Age-dependent plasticity of central auditory synapses

中枢听觉突触的年龄依赖性可塑性

• 批准号: 10496286
• 负责人: Ruili Xie
• 金额: $ 30.33万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10496286
• 关键词: 3-Dimensional; Ablation; Acoustic Nerve; Acute; Affect; Age; Aging; Auditory; Auditory system; Cells; Cellular Morphology; Cochlea; Cochlear nucleus; Collaborations; Computer Models; Confocal Microscopy; Data; Degenerative Disorder; Development; Elderly; Electrophysiology (science); Exhibits; Face; Genes; Goals; Health; Image; Immunofluorescence Immunologic; Immunohistochemistry; Knock-in; Knock-in Mouse; Label; Link; Longevity; Membrane; Morphology; Mus; Neurons; Output; Perception; Peripheral; Pharmacogenetics; Physiological; Physiology; Potassium; Presbycusis; Property; Role; Scanning Electron Microscopy; Site; Slice; Specificity; Structure; Synapses; Synaptic Transmission; Techniques; Testing; Whole-Cell Recordings; age group; age related; auditory processing; calretinin; confocal imaging; experimental study; functional decline; hearing impairment; inhibitory neuron; insight; molecular marker; neuromechanism; postsynaptic neurons; sensory input; signal processing; sound; spiral ganglion; stellate cell; transmission process; voltage clamp

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.

项目概要/摘要 年龄相关性听力损失（ARHL）是老年人最普遍的健康状况之一。结构性 外周和中枢听觉系统的退化和功能衰退是听觉功能逐渐丧失的基础。 随着年龄的增长的认知。特别是，最近的研究结果表明，螺旋的选择性亚型的优先损伤 神经节神经元（SGN）先于明显的听力损失。目前尚不清楚与年龄相关的 SGN 变化如何与 中枢听觉系统的结构和生理变化有助于 ARHL 的发展。 耳蜗核 (CN) 是所有 SGN 的唯一目标，代表中枢听觉的起始位点 加工。该角色强调了解衰老过程中中枢神经系统结构和功能的变化 对于阐明 ARHL 的机制至关重要。我们的总体假设是，年龄相关的变化 耳蜗导致中枢神经回路发生改变，从而影响整个中枢听觉的信号处理 系统。这项 CN 的研究旨在识别听觉神经 (AN) 突触中与年龄相关的可塑性改变 他们的兴奋性和抑制性 CN 目标，以确定 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学和形态学随年龄变化的变化 ARHL 期间的 AN 突触。我们将结合电生理学和免疫组织化学来识别三种 根据不同 SGN 分子标记的表达来确定 AN 突触的亚型，并确定这些亚型 不同年龄组急性CN切片突触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 ARHL 期间 CN 主要神经元的形态。我们假设 CN 主要的浓密神经元 AN突触输入的不同亚型在生理学和形态学上随着年龄的增长而发生差异性改变， 导致 ARHL 期间尖峰输出受损。我们将确定不同人群之间与年龄相关的变化 浓密神经元的内在特性、尖峰输出、钾电导和细胞形态 结合他们收到的 AN 输入的特定子类型。 Aim3将阐明削弱的机制 ARHL 期间 CN 的抑制。我们将检验抑制性 D 星状神经元受到神经支配的假设 主要是由于低自发率/高阈值 SGN，其随着年龄的增长而选择性丢失导致输出减少 CN 的抑制作用减弱。这种抑制机制将通过消融特定的 SGN 来进一步测试 不同年龄的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 主要和局部抑制神经元输出的影响。