Molecular and Functional Mechanisms of the aging auditory neuron

衰老听觉神经元的分子和功能机制

• 批准号: 10496285
• 负责人: EBENEZER N YAMOAH
• 金额: $ 46.75万
• 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/10496285
• 关键词: Action Potentials; Address; Affect; Afferent Neurons; Age; Aging; Anatomy; Auditory; Auditory Brainstem Responses; Auditory area; Backcrossings; Biological Markers; Brain Stem; Cell Nucleus; Cochlea; Cochlear nucleus; Complex; Computer Analysis; Computer Models; Coupled; Demyelinations; Dependence; Development; Elderly; Electrophysiology (science); Environment; Etiology; Evaluation; Frequencies; Generations; Hair Cells; Human; In Situ; Injections; Injury; Ion Channel; Kinetics; Knock-in; Knock-in Mouse; Light; Maps; Measures; Mediating; Microscopy; Molecular; Mus; Nerve Degeneration; Neurons; Noise-Induced Hearing Loss; Persons; Pharmacogenetics; Pharmacology; Phase; Phenotype; Physiological; Population; Predisposition; Presbycusis; Process; Property; Reflex action; Resolution; Sensory; Signal Transduction; Speed; Stimulus; Synapses; Synaptic Vesicles; Variant; Visualization; Work; age effect; age related; aged; biophysical properties; calbindin; calretinin; density; excitotoxicity; experimental study; hearing impairment; insight; mouse model; neural; neuron loss; neurosensory; optogenetics; otoacoustic emission; patch clamp; postsynaptic; pressure; presynaptic; response; signal processing; sound; spiral ganglion; vector; voltage; voltage clamp

Abstract During development, cochlear hair cells (HCs) and neurons must be wired correctly, qualitatively, and quantitatively. These include specific auditory afferent neurons (AN) wired to the brainstem cochlear nuclei (CN). The activity of HCs maintains the number, size, and functions of ANs. Previous studies suggest that aging may result in preferential loss of specific AN subtypes. We hypothesize that ARHL arises from a loss of ultrafast afferent responses, accompanied by remodeling of central auditory circuits and functions—changes that result in deficiencies in phase-locked response functions in older adults. We propose to examine age-related changes in distinct AN using three knockin mouse models: calretinin (Calb2)-eGFP, calbindin (Calb1)-mCherry, Pou4f1 and (brn3a)-CFP, and optogenetic and pharmacogenetic mouse models. The work will focus on longitudinal changes in: 1) structural (anatomic) projections from HCs to the brainstem nuclei (CN), 2) afferent neuron subtype distributions and functions, and 3) Identify the age dependence of ionic conductances in AN afferents Aim 1 will trace afferent neuron subtype-specific projections from the cochlea to the CN and determine the age- dependent changes to identify potential anatomic plasticity. We will measure age-dependent auditory function, auditory brainstem responses (ABR), and distortion product otoacoustic emissions (DPOAE). We will evaluate and perform these studies in parallel with changes in age-related auditory phenotype. For Aim 2, we will determine regional and afferent neuron subtype variations in the response properties and the age-dependent changes. We will evaluate the regularity of inter-spike intervals, synchronization parameters, including vector strength (VS), winding ratio (k), and sensitivity to current injection, using experimental and physiological stimulation. Finally, for Aim 3, we will identify the age dependence of ionic conductances in three groups of afferent neurons. We will use patch-clamp analyses of the kinetics, voltage-dependence, pharmacology, and conductance in young and aged neurons to determine the underlying mechanisms for the differences in response properties of three neuronal subtypes, using computational analyses. Thus, we will address the complexity of anatomic projections and signal processing and subsequent age- dependent changes, which are necessary for developing a treatment for ARHL.

抽象的 在发育过程中，耳蜗毛细胞 (HC) 和神经元必须正确、高质量地连接，并且 定量地。其中包括连接到脑干耳蜗核（CN）的特定听觉传入神经元（AN）。 HC 的活性维持了 AN 的数量、大小和功能。先前的研究表明，衰老可能 导致特定 AN 亚型优先丢失。 我们假设 ARHL 是由于超快传入反应的丧失引起的，并伴有神经元重塑 中枢听觉回路和功能——导致锁相响应功能缺陷的变化 在老年人中。 我们建议使用三种敲入小鼠模型检查不同 AN 中与年龄相关的变化： 钙视网膜蛋白 (Calb2)-eGFP、钙结合蛋白 (Calb1)-mCherry、Pou4f1 和 (brn3a)-CFP，以及光遗传学和药物遗传学 鼠标模型。这项工作将重点关注以下方面的纵向变化： 1) 从 HC 到脑干核 (CN) 的结构（解剖）投影， 2）传入神经元亚型分布和功能，以及 3) 确定 AN 传入离子电导的年龄依赖性 目标 1 将追踪从耳蜗到 CN 的传入神经元亚型特异性投射，并确定年龄 依赖变化来识别潜在的解剖可塑性。我们将测量与年龄相关的听觉功能， 听觉脑干反应（ABR）和失真产物耳声发射（DPOAE）。我们将评估 并与年龄相关的听觉表型的变化同时进行这些研究。对于目标 2，我们将 确定反应特性和年龄依赖性的区域和传入神经元亚型变化 变化。我们将评估尖峰间间隔的规律性、同步参数，包括向量 强度 (VS)、绕线比 (k) 以及对电流注入的灵敏度，使用实验和生理学数据 刺激。最后，对于目标 3，我们将确定三组离子电导的年龄依赖性 传入神经元。我们将使用膜片钳分析动力学、电压依赖性、药理学和 年轻和老年神经元的电导以确定反应差异的潜在机制 使用计算分析三种神经元亚型的特性。 因此，我们将解决解剖预测和信号处理以及随后的年龄的复杂性 依赖性变化，这是开发 ARHL 治疗方法所必需的。