Afferent Influences on Auditory System Ontogeny

描述（由申请人提供）：理解正常和异常的大脑发育需要了解细胞事件，不同的经历影响神经结构和功能的个体发生。通过普遍的新生儿筛查和在先天性和语前听力受损婴儿中大量使用人工耳蜗，听觉神经科学领域的研究已经达到了一个新的临床重要性水平。本申请寻求继续资助一个研究项目，旨在了解细胞事件，即内部的完整性和生物电活动影响脑干听觉通路的发展。提出了两种不同的调查方法。1. 我们将继续研究细胞间和细胞内的信号通路，它们是哺乳动物耳蜗核兴奋性突触输入消失后神经元死亡易感性关键时期的基础。我们提出了一系列的实验来进一步研究小鼠耳蜗核在听力发育过程中转录和蛋白表达的发育变化。这种模式将与来自几种早期内耳结构和功能病变引起耳聋的突变小鼠模型的耳蜗核组织的类似分析数据进行比较。这些研究将为更好地了解正常和听力剥夺的耳蜗核发育提供一个生物标记谱库，可用于评估疾病状态和尝试修复。2. 我们结合单细胞标记、电生理学、钙成像和动态结构成像等方法，研究树突结构传入调控的细胞通路。我们还测试了一种假设，即负责将细胞内钙转运到细胞外环境的蛋白质PMCA2对维持正常树突稳定性至关重要。这些研究利用层状海胆细胞独特的空间分离双耳神经支配，对传入刺激、钙稳态、钙调节蛋白和树突结构动力学之间的关系进行空间解析。

DESCRIPTION (provided by applicant): Understanding normal and abnormal brain development requires knowledge of the cellular events whereby differential experience influences the ontogeny of neural structure and function. Research in this area of auditory neuroscience has achieved a new level of clinical importance through universal newborn screening and enormously increased use of cochlear implants in congenitally and prelingually hearing impaired infants. This application seeks continued funding for a research program aimed at understanding the cellular events whereby the integrity and bioelectric activity of the inner influences development of brainstem auditory pathways. Two separate lines of investigation are proposed. 1. We will continue investigating the intercellular and intracellular signaling pathway(s) that underlie a critical period for susceptibility to neuronal death following the elimination of excitatory synaptic input to the mammalian cochlear nucleus. We propose a series of experiments to further examine developmental changes in transcription and protein expression in the murine cochlear nucleus over the period of hearing development. This pattern will be compared with data from similar analyses of cochlear nucleus tissue from several mutant mouse models of early onset inner ear structural and functional pathologies causing deafness. These studies will provide a library of biomarker profiles for better understanding of normal and hearing deprived cochlear nucleus development that can be used to assess disease states and attempts at remediation. 2. We combine single cell labeling, electrophysiology, calcium imaging and dynamic structural imaging methods to study the cellular pathways underlying afferent regulation of dendritic structure. We also test the hypothesis that a protein responsible for transporting intracellular calcium to the extracellular environment, PMCA2, is essential for maintenance of normal dendritic stability. These studies make use of the unique spatially segregated binaural innervation of n. laminaris cells to allow spatial resolution of the relationships between afferent stimulation, calcium homeostasis, calcium regulatory proteins and structural dynamics of dendrites. PUBLIC HEALTH RELEVANCE: This project encompasses three interrelated areas: development of auditory information processing, neuroembryology of the auditory system, and the effects of experience on brain development. It is imperative that we understand how the various parts of the auditory system develop normally, in order to be able to therapeutically intervene in cases of congenital hearing loss. It is estimated that 10 to 20 percent of the US population have hearing impairments that significantly affect quality of life. Furthermore, 1 out of every 1,000 babies born in this country is seriously hearing impaired.