Cellular mechanisms of age related hearing loss

年龄相关性听力损失的细胞机制

基本信息

批准号：
10174904
负责人：
Ruili Xie
金额：
$ 39万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-19 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10174904
关键词：
Acoustic Nerve Acute Affect Age Aging Animal Model Auditory Auditory Brainstem Responses Auditory Perception Auditory system Behavioral Brain CBA/CaJ Mouse Calcium Calcium Channel Calcium Signaling Calmodulin Clinical Cochlear nucleus Detection Development Elderly Environment Excision Goals Health Hearing Tests Hearing problem Immunohistochemistry Impairment Interneurons Intervention Ion Channel Gating Knowledge Link Membrane Mitochondria Modification 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 insight neural circuit normal hearing postsynaptic presynaptic relating to nervous system restoration sensor signal processing sound synaptotagmin II synaptotagmin VII uptake vesicular release voltage voltage clamp

项目摘要

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.

项目摘要/摘要耳蜗核（CN）是中央听觉系统的第一个神经站，它处理所有声音来自听觉神经的信息（AN）。 CN的主要神经元编码声音的不同方面，包括有关诸如声音之类的听觉任务必不可少的时间精细结构（TFS）的信息在嘈杂的环境中的本地化和语音检测。在与年龄相关的听力损失（ARHL）期间，中央 TFS信息的处理受到损害，导致感知缺陷。总体假设是衰老过程中CN神经元和神经回路的修改导致听觉时间出现故障处理ARHL的基础。该项目研究了CN Bushy中ARHL的细胞机制神经元专门从事TFS信息，以及来自AN和衰老过程中CN中间神经元的抑制输入。我们先前的研究表明，突触病发生在 ARHL期间的中央终端，特别是持有突触的末端，它们显示了相关的年龄将听觉信息传输到突触后灌木神经元中的降解。末端的减少功能是由于与钙信号失调相关的突触传播所致突触终端。在AIM1中，该项目研究了不同钙信号的机制在持续突触的末端老化期间的途径，包括钙吸收和去除，钙涌入通过电压门控钙通道，突触囊泡补充以及不同的表达钙传感器。我们先前的研究还发现，浓密的神经元在老化。在AIM2中，该项目将检验以下假设：听觉系统可以增强浓密的中心收益神经元补偿ARHL期间的输入弱。电压门控离子通道的机理在ARHL期间，将通过量化灌木丛中神经兴奋性的膜电导来研究衰老期间的神经元。在AIM3中，该项目将阐明ARHL期间抑制机制调查抑制对浓密神经元发射特性的影响，评估甘体能输入，并评估CN中间神经元的神经兴奋性以及它们在老化。为了实现这些目标，该项目利用包括行为听力测试在内的技术（听觉脑干响应），使用急性脑切片在电流或电压夹下的全细胞记录，使用CBA/CAJ小鼠作为动物模型的药理操作以及免疫组织化学 ARHL年龄长达30个月。这些研究将对我们对突触的理解产生重大影响 ARHL的基础机制和细胞机制，这对于发展治疗是基本的，至关重要恢复中央听觉系统中神经处理的方法，并最终恢复声音听力障碍患者的感知。