Anatomy of the Auditory System

描述（由申请人提供）：噪声性听力损失是一种无法治愈的，通常是进行性的疾病，会损害生活质量。该项目使用动物模型，提供了证据表明，除了耳蜗毛细胞的损失外，大脑突触末梢的退化是该疾病的主要因素。这项研究提供了初步的数据，表明随着时间的推移，耳蜗核的兴奋性和抑制性末梢之间的平衡向兴奋性和多动性转移。总的假设是，这些变化为噪声暴露后的耳鸣和听觉亢进提供了结构基础。该项目将在细胞和分子水平上描述退化过程，并追踪突触组织的变化，包括令人兴奋的发现，即在初始损伤后可以形成新的突触。这些实验旨在揭示保护突触或促进噪声后恢复的因素。利用光镜和电子显微镜检查小鼠耳蜗核的损伤。在噪声暴露后1-120天内，将量化兴奋性和抑制性末梢比例的变化。光镜下的突触囊泡组织化学可以显示末梢的数量和位置。电子显微镜将显示末梢兴奋性或抑制性细胞学的比例，使用立体学方法来验证这一假设。免疫细胞化学通过光镜和电子显微镜将识别这些变化背后的分子。递质相关分子，包括兴奋性和抑制性受体和转运体，将定位于特定类型的神经元和突触，并在存活期间进行追踪。这些数据将确定在耳蜗核的何处和何时细胞可能发生兴奋性毒性过程。神经营养因子和受体将被识别和定位，以表明营养机制的作用。成纤维细胞生长因子的作用将在过表达该因子的转基因小鼠中进行评估。假设是这个因子可以防止损伤，而神经营养因子可以促进突触的新生长。研究结果应该会引发新疗法的建议。

DESCRIPTION (provided by applicant): Noise-induced hearing loss is an incurable, often progressive disease that impairs the quality of life. This project, using animal models, has provided evidence for degeneration of synaptic endings in the brain, besides loss of cochlear hair cells, as a major factor in this disease. This research offers preliminary data that the balance between excitatory and inhibitory endings in the cochlear nucleus shifts over time towards excitation and hyperactivity. The overall hypothesis is that these shifts provide a structural basis for tinnitus and hyperacusis after noise exposure. The project will characterize the degenerative process, at the cell and molecular levels, and trace changes in synaptic organization, including the exciting discovery that new synapses can form after the initial damage. The experiments aim to uncover factors that protect synapses or promote recovery after noise. Light and electron microscopy are used to examine damage in the cochlear nucleus of mice. Changes in the proportion of excitatory and inhibitory endings will be quantitated over 1-120 days after noise exposure. Synaptic vesicle histochemistry with light microscopy will show the numbers and locations of endings. Electron microscopy will show the proportion of endings with excitatory or inhibitory cytology using stereological approaches to test the hypothesis. Immunocytochemistry by light and electron microscopy will identify molecules underlying these changes. Transmitter-related molecules, including excitatory and inhibitory receptors and transporters, will be localized to specific types of neurons and synapses and tracked over the survival period. These data will pinpoint where and when in the cochlear nucleus an excitotoxic process may occur in cells. Neurotrophic factors and receptors will be identified and localized to indicate a role for trophic mechanisms. The role of fibroblast growth factor will be evaluated in a transgenic mouse that over expresses this factor. The hypothesis is that this factor protects against damage, and neurotrophins promote new growth of synapses. The results should lead to proposals for new therapies.