Glial Influences on Auditory Brainstem Development

描述(由申请人提供)：听力依赖于通过非常精确地安排的神经元连接来传输声音诱发的反应。这个回路的缺陷可能会导致声音感知、语言和交流的障碍。听觉神经科学的一个中心目标是了解组装这一回路的发育机制。这些知识将促进分子和细胞疗法的发展，以纠正先天或后天的听觉处理缺陷。鸟类的脑干提供了一个优雅的模型，因为电路的特点很好，很容易接触到。在这条通路中，大细胞核团(NM)接受来自耳蜗节细胞轴突的同侧输入，然后向板层核团(NL)投射。此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。这项研究的目的是确定这一途径成熟的机制。一个重要的考虑是神经元和神经胶质细胞之间的相互作用，这对正常发育和对损伤的反应是必不可少的。虽然胶质细胞的许多发育功能已经被确定，但它们在听觉回路组装中所起的作用在很大程度上是未知的。我们已经确定了存在于听觉脑干中的胶质细胞的时空外观。星形胶质细胞在NL抑制性突触成熟之前和广泛的树突重塑之前出现。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和星形胶质细胞条件培养液对NL树突状细胞形态的影响。其次，将确定星形胶质细胞对NL抑制输入的成熟和分布的影响。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是否对星形胶质细胞对下丘脑神经元的调节是必要的。这些研究将有助于深入了解听觉系统发育过程中神经元与神经胶质细胞的相互作用，有助于理解听觉功能和治疗听觉加工障碍。

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.