Afferent Influences on Auditory System Ontogeny

描述(由申请人提供)：了解正常和不正常的大脑发育需要了解细胞事件，通过不同的经验影响神经结构和功能的个体发育。这一听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，通过普遍的新生儿筛查，并极大地增加了对先天和语言前听力障碍婴儿的人工耳蜗的使用。这项申请寻求继续为一项旨在了解细胞事件的研究项目提供资金，通过该项目，内部的完整性和生物电活动影响脑干听觉通路的发育。提出了两条不同的调查路线。1.我们将继续研究细胞间和细胞内的信号通路(S)，该通路是哺乳动物耳蜗核兴奋性突触输入消除后神经元死亡的关键时期。我们提出了一系列实验，以进一步研究小鼠耳蜗核在听力发育期间转录和蛋白表达的发育变化。这一模式将与对耳蜗核组织的类似分析数据进行比较，这些数据来自几种早发性内耳结构和功能病理导致耳聋的突变小鼠模型。这些研究将提供一个生物标志物分布库，以更好地了解正常和听力障碍的耳蜗核发育，可用于评估疾病状态和补救尝试。2.结合单细胞标记、电生理学、钙离子成像和动态结构成像等方法，研究树突状结构传入调控的细胞通路。我们还检验了一种假设，即一种负责将细胞内钙运输到细胞外环境的蛋白质PMCA2对于维持正常的树突状细胞稳定性是必不可少的。这些研究利用纹状体神经细胞独特的空间分离的双耳神经支配来空间分辨传入刺激、钙稳态、钙调节蛋白和树突结构动力学之间的关系。 公共卫生相关性：这个项目包括三个相互关联的领域：听觉信息处理的发展，听觉系统的神经胚胎学，以及经验对大脑发育的影响。我们必须了解听觉系统的各个部分是如何正常发育的，以便能够对先天性听力损失进行治疗干预。据估计，10%到20%的美国人口患有严重影响生活质量的听力障碍。此外，在这个国家出生的婴儿中，每1000人中就有1人严重听力受损。

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.