the IHC area, (4) in contrast to other mammalian species there is no radial gradient of OC innervation of the OHCs, and (5) all OHC efferent terminals arise from the medial OC system and terminals in the IHC area arise from the lateral OC system.