Strengthening Medial Olivocochlear Feedback Reduces the Developmental Impact of Early Noise Exposure.

The early onset of peripheral deafness significantly alters the proper development of the auditory system. Likewise, exposure to loud noise during early development produces a similar disruptive effect. Before hearing onset in altricial mammals, cochlear inner hair cells exhibit spontaneous electrical activity that drives auditory circuit development. This activity is modulated by medial olivocochlear (MOC) efferent feedback through α9α10 nicotinic cholinergic receptors in inner hair cells. In adults, these receptors are restricted to outer hair cells, where they mediate MOC feedback to regulate cochlear amplification. Although the MOC system's protective role to prevent noise-induced hearing loss in adulthood is well-established, its influence during early developmental stages -especially in response to exposure to loud noise- remains largely unexplored. In this study, we investigated the role of MOC feedback during early postnatal development using α9 knockout (KO) and α9 knock-in (KI) mice of either sex, which respectively lack or exhibit enhanced cholinergic activity. Our findings reveal that both increased and absent olivocochlear activity result in altered auditory sensitivity at the onset of hearing, along with long-range alterations in the number and morphology of ribbon synapses. Early noise exposure caused lasting auditory damage in both wild-type and α9KO mice, with deficits persisting into adulthood. In contrast, α9KI mice were protected from noise-induced damage, with no long-term effects on auditory function. These results highlight the increased susceptibility of the auditory system during early postnatal development. Moreover, they indicate that an enhanced MOC feedback shields the auditory system from noise damage during this period. Early development represents a sensitive window for shaping auditory function. We show that the medial olivocochlear system is critical for establishing normal ribbon synapse density and size; key features for proper hearing onset. We also show that the developing auditory system is especially vulnerable to loud noise, with early exposure causing more severe and lasting effects than similar noise later in life. Notably, enhancing α9α10 nAChR receptor activity during this early stage offers protection against noise-induced damage, revealing a time-sensitive opportunity to safeguard auditory development.