Cholinergic efferent re-wiring of hair cells in the aging cochlea: understanding mechanisms and functional significance

年龄相关性听力损失（ARHL）是老年人最常见的健康状况。大约有一半的70多岁的成年人表现出严重到足以影响交流的ARHL。预计到2030年，英国约有1450万人将受到听力损失的影响，其中ARHL是最大的单一原因。ARHL是一种进行性障碍，会降低理解语言的能力，尤其是在嘈杂的环境中。ARHL还与社会孤立、抑郁和神经退行性疾病风险增加有关。虽然助听器和人工耳蜗是有益的，但它们不能恢复听力，特别是如果耳朵里的细胞缺失或不起作用，这都是ARHL的特征。阻碍ARHL新疗法发展的主要障碍是缺乏对我们随着年龄增长而逐渐丧失听力的原因的理解，这使得预防、减缓甚至逆转ARHL成为不可能。声音是由极其敏感的毛细胞探测到的，毛细胞位于内耳的骨性结构耳蜗内。它们的名字来源于它们顶端表面突出的毛状成分（立体纤毛）。当声音进入耳道时，它会产生立体纤毛的微小振动。这些振动将声波转化为电流，这种电流是由带电离子通过毛细胞立体纤毛中机械门控通道的打开而产生的；这个过程被称为机电转导。这些电流比用来给手机充电的电流小十亿倍。然而，这些由毛细胞产生的微小电流通过特殊的感觉神经纤维传送到大脑，使我们能够感知语音和音乐等声音。运动神经纤维的存在对正常听力至关重要，大脑利用运动神经纤维向毛细胞和感觉神经纤维发送指令（见上文），以改变它们的功能。例如，在非常大的噪音下，运动神经纤维会减少毛细胞的活动以避免损伤。因此，这些运动神经元通常起到保护作用，通常有助于保持毛细胞和感觉神经纤维的健康。然而，最近发现的ARHL的一个特征是运动神经纤维和毛细胞之间的连接发生了变化，恢复到只存在于耳蜗发育前听力阶段的组织。这种变化是特殊的，因为未成熟耳蜗中的运动神经纤维不起保护作用，而是在早期发育过程中影响听觉通路的形成。目前，我们还不知道为什么运动神经纤维在老化的耳蜗中发生变化。我们计划在这项资助中测试的假设是，运动神经纤维的变化是通过“重现”早期发育来修复有缺陷的老化耳蜗的一种尝试。在这个项目中，我们将使用有ARHL迹象的老年小鼠。然而，老龄小鼠的研究具有挑战性，而且成本极高，因为耳蜗的变化是在很长一段时间内发生的。因此，我们还将使用一些转基因小鼠，它们在运动神经纤维中表现出与老年小鼠相同的变化，但时间窗要短得多。我们不仅将研究运动神经纤维组织的这些变化发生的时间、方式和原因，而且还将提供有关其功能作用的证据，以及有缺陷的耳蜗在修复后是否有可能恢复到正常的成熟结构。该项目将更好地了解与ARHL相关的关键生物学方面，这将有助于在未来确定可靶向基因，从而开发人类诊断和治疗干预措施。

Age-related hearing loss (ARHL) is the most common health condition in the elderly. Approximately half of adults in their 70's exhibit ARHL severe enough to affect communication. It is expected that approximately 14.5 million people in the UK will be affected by hearing loss by 2030, with ARHL being the single biggest cause. ARHL is a progressive disorder decreasing the ability to understand speech, especially in a noisy environment. ARHL is also associated with social isolation, depression, and an increased risk for neurodegenerative diseases. Although hearing aids and cochlear implants are beneficial, they cannot restore hearing especially if the cells in the ear are missing or do not function, which are both characteristic features in ARHL. The major obstacle preventing the development of new treatments for ARHL is a lack of understanding about why we progressively lose our sense of hearing with age, making it impossible to prevent, slowdown or even reverse ARHL.Sound is detected by extremely sensitive sensory cells named hair cells that are located inside a bony structure called the cochlea in the inner ear. Their name derives from the hair-like elements (stereocilia) that project from their apical surface. When sound enters the ear canal it produces minute vibrations of the stereocilia. These vibrations initiate the conversion of sound waves into an electrical current generated by the movement of charged ions through the opening of mechanically gated channels present in the hair cell stereocilia; a process known as mechano-electrical transduction. These electrical currents are a billion times smaller than those used to charge, for example, a mobile phone. Nevertheless, these tiny currents produced by the hair cells are sent to the brain via specialized sensory nerve fibres, allowing us to perceive sound such as speech and music.Crucial for normal hearing is the presence of motor nerve fibres, which are used by the brain to send instructions to hair cells and sensory nerve fibres (see above) in order to make a change in how they are functioning. For example, in the presence of a very loud noise, the motor nerve fibres reduce the activity of hair cells to avoid damage. Therefore, these motor neurons normally serve a protective role and generally help to keep the hair cells and sensory nerve fibres healthy. However, a recently discovered feature of ARHL is a change in the connections between the motor nerve fibres and hair cells, reverting back to an organization that is only present during pre-hearing stages of cochlear development. This change is peculiar since the motor nerve fibres in the immature cochlea do not serve a protective role, but instead influence the formation of the auditory pathway during early development. Currently, we do not know why the motor nerve fibres are changing in the aging cochlea. The hypothesis we plan to test in this grant is that the changes in the motor nerve fibre is an attempt to repair the faulty aged cochlea by "recapitulating" early development.In this project we will use aged mice showing signs of ARHL. However, working with aged mice is challenging and extremely costly because changes in the cochlea occur over long periods of time. Therefore, we will also use a few genetically modified mice that show the same changes in the motor nerve fibres as seen in aged mice, but within a much shorter time window. We will not only investigate when, how and why these changes in the organization of the motor nerve fibre occur, but also provide evidence about their functional role and whether the faulty cochlea has the potential to revert back to its normal mature structure following repair. This project will provide a better understanding of a crucial biological aspect associated with ARHL, which will contribute, in the future, to the identification of targetable genes allowing the development of diagnostic and therapeutic interventions in humans.