Cellular mechanisms of age related hearing loss

年龄相关性听力损失的细胞机制

• 批准号: 9454682
• 负责人: Ruili Xie
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-19 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9454682
• 关键词: Acoustic Nerve; Acute; Affect; Age; Aging; Animal Model; Auditory; Auditory Brainstem Responses; Auditory system; Behavioral; Brain; CBA/CaJ Mouse; Calcium; Calcium Channel; Calcium Signaling; Calmodulin; Clinical; Cochlear nucleus; Detection; Development; Elderly; Environment; Excision; Gated Ion Channel; Goals; Health; Hearing; Hearing Tests; Hearing problem; Immunohistochemistry; Impairment; Interneurons; Intervention; Ion Channel Gating; Knowledge; Link; Membrane; Mitochondria; Modification; Molecular Profiling; Mus; Nervous system structure; Neuraxis; Neurons; Outcome; Patients; Pattern; Pharmacology; Potassium; Presbycusis; Presynaptic Terminals; Process; Property; Research; Signal Pathway; Signal Transduction; Slice; Sound Localization; Speech; Structure; Synapses; Synaptic Transmission; Synaptic Vesicles; System; Techniques; Testing; Therapeutic; Whole-Cell Recordings; Work; age related; auditory processing; base; calcium uniporter; clinical development; cost; hearing impairment; information processing; insight; neural circuit; postsynaptic; presynaptic; relating to nervous system; restoration; sensor; signal processing; sound; synaptotagmin II; synaptotagmin VII; therapy development; uptake; vesicular release; voltage; voltage clamp

PROJECT SUMMARY/ABSTRACT Cochlear nucleus (CN) is the first neural station of the central auditory system that processes all sound information from the auditory nerve (AN). Principal neurons of CN encode different aspects of sound, including information about the temporal fine structure (TFS) that is essential for auditory tasks like sound localization and speech detection in noisy environment. During age related hearing loss (ARHL), the central processing of TFS information is compromised, leads to perceptual deficits. The overall hypothesis is that modifications in CN neurons and neural circuits during aging contribute to the malfunction of auditory temporal processing that underlies ARHL. The project investigates the cellular mechanisms of ARHL in CN bushy neurons, which are specialized in processing TFS information, as well as their excitatory inputs from AN and inhibitory inputs from CN interneurons during aging. Our previous studies showed that synaptopathy occurs at AN central terminals during ARHL, specifically the endbulb of Held synapses, which show age related degradation in transmitting auditory information to postsynaptic bushy neurons. The decrease in endbulb function is due to compromised synaptic transmission that is associated with dysregulated calcium signaling at the synaptic terminal. In Aim1, the project investigates the mechanisms of different calcium signaling pathways during aging at the endbulb of Held synapse, including calcium uptake and removal, calcium influx via voltage gated calcium channels, synaptic vesicle replenishment, as well as the expression of different calcium sensors. Our prior study also found that bushy neurons are depolarized and more excitable during aging. In Aim2, the project will test the hypothesis that auditory system enhances central gain in bushy neurons to compensate for the weakened AN input during ARHL. Mechanisms of voltage-gated ion channels during ARHL will be studied by quantifying membrane conductances that underlie neural excitability in bushy neurons during aging. In Aim3, the project will elucidate the mechanisms of inhibition during ARHL by investigating the effect of inhibition on firing property of bushy neurons, assessing synaptic strength of glycinergic inputs, and evaluating the neural excitability of CN interneurons as well as their AN inputs during aging. To achieve these goals, the project utilizes techniques including behavioral hearing test (auditory brainstem response), whole-cell recording under current or voltage clamp mode using acute brain slices, pharmacological manipulation, as well as immunohistochemistry, using CBA/CaJ mice as the animal model for ARHL at ages up to 30 months. These studies will have a significant impact on our understanding of synaptic and cellular mechanisms underlying ARHL, which is fundamental and essential for developing therapeutic approaches to restore neural processing in the central auditory system and eventually reinstate sound perception in patients with hearing impairments.

项目概要/摘要 耳蜗核（CN）是中枢听觉系统的第一个神经站，负责处理所有声音 来自听觉神经（AN）的信息。 CN 的主要神经元编码声音的不同方面， 包括关于时间精细结构 (TFS) 的信息，这对于声音等听觉任务至关重要 噪声环境中的定位和语音检测。在年龄相关性听力损失（ARHL）期间，中枢 TFS 信息的处理受到损害，导致知觉缺陷。总体假设是 衰老过程中中枢神经元和神经回路的改变导致听觉颞叶功能障碍 ARHL 的基础处理。该项目研究 CN 灌木丛中 ARHL 的细胞机制 神经元，专门处理 TFS 信息以及来自 AN 和 AN 的兴奋性输入 衰老过程中 CN 中间神经元的抑制输入。我们之前的研究表明突触病发生在 ARHL 期间的中央终端，特别是 Held 突触的端球，显示与年龄相关的 向突触后浓密神经元传递听觉信息的退化。尾球减少 功能是由于突触传递受损造成的，而突触传递与钙信号传导失调有关。 突触末端。在 Aim1 中，该项目研究了不同钙信号传导的机制 Held 突触末端衰老过程中的途径，包括钙的吸收和去除、钙流入 通过电压门控钙通道、突触小泡补充以及不同的表达 钙传感器。我们之前的研究还发现，浓密的神经元在工作期间会去极化并且更加兴奋。 老化。在 Aim2 中，该项目将测试听觉系统增强浓密中的中央增益的假设 神经元来补偿 ARHL 期间减弱的 AN 输入。电压门控离子通道的机制 ARHL期间将通过量化膜电导来研究，膜电导是浓密神经兴奋性的基础 衰老过程中的神经元。在 Aim3 中，该项目将通过以下方式阐明 ARHL 期间的抑制机制： 研究抑制对浓密神经元放电特性的影响，评估突触强度 甘氨酸输入，并评估 CN 中间神经元的神经兴奋性及其 AN 输入 老化。为了实现这些目标，该项目利用了包括行为听力测试（听觉 脑干反应），使用急性脑切片在电流或电压钳模式下进行全细胞记录， 使用 CBA/CaJ 小鼠作为动物模型进行药理操作以及免疫组织化学 ARHL 年龄不超过 30 个月。这些研究将对我们对突触的理解产生重大影响 ARHL 的基础和细胞机制，这对于开发治疗方法至关重要 恢复中枢听觉系统神经处理并最终恢复声音的方法 听力障碍患者的感知能力。