Deciphering the molecular heterogeneity of spiral ganglion neurons by single-cell gene expression profiling.

人的耳朵是一个非凡的感觉器官，其中的感觉细胞和它们的神经连接能够分析一个令人印象深刻的声音频率和强度范围。感觉毛细胞的作用是将来自外界的声音信息转化为电信号，通过专门的神经纤维发送到大脑，使我们能够听到演讲和音乐。听觉器官——耳蜗的发育是一个极其有序的过程，它允许建立感觉细胞和神经连接，例如，根据它们在感觉器官上的位置，对低频或高频声音有优先反应。年龄相关性听力障碍（ARHI）是一种由遗传和环境因素共同引起的复杂疾病。噪音暴露是引起急性呼吸道感染的主要环境因素。临床上很难区分这两种最常见的听力障碍：噪音引起的听力障碍和年龄相关的听力障碍（分别为NIHI和ARHI）。NIHI和ARHI对人类健康的巨大影响是由于人口平均寿命的持续增加，以及我们的耳朵不能很好地适应长期暴露在现代社会的大声声音中。目前，改善听力损失的唯一选择是使用助听器和人工耳蜗，这是有益的，但它们远不能恢复正常的听力。问题是，我们对NIHI和ARHI的生物学机制仍然知之甚少，无法开发出有效的替代疗法来预防或治愈这种疾病。直到最近，感觉细胞一直被认为是最容易受到老化和噪音影响的因素，但最近的发现表明，它们的神经连接在侮辱中更容易受损。在成人的听觉系统中，耳朵里的每个感觉细胞（内耳毛细胞）都是由多个神经连接连接的，这些神经连接在解剖学和生理学上都是不同的，因此能够将不同的声音强度和频率传递给大脑。特别是，有研究表明，具有最高可探测声音强度的神经连接似乎更容易受到噪音和老化的影响，从而导致它们的特定损伤。然而，与那些对最低可探测强度的声音有反应的人相比，为什么这些特定的神经连接主要受到年龄和/或噪音的影响，并没有直接的证据。因此，识别使这些神经连接更容易受到老化和/或噪音创伤影响的遗传因素和分子的能力，对于设计ARHI和NIHI的早期诊断、干预和/或治疗至关重要。识别人类遗传因素和分子一直受到许多固有困难的阻碍：1)并非所有具有相同遗传缺陷的个体都有相同的临床表现，这可能取决于暴露于噪声的强度和持续时间；相似的环境暴露有时会对个体产生不同的影响，这可能是因为他们潜在基因组成的差异。由于这些原因，我们将通过研究老鼠的基因-噪音相互作用来解决人类生物学的这个重要方面，这两个因素都是可以控制的，我们知道耳朵的结构和生理与人类相似。在这个项目中，我们将结合遗传学和生理学的专业知识来评估神经连接中的基因表达和功能。我们的方法将产生新的小鼠模型，以解决为什么特定的神经连接群体会选择性地受到噪音和衰老的损害。这些步骤对于理解人类噪音引起的和与年龄相关的听力损伤的病因学（长期目标）是重要的，并且将使我们更接近开发合适的治疗干预措施来治疗患者的目标。

The human ear is an extraordinary sensory organ, in which sensory cells and their nerve connections are able to analyse an impressive range of sound frequencies and intensities. The role of the sensory hair cells is to convert sound information from the outside world into electrical signals that are sent to the brain via specialized nerve fibres, allowing us hear speech and music. The development of the auditory organ, the cochlea, is an extremely ordered process, which allows to build sensory cells and nerve connections that, for example, respond preferencially to either low- or high-frequency sound depending on their location along the sensory organ.Age-related hearing impairment (ARHI) is a complex disorder caused by a combination of genetic and environmental factors. Noise exposure is the major environmental factor that causes ARHI. It is clinically very difficult to distinguish between these two most common forms of hearing impairment: noise-induced and age-related hearing impairments (NIHI and ARHI respectively). The large impact of NIHI and ARHI on human health is caused by the continuous increase in the average lifespan of the population, and by the fact that our ears are not well adapted to cope with long-lasting exposure of loud sounds characteristic of modern society. Currently, the only option available to ameliorate hearing loss is using hearing aids and cochlear implants, which are beneficial but they are far from restoring normal hearing. The problem is that we still know very little about the biological mechanisms causing NIHI and ARHI to be able to develop effective alternative treatments to either prevent or cure this disease.Until very recently the sensory cells have been considered the most vulnerable elements to aging and noise exposure but recent finding have shown that their nerve connections are more easily damaged during insults. In the adult auditory system, each sensory cell in the ear (inner hair cell) is contacted by multiple nerve connections that are anatomically and physiologically diverse, and as such able to carry a different sound intensity and frequencies to the brain. In particular, it has been suggested that the nerve connections having the highest detectable sound intensities seem more vulnerable to noise and aging, resulting in their specific damage. However, there is no direct evidence as to why these specific nerve connections are predominantly affected by aging and/or noise exposure as compared to those responding to lowest detectable intensity sound. Therefore, the ability to identifying genetic factors and molecules that render these nerve connections more susceptible to aging and/or noise trauma is essential for devising early diagnostic, intervention and/or treatments for both ARHI & NIHI. Identifying the genetic factors and molecules in humans has been hampered by many inherent difficulties: 1) not all individuals with the same genetic defects have the same clinical presentations, probably depending on the intensity and the duration of the noise exposed to; 2) similar environmental exposures sometimes have different effects on individuals, probably because of differences in their underlying genetic makeup.For these reasons we will address this important aspect of human biology by studying gene-noise interaction in mice where both factors can be controlled and we know that the structure and physiology of the ear is similar to that of humans. In the proposed project, we will combine expertise in genetic and physiology to evaluate gene expression and function in the nerve connections. Our approach will generate new mouse models to address why a specific population of nerve connections is selectively damaged to noise and aging. These steps are important towards understanding the etiology of human noise-induced and age related hearing impairment (long-term goal), and will take us closer to the goal of developing a suitable therapeutic intervention to treat patients.