Understanding the mechanisms underlying noise-induced damage of hair cell ribbon synapses

年龄相关性听力损失(ARHL)是一种进行性听力损失，是老年人最常见的感觉障碍和健康状况之一。在所有70岁的成年人中，大约有一半的人表现出听力损失，影响了他们的日常生活。这还与严重的心理和医学发病率有关，包括社交孤立、虚弱和抑郁。听力损失的人数正在增加。预计到2050年，英国将有超过1500万人受到听力损失的影响，其中大部分将与老龄化有关(世界卫生组织)。然而，ARHL的发病机制仍然知之甚少。这在一定程度上是因为ARHL是一种复杂的疾病，有许多致病因素，包括遗传易感性和环境因素，如噪音暴露。众所周知，噪声暴露会加速ARHL的发生和发展，但发生这种情况的机制在很大程度上尚不清楚。在哺乳动物的耳蜗里，声音是由称为毛细胞的感觉细胞传递的。这些细胞形成特殊的突触，称为带状突触，是神经递质释放到听觉传入神经元的场所。这些突触将声音强度和时间等信息编码为神经活动，这是我们感知声音所必需的。最近的许多证据表明，带状突触是噪音暴露后耳蜗内首批丢失的结构，这很可能是这些情况下听力损失的主要原因。我假设，当毛细胞受到噪音的过度刺激时，它们会释放过量的谷氨酸，这会通过激活钙依赖的蛋白水解酶(兴奋性毒性)而导致毒性。因此，这个项目的目的是研究噪声对哺乳动物耳蜗突触传递的影响。我将使用体外和体内两种方法，确定对带状突触有害的谷氨酸释放水平，以及暴露在噪声中的耳蜗突触兴奋性毒性的潜在机制。我将使用体内功能成像来量化噪声暴露期间突触小泡的释放。噪声暴露导致的更持久的突触变化将在体外利用膜片钳电生理学和功能成像进行研究。此外，我还将研究蛋白质降解途径作为噪音诱导损伤的关键机制。总体而言，该项目将建立噪音如何影响毛细胞和传入神经元之间的通信以及潜在功能障碍的机制，这将使治疗噪音相关的听力功能障碍，如年龄相关性听力损失的开发成为可能。

Age-related hearing loss (ARHL) is a progressive form of hearing loss and is one of the most common sensory deficits and health conditions in the elderly. Approximately half of all adults in their seventh decade exhibit hearing loss that affect their daily lives. This is further associated with significant psychological and medical morbidity, including social isolation, frailty and depression.The number of people with hearing loss is increasing. It is expected that more than 15 million people in the UK will be affected by hearing loss by 2050, the majority of which will be related to ageing (World Health Organisation). However, the mechanisms underlying ARHL remain poorly understood. This is partly because ARHL is a complex disorder with many contributing factors, including genetic predisposition and environmental factors such as noise exposure. Noise exposure is known to accelerate the onset and progression of ARHL but the mechanisms by which this occurs are largely unknown.In the mammalian cochlea, sound is transduced by sensory cells called hair cells. These cells form specialised synapses, called ribbon synapses, which are the sites of neurotransmitter release onto auditory afferent neurons. Information such as sound intensity and timing is encoded by these synapses into neural activity, which is required for us to perceive sound. A lot of recent evidence has shown that ribbon synapses are the first structures within the cochlea to be lost after noise exposure, which is likely to be the primary cause of hearing loss in these cases. I hypothesise that when the hair cells are over-stimulated by noise they release an excessive amount of glutamate, which causes toxicity by activating calcium-dependent proteases (excitotoxicity). Therefore, the aim of this project is to investigate how synaptic transmission is affected by noise insult in the mammalian cochlea.Using both ex vivo and in vivo approaches, I will determine the level of glutamate release that is detrimental to ribbon synapses, as well as the mechanisms that underlie excitotoxicity at cochlear synapses exposed to noise. I will quantify the synaptic vesicle release by using in vivo functional imaging during noise exposure. The more sustained synaptic changes that result from noise exposure will be investigated in vitro using both patch-clamp electrophysiology and functional imaging. In addition, I will also investigate the protein degradation pathway as a key mechanism underlying noise-induced damage.Overall, this project will establish how noise affects the communication between hair cells and afferent neurons and the mechanisms underlying dysfunction, which will allow the development of treatments for noise-associated hearing dysfunction such as age-related hearing loss.