Cellular mechanisms of age related hearing loss

项目总结/摘要 中枢听觉系统的第一个神经站--耳蜗核（CN），负责处理所有的声音信号 听觉神经（AN）的信息。CN的主要神经元编码声音的不同方面， 包括有关时间精细结构（TFS）的信息，这对声音等听觉任务至关重要 噪声环境下的定位和语音检测。在年龄相关性听力损失（ARHL）中， TFS信息的处理受到损害，导致感知缺陷。总的假设是， CN神经元和神经回路在衰老过程中的变化有助于听觉颞叶功能障碍 ARHL基础的处理。该项目研究了CN灌木中ARHL的细胞机制 神经元，专门处理TFS信息，以及它们来自AN的兴奋性输入， 抑制输入CN中间神经元在老化。我们以前的研究表明，突触病发生在 在ARHL期间，AN中央终末，特别是Held突触的内球，这表明年龄相关 听觉信息传递到突触后神经元的能力下降。终球减少 功能是由于受损的突触传递，这与钙信号失调有关， 突触末端在Aim1中，该项目研究了不同钙信号传导的机制， Held突触终球老化过程中的钙通道，包括钙摄取和清除，钙内流 通过电压门控钙通道，突触囊泡补充，以及不同的表达， 钙传感器我们之前的研究还发现，在大脑皮层中， 衰老在Aim2中，该项目将测试听觉系统增强灌木丛中的中枢增益的假设。 神经元以补偿ARHL期间减弱的AN输入。电压门控离子通道的作用机制 在ARHL期间，将通过量化作为灌木丛神经兴奋性基础的膜电导来研究 神经元老化。在Aim3中，该项目将通过以下方式阐明ARHL期间的抑制机制： 研究抑制对丛状神经元放电特性的影响，评估突触强度， 甘氨酸能输入，并评估CN中间神经元的神经兴奋性以及它们的AN输入， 衰老为了实现这些目标，该项目利用包括行为听力测试（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， ARHL在年龄达30个月。这些研究将对我们理解突触 以及ARHL的细胞机制，这是开发治疗药物的基础和必要条件。 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。

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.