Impairments of the Medial Olivocochlear System Increase the Risk of Noise-Induced Auditory Neuropathy in Laboratory Mice

Auditory neuropathy spectrum disorder (ANSD) describes a prevalent hearing disorder that is characterized by normal cochlear outer hair cell (OHC) function and abnormal auditory nerve function (1). Minimum diagnostic criteria include normal otoacoustic emissions (OAEs) and missing or aberrant auditory brainstem responses (ABRs). Changes in the ABR are assumed to arise from a dys-synchronization of sound-driven activity in the auditory nerve. The loss of temporal processing can impair speech, sound localization, and listening in noise. The impact of ANSD on speech has encouraged neonatal screening programs for early diagnosis of the disorder. These programs have revealed a higher incidence of ANSD among infants who have been treated in neonatal intensive care units (NICUs)(2,3). Although the health concerns that necessitate early hospitalization are varied, a constant factor in NICU treatments is the noise exposure that is generated by equipment, procedures, and staff (4,5). Several surveys have reported NICU noise levels consistently above the recommendations of the American Academy of Pediatrics (AAP) for both sustained (Leq) and maximum transient exposures (Lmax) (6). At present, significant ambiguities remain on what constitutes an acceptable level of noise exposure in human infants. While it is clear that a single loud exposure at a young age can accelerate hearing loss and promote spiral ganglion degeneration (7), the effects of persistent moderate exposures are difficult to estimate because environmental noise exerts pervasive effects on the developing auditory system. The deficits often manifest as perceptual disorders that are independent of overt hearing loss (8,9). Physiological studies of the cochlea and auditory nerve have provided detailed functional analyses of the medial olivocochlear system (MOCS). In normal individuals, the release of acetylcholine by the MOCS hyperpolarizes the membrane potentials of OHCs (10). The resulting decrease in cochlear mechanical sensitivity protects the ear from damaging levels of noise (11) and enhances auditory processing in distracting levels of noise (12,13). Recent clinical evidence suggests that ANSD is more prevalent among MOCS-compromised children (14). One explanation for this increased risk is that synaptic development of the central auditory pathways requires regulated sound-driven activity in the ascending inputs of the auditory nerve (15–17). When young individuals are exposed to environmental noise, MOC feedback may preserve normal synaptic development by regulating potentially disruptive levels of noise-driven activity. To investigate this novel developmental role for the MOCS, the feedback system was silenced in laboratory mice by a genetic modification of cholinergic signaling (18). The mice were reared in background noise, and then screened for ANSD using established diagnostic criteria. The audiological implications of the observed processing deficits were further delineated with a behavioral assay of temporal acuity. The refinement of this animal model allowed us to relate common clinical observations to direct electrophysiological recordings from the post-synaptic targets of the auditory nerve in the ventral cochlear nucleus. These recordings revealed significant functional impairments of the synaptic specializations that dictate the quality of temporal coding in the auditory brainstem.