Anatomical and Functional Properties of Auditory Nerve Synapses

听神经突触的解剖和功能特性

• 批准号: 8804940
• 负责人: Maria Eulalia Rubio
• 金额: $ 55.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8804940
• 关键词: AMPA Receptors; Acoustic Nerve; Acute; Adult; Applications Grants; Auditory; Auditory Brainstem Responses; Auditory system; Brain; Brain Stem; Cells; Characteristics; Clinical; Cochlea; Cochlear Implants; Cochlear nucleus; Code; Complex; Conductive hearing loss; Cues; Data; Earplug; Electrophysiology (science); Freeze Fracturing; Fusiform Cell; Glutamate Receptor; Glutamates; Goals; Health; Hearing; Hearing Aids; Hearing Tests; Hearing problem; Inferior Colliculus; Kinetics; Knock-out; Knockout Mice; Label; Lead; Light; Long-Term Effects; Mediating; Molecular; Mus; Nerve Fibers; Neurons; Population; Population Projection; Procedures; Process; Property; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Slice; Stimulus; Synapses; Synaptic Transmission; Techniques; Testing; Therapeutic; Time; Whole-Cell Recordings; base; cell type; density; dorsal cochlear nucleus; experience; genetic approach; hearing impairment; in vivo; novel; postsynaptic; response; sound

DESCRIPTION (provided by applicant): The auditory nerve (AN) transmits all auditory information from the cochlea to the brain. In the cochlear nucleus (CN), AN fibers bifurcate to innervate multiple cell populations, including bushy cells (BCs) in the ventral CN, and fusiform cells (FCs) in the dorsal CN. These two cell types differ significantly in their ability to encode temporal properties of sound stimuli. BCs project to binaural circuits in the superior olivary complex and encode spectral and temporal characteristics that allow sounds to be localized in the horizontal plane. FCs project to monaural circuits in the inferior colliculus and detect spectrl cues for localizing sounds in the vertical plane. AN synapses on BCs and FCs are both glutamatergic and involve AMPARs as major postsynaptic glutamate receptors. At AN-BC synapses, synaptic transmission is extremely fast and reliable to preserve information contained in the timing of AN spikes. At AN-FC synapses, synaptic transmission is significantly slower than at AN-BC synapses. Understanding the synaptic mechanisms that make AN-BC synapses faster than AN-FC synapses has been an important question that has been intensely studied. However, which specific AMPAR subunits actually mediate fast synaptic transmission at AN synapses is still unresolved. The goal of the proposed studies is to provide understanding of the functional role of GluA3 AMPAR subunits at AN synapses on brainstem neurons and the sensitivity of AN synapses to auditory experience. Data obtained from this proposal will advance understanding of the cellular mechanisms underlying the temporal precision of sound coding in the normal and in the hearing impaired. Thus in Aim 1 we will test the hypothesis that GluA3 in AN-BC synapses is the AMPAR subunit that determines fast AMPAR kinetics. Aim 2 will test the hypothesis that increase in expression and localization within the PSD of GluA3 AMPAR subunits mediates the experience-dependent plasticity of AN-BC and AN-FC synapses. To achieve these goals, we will combine hearing tests (auditory brainstem responses, ABRs) to analyze the ability of the brainstem to respond to sound stimuli in vivo, quantitative ultrastructural and molecular techniques, genetic approaches (knockouts) and electrophysiology in acute brainstem slices of adult normal hearing and monaurally earplugged mice. Specifically, we will use freeze-fracture and postembedding immunogold labeling, qRT-PCR together with whole-cell recording to identify morphological, molecular and functional alterations at AN synapses. The results of our studies can be applied to efforts to optimize strategies for treating hearing loss and other hearing disorders. A large body of evidence indicates that the auditory system is highly specialized. Systematic, rigorous studies of the synaptic mechanisms underlying the specializations will both suggest and inform rational therapeutic approaches.

描述（由申请人提供）：听觉神经（AN）将所有听觉信息从耳蜗传输到大脑。在人工耳蜗核（CN）中，纤维分叉以支配多个细胞群，包括腹CN中的浓细胞（BC）和背侧CN中的梭形细胞（FCS）。这两种细胞类型在编码声音刺激的时间特性的能力上有显着差异。 BCS在上橄榄络合物和编码光谱和时间特征中进行双耳电路的项目，这些频谱和时间特性允许声音位于水平面。 FCS项目针对下丘的单膜电路，并检测spectrl提示，以将声音定位在垂直平面中。在BC和FC上的突触既是谷氨酸能，又涉及AMPAR作为主要突触后谷氨酸受体。在AN-BC突触时，突触传输非常快且可靠，可以保留尖峰时间内包含的信息。在AN-FC突触时，突触传输的速度明显慢于AN-BC突触。了解使AN-BC突触比AN-FC突触更快的突触机制是经过深入研究的重要问题。但是，哪些特定的AMPAR亚基实际上介导突触处的快速突触传递尚未解决。拟议的研究的目的是提供对脑干神经元突触中GLUA3 AMPAR亚基的功能作用以及突触对听觉体验的敏感性的理解。从该提案中获得的数据将提高对正常和听力障碍中声音编码时间精度的细胞机制的理解。因此，在AIM 1中，我们将测试以下假设：AN-BC突触中的GLUA3是决定快速AMPAR动力学的AMPAR亚基。 AIM 2将检验以下假设：GLUA3 AMPAR亚基PSD中表达和定位的增加会介导AN-BC和AN-FC突触的经验依赖性可塑性。为了实现这些目标，我们将结合听力测试（听觉的脑干反应，ABR），以分析脑干在体内对声音刺激的反应能力，定量的超微结构和分子技术，遗传学方法（敲除）和电生理学在成人正常听力和莫名其妙的耳置耳置小鼠的急性脑干中的能力。具体而言，我们将使用冻结和后置Immunogold标签，QRT-PCR以及全细胞记录，以识别突触时形态学，分子和功能变化。我们的研究结果可以应用于优化治疗听力损失和其他听力障碍策略的努力。大量证据表明听觉系统高度专业化。对专业的突触机制进行系统的严格研究将暗示并为理性的治疗方法提供信息。