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形式，是老年人最常见的感觉缺陷和健康状况之一。大约有一半的成年人在70岁时表现出影响他们日常生活的听力损失。这还与严重的心理和医疗疾病有关，包括社会孤立、虚弱和抑郁。听力损失的人数正在增加。据预计，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。这部分是因为ARHL是一种复杂的疾病，有许多因素，包括遗传易感性和环境因素，如噪音暴露。已知噪声暴露可加速ARHL的发生和发展，但其发生的机制在很大程度上尚不清楚。在哺乳动物的耳蜗中，声音是由被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，这是神经递质释放到听觉传入神经元的地方。声音强度和时间等信息被这些突触编码成神经活动，这是我们感知声音所必需的。最近的许多证据表明，带状突触是耳蜗内在噪声暴露后首先丢失的结构，这可能是这些病例中听力损失的主要原因。我推测，当毛细胞受到噪音的过度刺激时，它们会释放出过量的谷氨酸，这通过激活钙依赖性蛋白酶（兴奋性毒性）而导致毒性。因此，本项目的目的是研究噪声对哺乳动物耳蜗突触传递的影响。使用离体和体内两种方法，我将确定谷氨酸释放对带状突触有害的水平，以及暴露于噪音的耳蜗突触兴奋性毒性的机制。我将量化突触囊泡释放在噪声暴露期间使用体内功能成像。由噪声暴露引起的更持久的突触变化将在体外使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声诱导损伤的关键机制。总的来说，这个项目将确定噪音如何影响毛细胞和传入神经元之间的交流，以及潜在的功能障碍机制，这将有助于开发与噪音相关的听力障碍的治疗方法，如与年龄相关的听力损失。

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.