Preventing presbycusis in mice with enhanced medial olivocochlear feedback
Preventing presbycusis in mice with enhanced medial olivocochlear feedback
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DOI：
10.1073/pnas.2000760117
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发表时间：
2020-05-26
影响因子：
11.1
通讯作者：
Eugenia Gomez-Casati, Maria
中科院分区：
文献类型：
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作者：
Boero, Luis E.;Castagna, Valeria C.;Eugenia Gomez-Casati, Maria
“变老”是听力损失最常见的原因。听觉相关性听力损失（ARHL）（老年性耳聋）首先影响在背景噪声中理解语音的能力，即使安静时的听觉阈值正常。已经提出耳蜗去神经支配（“突触病”）是与年龄相关的听觉下降的早期贡献者。在目前的工作中，我们通过增强的α 9 α 10胆碱能尼古丁受体门控动力学（“功能获得”nAChR）来表征小鼠中与年龄相关的耳蜗突触变性和毛细胞丢失。它们通过激活相关的钙门控钾通道介导抑制性橄榄耳蜗反馈。通过畸变产物耳声发射和听性脑干反应评估耳蜗功能。免疫标记的Corti器官的整体坐骑，使用共聚焦显微镜定量毛细胞，听觉神经元，突触前带，和突触后谷氨酸受体的特点是coconnar结构。老年野生型小鼠的听觉阈值升高，突触丢失。整个老年耳蜗内毛细胞传入突触丢失，外毛细胞也有一定程度的丢失。相比之下，耳蜗结构和功能保留在老年小鼠与功能获得性nAChR，提供增强的橄榄耳蜗抑制，这表明传出反馈是重要的内耳功能的长期维持。我们的工作提供了证据，橄榄耳蜗介导的抵抗老年性ARHL发生通过α 9 α 10 nAChR复合物外毛细胞。因此，增强内侧橄榄耳蜗系统可能是预防年龄相关性听力损失的可行策略。
"Growing old" is the most common cause of hearing loss. Age-related hearing loss (ARHL) (presbycusis) first affects the ability to understand speech in background noise, even when auditory thresholds in quiet are normal. It has been suggested that cochlear denervation ("synaptopathy") is an early contributor to age-related auditory decline. In the present work, we characterized age-related cochlear synaptic degeneration and hair cell loss in mice with enhanced alpha 9 alpha 10 cholinergic nicotinic receptors gating kinetics ("gain of function" nAChRs). These mediate inhibitory olivocochlear feedback through the activation of associated calcium-gated potassium channels. Cochlear function was assessed via distortion product otoacoustic emissions and auditory brainstem responses. Cochlear structure was characterized in immunolabeled organ of Corti whole mounts using confocal microscopy to quantify hair cells, auditory neurons, presynaptic ribbons, and postsynaptic glutamate receptors. Aged wild-type mice had elevated acoustic thresholds and synaptic loss. Afferent synapses were lost from inner hair cells throughout the aged cochlea, together with some loss of outer hair cells. In contrast, cochlear structure and function were preserved in aged mice with gain-of-function nAChRs that provide enhanced olivocochlear inhibition, suggesting that efferent feedback is important for long-term maintenance of inner ear function. Our work provides evidence that olivocochlear-mediated resistance to presbycusis-ARHL occurs via the alpha 9 alpha 10 nAChR complexes on outer hair cells. Thus, enhancement of the medial olivocochlear system could be a viable strategy to prevent age-related hearing loss.