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Cellular and Molecular Basis of Tonotopic Map Formation in the Mouse Cochlear Nucleus

小鼠耳蜗核中音位图形成的细胞和分子基础

基本信息

批准号：
10640620
负责人：
Wei-Ming Yu
金额：
$ 43.65万
依托单位：
LOYOLA UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640620
关键词：
Acoustic Nerve Acoustics Affect Afferent Neurons Animals Apical Auditory Auditory system Biological Assay Brain Central Auditory Processing Disorder Clinical Cochlea Cochlear nucleus Complex Data Development Discrimination Disease Dorsal Dyes Eph Family Receptors Ephrin-A3 Ephrin-B2 Ephrins FOS gene Fiber Frequencies Functional disorder Hair Cells Hearing Hearing problem Impairment In Situ Hybridization Label Ligands Maps Mediating Molecular Mus Mutant Strains Mice Nerve Fibers Neurons Outcome Pathogenesis Pattern Play Process Proteins Role Signal Transduction Signaling Molecule Startle Reaction Testing Work auditory pathway auditory processing candidate identification differential expression insight language impairment lipophilicity neurodevelopment novel prepulse inhibition receptor response segregation sensory system sound sound frequency sound frequency discrimination spiral ganglion targeted treatment

项目摘要

Project Summary Tonotopy is the most fundamental organizing principle of the vertebrate auditory system, meaning neurons at all levels of the auditory pathway are topographically arranged based on their preferred sound frequency. It allows animals to separate a complex sound into its frequency components, forming the basis for sound discrimination. Disruption of tonotopy may result in difficulty processing sound frequencies. Despite its clinical implications and importance in auditory function, very little is known about the mechanisms that govern the formation of tonotopy in the auditory system. Knowing how auditory neurons generate tonotopic maps to process sound information, is, therefore, crucial for understanding auditory functions and dysfunctions such as central auditory processing disorders. Ephrins and Eph receptors are signaling molecules that play essential roles in topographic mapping in other sensory systems during neural development. Our previous studies have demonstrated that ephrin-A3 is required for tonotopic map precision and auditory functions in mouse cochlear nucleus (CN). In ephrin-A3 mutant mice, although the tonotopic map is degraded, the gross tonotopic organization is still maintained, suggesting that other ephrin and Eph molecules could also be involved in tonotopic map formation in the CN. Our preliminary studies indicate that another ephrin molecule, ephrin-B2, is differentially expressed along the tonotopic axis in the CN. Moreover, ephrin-B2 signaling is sufficient to repel auditory nerve fibers in region-dependent and developmental stage-dependent manners. Based on these observations, we hypothesize that that ephrin-B2 signaling works in concert with ephrin-A3 signaling to regulate tonotopic map formation in the CN. To test our hypotheses and to elucidate the mechanisms that underlie tonotopic map formation in the CN, we propose three major aims: 1) we will use lipophilic dye tracing studies and neuronal c-fos induction assays after pure tone stimulation to determine if the tonotopic map becomes less precise and is degraded in mice lacking ephrin-B2 specifically in the CN; 2) we will use prepulse inhibition of the acoustic startle response to assess whether mice lacking ephrin-B2 specifically in the CN show impaired abilities to discriminate sound frequency change; 3) we will use in situ hybridization and ephrin stripe assays of cochlear explants to identify candidate Eph receptors in the developing spiral ganglion neurons that mediate the effects of ephrin-A3 and/or ephrin-B2 signaling in the CN. Results from these studies will provide novel insights into the cellular and molecular basis of how tonotopic maps are formed in the CN and how Eph/ephrin signaling plays a role in regulating these processes. These studies will also allow us to better understand how disruption of tonotopy results in auditory dysfunctions.

项目摘要音调是脊椎动物听觉系统最基本的组织原则，这意味着神经元在听觉通路的所有层级基于它们的优选声音频率而地形学地布置。它使动物能够将复杂的声音分解成频率成分，形成声音的基础。歧视音调学的破坏可能会导致处理声音频率的困难。尽管其临床的影响和重要性，在听觉功能，很少有人知道的机制，支配听觉系统中音调的形成。了解听觉神经元如何产生音调映射，因此，处理声音信息对于理解听觉功能和功能障碍至关重要，中枢听觉处理障碍Ephrin和Eph受体是信号分子，在神经发育过程中在其他感觉系统的地形图绘制中的作用。我们以往的研究表明ephrin-A3是小鼠耳蜗中音调定位图精确性和听觉功能所必需的，核（CN）。在ephrin-A3突变小鼠中，尽管音调分布图被降解，但总音调分布图仍被破坏。组织仍然保持，这表明其他ephrin和Eph分子也可能参与在CN中的tonotopic地图的形成。我们的初步研究表明，另一种肝配蛋白分子，肝配蛋白-B2，在CN中沿着音调轴差异表达沿着。此外，肝配蛋白-B2信号传导足以排斥听觉神经纤维的发育具有区域依赖性和发育阶段依赖性。基于这些通过观察，我们假设肝配蛋白-B2信号与肝配蛋白-A3信号协同作用，调节CN中的色调拓扑图形成。为了验证我们的假设并阐明在CN中形成色调拓扑图的基础上，我们提出了三个主要目标：1）我们将使用亲脂性染料示踪研究和纯音刺激后的神经元c-fos诱导测定，以确定是否变得不那么精确，并且在CN中特异性缺乏肝配蛋白-B2的小鼠中降解; 2）我们将使用预脉冲抑制声惊吓反应以评估CN中特异性缺乏肝配蛋白-B2的小鼠是否表现出辨别声音频率变化的能力受损; 3）我们将使用原位杂交和ephrin条纹耳蜗外植体的测定以鉴定发育中的螺旋神经节神经元中的候选Eph受体，介导CN中肝配蛋白-A3和/或肝配蛋白-B2信号传导的作用。这些研究的结果将提供新的见解的细胞和分子的基础上如何tonotopic地图形成的CN和如何 Eph/ephrin信号在调节这些过程中起作用。这些研究也将使我们能够更好地了解音调异常如何导致听觉功能障碍。