Glial Influences on Auditory Brainstem Development

描述（由申请人提供）：听觉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。这种电路的缺陷会导致声音感知、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，以纠正先天性或后天听觉处理缺陷。鸟类的脑干提供了一个优雅的模型，因为它的电路很好地表征了，而且很容易接近。在这条通路中，大细胞神经元（NM）接受来自耳蜗神经节细胞轴突的同侧输入，然后向双侧纹层神经元（NL）传递信号。这种投影专门用于计算声源定位中使用的主要线索——声间时差。本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之间的相互作用，这是正常发育和对损伤的反应所必需的。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。我们已经确定了位于听觉脑干的神经胶质的时空外观。星形胶质细胞在NL的抑制性突触成熟之前出现，在广泛的树突重塑之前出现。建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基对NL树突形态的影响。其次，星形胶质细胞对NL的成熟和抑制输入分布的影响将被确定。第三，探索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NL神经元的星形细胞调节是必要的。总之，这些研究将提供听觉系统发育中神经元-神经胶质相互作用的见解，这将有助于理解听觉功能和治疗听觉处理障碍。

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. 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.