Cellular mechanisms of age related hearing loss

项目摘要/摘要 耳蜗核是中枢听觉系统中处理所有声音的第一个神经站 来自听神经(AN)的信息。CN的主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，这对于声音等听觉任务是必不可少的 噪声环境下的定位与语音检测。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 中枢神经元和神经回路在衰老过程中的改变与听觉颞叶功能障碍有关 ARHL背后的加工过程。该项目研究了CN灌木丛ARHL的细胞机制。 神经元，专门处理TFS信息，以及它们来自AN和AND的兴奋性输入 衰老过程中来自CN中间神经元的抑制性输入。我们之前的研究表明，突触发生在 ARHL期间的中央终末，特别是持有的突触的末端，显示与年龄有关的 向突触后丛状神经元传递听觉信息的退化。内球的减少 功能是由于突触传递受损，而突触传递与钙信号失控有关 突触终末。在Aim1中，该项目研究了不同的钙信号转导机制 握持突触终球衰老过程中的钙摄取和清除、钙内流 通过电压门控性钙通道、突触小泡的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 衰老。在AIM2中，该项目将测试听觉系统增强灌木丛中枢增益的假设 神经元来补偿ARHL过程中减弱的一种输入。电压门控离子通道的作用机制 将通过量化神经兴奋性背后的膜电导来研究ARHL。 神经元在老化过程中。在AIM3中，该项目将阐明ARHL期间的抑制机制，通过 研究抑制对灌木状神经元放电特性的影响，评估突触强度。 甘氨酸能传入，并评估中枢神经系统中间神经元及其AN传入的兴奋性 衰老。为了实现这些目标，该项目利用了包括行为听力测试(听觉测试)在内的技术 脑干反应)，使用急性脑片在电流或电压钳制模式下进行全细胞记录， 以CBA/CAJ小鼠为动物模型，进行药理操作和免疫组织化学研究。 急性淋巴细胞性白血病，年龄可达30个月。这些研究将对我们对突触的理解产生重大影响 和ARHL背后的细胞机制，这是开发治疗方法的基础和关键 恢复中枢听觉系统神经处理并最终恢复声音的方法 听力障碍患者的知觉。

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.