Castagna Valeria C, Boero Luis E, Di Guilmi Mariano N, Catalano Di Meo Camila, Ballestero Jimena A, Fuchs Paul A, Lauer Amanda M, Elgoyhen Ana, Gomez-Casati Maria
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr. Héctor N. Torres, Consejo Nacional de Investigaciones Científicas y Técnicas, 1428 Buenos Aires, Argentina.
Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, 1121 Buenos Aires, Argentina and Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina.
J Neurosci. 2025 Aug 19. doi: 10.1523/JNEUROSCI.0805-25.2025.
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.
外周性耳聋的早期发作会显著改变听觉系统的正常发育。同样，在早期发育过程中暴露于高强度噪声也会产生类似的破坏作用。在晚成性哺乳动物听力开始之前，耳蜗内毛细胞会表现出驱动听觉回路发育的自发电活动。这种活动通过内毛细胞中α9α10烟碱型胆碱能受体受到内侧橄榄耳蜗（MOC）传出反馈的调节。在成年动物中，这些受体局限于外毛细胞，在那里它们介导MOC反馈以调节耳蜗放大。虽然MOC系统在预防成年期噪声性听力损失方面的保护作用已得到充分证实，但其在早期发育阶段的影响——尤其是对暴露于高强度噪声的反应——在很大程度上仍未得到探索。在本研究中，我们使用了分别缺乏或表现出增强胆碱能活性的雄性和雌性α9基因敲除（KO）和α9基因敲入（KI）小鼠，研究了产后早期发育过程中MOC反馈的作用。我们的研究结果表明，橄榄耳蜗活动的增加和缺失都会导致听力开始时听觉敏感性的改变，以及带状突触数量和形态的远距离改变。早期噪声暴露在野生型和α9KO小鼠中均造成了持久的听觉损伤，这些缺陷一直持续到成年期。相比之下，α9KI小鼠免受噪声诱导的损伤，对听觉功能没有长期影响。这些结果突出了产后早期发育过程中听觉系统易感性的增加。此外，它们表明增强的MOC反馈在此期间可保护听觉系统免受噪声损伤。早期发育是塑造听觉功能的敏感窗口。我们表明，内侧橄榄耳蜗系统对于建立正常的带状突触密度和大小至关重要；这是听力正常开始的关键特征。我们还表明，发育中的听觉系统对高强度噪声特别敏感，早期暴露比生命后期类似的噪声造成更严重和持久的影响。值得注意的是，在这个早期阶段增强α9α10 nAChR受体活性可提供针对噪声诱导损伤的保护，揭示了一个保护听觉发育的时间敏感机会。
