Age-dependent plasticity of central auditory synapses

项目摘要/摘要 年龄相关性听力损失(ARHL)是老年人最常见的健康状况之一。结构性 外周和中枢听觉系统的退化和功能衰退是逐渐丧失的基础 随年龄增长的知觉。特别是，最近的研究结果表明，选择性螺旋亚型的优先损害 神经节神经元(SGN)先于显性听力损失。目前尚不清楚与年龄相关的SGN变化与 中枢听觉系统的结构和生理改变在ARHL的发展中起作用。 耳蜗核(CN)是所有SGN的唯一靶点，代表中枢听觉的起始点 正在处理。这一角色强调了对衰老过程中CN结构和功能变化的理解 是阐明急性淋巴细胞性白血病发病机制的关键。我们的总体假设是，年龄相关的变化 耳蜗会导致CN回路的改变，从而影响整个中枢听觉的信号处理 系统。这项关于CN的研究旨在确定与年龄相关的听神经(AN)突触和 它们的兴奋性和抑制性CN靶点确定了ARHL在CN中的突触和细胞机制。 目标1将确定不同亚型的生理和形态随年龄的变化 在急性呼吸窘迫综合征期间的突触。我们将结合电生理学和免疫组织化学来鉴定三个 根据不同SGN分子标志物的表达确定突触的亚型 不同年龄段急性CN脑片突触的电生理特性和形态特征 转基因小鼠。目标2将确定与年龄相关的生理和细胞变化 急性呼吸窘迫综合征时CN主神经元的形态变化。我们假设CN的主要丛生神经元与 突触输入的不同亚类型在生理和形态上随年龄而不同地修改， 导致ARHL期间的尖峰输出受损。我们将确定不同年龄段之间的相关变化 丛生神经元的固有特性、棘波输出、钾电导和细胞形态 与他们接收的输入的特定子类型相结合。AIM3将阐明弱化的机制 急性呼吸窘迫综合征时CN的抑制作用。我们将检验抑制性D-星状神经元被神经支配的假设 主要是低自发频率/高阈值SGN，其随年龄的选择性丧失导致产量减少 减弱了CN中的抑制作用。这种抑制机制将通过消融特定的SGN来进一步测试 不同年龄药物遗传学小鼠的亚型。我们的研究将确定CN中与年龄相关的变化 电路，并结合SGN亚型的选择性改变(项目1)，以确定受影响的AN 突触及其对CN主神经元和局部抑制性神经元输出的影响。

PROJECT SUMMARY/ABSTRACT Age-related hearing loss (ARHL) is one of the most prevalent health conditions in the elderly. Structural degradation and functional decline in the peripheral and central auditory systems underlie the gradual loss of perception with age. In particular, recent findings suggest that preferential damage of selective subtypes of spiral ganglion neurons (SGNs) precedes overt hearing loss. It remains unclear how age-related SGN changes link to structural and physiological alterations in the central auditory system in contributing to the development of ARHL. The cochlear nucleus (CN) is the only target for all SGNs and represents the starting site of central auditory processing. This role emphasizes that understanding changes in structure and function of the CN during aging is essential to elucidate the mechanisms of ARHL. Our overall hypothesis is that age-dependent changes in the cochlea results in alterations in the CN circuit that impact the signal processing of the entire central auditory system. This study of the CN aims to identify age-related plastic alterations in auditory nerve (AN) synapses and their excitatory and inhibitory CN targets to determine the synaptic and cellular mechanisms of ARHL in the CN. Aim 1 will determine the age-dependent changes in the physiology and morphology of different subtypes of AN synapses during ARHL. We will combine electrophysiology and immunohistochemistry to identify three subtypes of AN synapses based on the expression of different SGN molecular markers and determine these synapses' electrophysiological property and morphological features in acute CN slices from different age groups of genetically modified mice. Aim 2 will identify the age-related changes in the physiology and cellular morphology of CN principal neurons during ARHL. We hypothesize that CN principal bushy neurons with different subtypes of AN synaptic input are differentially modified with age in physiology and morphology, resulting in compromised spike output during ARHL. We will determine the age-related changes among different bushy neurons in intrinsic properties, spike output, potassium conductances, and cellular morphology in conjunction with specific subtypes of AN input they receive. Aim3 will elucidate the mechanisms of weakened inhibition in the CN during ARHL. We will test the hypothesis that inhibitory D-stellate neurons are innervated mainly by low spontaneous rate/high threshold SGNs whose selective loss with age results in reduced output and weakened inhibition in the CN. This mechanism of inhibition will be further tested by ablating specific SGN subtypes in pharmacogenetic mice at different ages. Our studies will identify age-related changes in the CN circuit, and in conjunction with selective alterations of SGN subtypes (Project 1), to determine the affected AN synapses and their impact on the output of CN principal and local inhibitory neurons.