Glial Influences on Auditory Brainstem Development

神经胶质对听觉脑干发育的影响

• 批准号: 8210807
• 负责人: Karina S Cramer
• 金额: $ 24.58万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8210807
• 关键词: Address; Appearance; Astrocytes; Auditory; Auditory Perceptual Disorders; Auditory system; Axon; Binding; Birds; Brain Stem; Cell Communication; Cell Culture Techniques; Cells; Coculture Techniques; Communication; Complex; Conditioned Culture Media; Contralateral; Cues; Defect; Dendrites; Dendritic Spines; Development; Dorsal; Ear; Embryonic Development; Eph Family Receptors; Ephrins; Equilibrium; Event; Family; Goals; Hearing; Hearing problem; Impairment; Inhibitory Synapse; Ipsilateral; Knowledge; Language; Lead; Ligands; Location; Mediating; Membrane; Modeling; Molecular; Morphology; Nervous System Part; Neuraxis; Neuroglia; Neurons; Neurosciences; Pathway interactions; Pattern; Play; Process; Proteins; Receptor Protein-Tyrosine Kinases; Recovery; Regulation; Role; Signal Transduction; Signaling Molecule; Slice; Source; Synapses; Systems Development; Testing; Time; Tinnitus; Trauma; auditory nuclei; cell type; ganglion cell; improved; insight; nervous system development; neurodevelopment; neuronal cell body; neurotrophic factor; public health relevance; research study; response; response to injury; sound; spatiotemporal; therapy development; transmission process

DESCRIPTION (provided by applicant): Hearing relies on transmission of sound-evoked responses through very precisely arranged neuronal connections. Defects in this circuitry can lead to impairments in sound perception, language, and communication. A central goal in auditory neuroscience is to understand the developmental mechanisms that assemble this circuitry. This knowledge will facilitate the development of molecular and cellular therapies to correct congenital or acquired deficits in auditory processing. The avian brainstem provides an elegant model, as the circuitry is well characterized and readily accessible. In this pathway n. magnocellularis (NM) receives ipsilateral input from cochlear ganglion cell axons and in turn projects bilaterally to n. laminaris (NL). This projection is specialized for the computation of interaural time differences, a major cue used in sound source localization. The goal of this study is to identify the mechanisms underlying maturation of this pathway. An important consideration is the interaction between neurons and glia, which are essential for normal development and response to injury. While many developmental functions for glial cells have been identified, the role that they play in the assembly of auditory circuitry is largely unknown. We have identified the spatiotemporal appearance of glia that reside in the auditory brainstem. Astrocytes emerge prior to the maturation of inhibitory synapses in NL and prior to a period of extensive dendritic remodeling. The proposed studies will determine the role of brainstem astrocytes on NL development. First, the effect of astrocyte co-cultures and astrocyte conditioned medium on NL dendritic morphology will be determined. Second, the effects of astrocytes on the maturation and distribution of inhibitory inputs to NL will be determined. Third, the molecular signals required for these astrocyte functions will be explored. Receptor tyrosine kinases of the Eph and Trk families are expressed in auditory neurons and glia and have demonstrated roles in auditory system development. These experiments will determine whether they are necessary for astrocyte regulation of NL neurons. Together these studies will provide insight into neuron-glial interactions in auditory system development that will contribute to understanding auditory function and treating disorders of auditory processing. PUBLIC HEALTH RELEVANCE: Hearing depends on precisely organized networks of neurons that receive input from the ears. Defects in central auditory circuitry can lead to language difficulties, problems with sound perception, or tinnitus. An understanding of how these networks are assembled during maturation will aid in the development of treatments to improve congenital or acquired hearing problems.

描述（由申请人提供）：听力依赖于通过非常精确排列的神经元连接传递声音诱发反应。该电路的缺陷可能导致声音感知、语言和交流障碍。听觉神经科学的一个中心目标是了解组装该电路的发育机制。这些知识将促进分子和细胞疗法的发展，以纠正听觉处理中的先天性或后天性缺陷。鸟类脑干提供了一个优雅的模型，因为其电路特征明确且易于访问。在此路径中n. magnocellularis (NM) 接收来自耳蜗神经节细胞轴突的同侧输入，然后向两侧投射到 n。昆布（荷兰）。该投影专门用于计算耳间时间差，这是声源定位中使用的主要线索。本研究的目的是确定该途径成熟的机制。一个重要的考虑因素是神经元和神经胶质细胞之间的相互作用，这对于正常发育和对损伤的反应至关重要。虽然神经胶质细胞的许多发育功能已被确定，但它们在听觉电路组装中所发挥的作用在很大程度上尚不清楚。我们已经确定了驻留在听觉脑干中的神经胶质细胞的时空外观。星形胶质细胞在 NL 中的抑制性突触成熟之前和广泛的树突重塑时期之前出现。拟议的研究将确定脑干星形胶质细胞在 NL 发育中的作用。首先，将确定星形胶质细胞共培养物和星形胶质细胞条件培养基对NL树突形态的影响。其次，将确定星形胶质细胞对 NL 的成熟和抑制输入分布的影响。第三，将探索这些星形胶质细胞功能所需的分子信号。 Eph 和 Trk 家族的受体酪氨酸激酶在听觉神经元和神经胶质细胞中表达，并在听觉系统发育中发挥作用。这些实验将确定它们对于星形胶质细胞调节 NL 神经元是否是必需的。这些研究将共同​​深入了解听觉系统发育中神经元-胶质细胞的相互作用，这将有助于理解听觉功能和治疗听觉处理障碍。 公共卫生相关性：听力取决于从耳朵接收输入的精确组织的神经元网络。中枢听觉回路的缺陷可能导致语言困难、声音感知问题或耳鸣。了解这些网络在成熟过程中如何组装将有助于开发改善先天性或后天性听力问题的治疗方法。