ONTOGENY OF COCHLEAR NUCLEUS RESPONSES TO AMINO ACIDS

拟议研究的广泛、长期目标是描述 神经元的神经生理学和神经药理学方面 耳蜗核（CN）复合体的发育。 这项研究是 一个更广泛的目标，即开发一个全面的模型， 哺乳动物的听觉发展将支持生物医学研究 旨在确定环境危害对 人类听觉功能的发展，以及 药物工程，以改善先天性和环境 诱发听觉病理学。 根据以前的研究结果， 在拟议的实验中将检验几个假设：（1）在 根据已知的神经支配时间进程，兴奋性的发展， 通过多巴胺能膜受体实现的功能先于 功能性GABA和甘氨酸介导的抑制的发展，（2） 外部影响（耳蜗、其他神经网络等），而不是 CN神经元的内在特性，是观察到的反应不成熟的基础 （3）突触前成分的发育速率限制 CN中的“功能性突触发生”。 的频率依赖方面， GABA和甘氨酸介导的CN神经元抑制的发展将 第一次直接在听觉结构中进行研究， 这是一群以前从未研究过的神经元。 与此同时， 将研究内源性氨基酸的浓度和功能 在发育期间表现出广泛的突触发生和 神经营养活性 为了达到既定目标，实验 包括标准的单神经元电生理学， 将进行微离子电泳程序，并进行标准生理学检查。 并且将使用药理学方法（即，当前/或 剂量/反应曲线分析，放电速率的氨基酸调节与 声级函数，声诱发的时间放电模式， 等等）。来描述这个脑干核团中的神经元。 此外，高 高效液相色谱-电化学联用 检测方法将用于确定GABA的浓度， 在整个出生后发育过程中，特定CN区域可获得甘氨酸。 将分析其浓度与电生理学的关系， 药理学结果，特别是关于实验范式 旨在阐明我们对发展相关性的理解， 与内源性配体作用相关的变化。 拟议结果 研究将提供对某些关键分子事件的坚定理解 中枢听觉系统的发展

The broad, long-term objective of the proposed research is to characterize the neurophysiological and neuropharmacological aspects of neuronal development in the cochlear nuclear (CN) complex. This research is part of an even broader objective, which is to develop a comprehensive model of mammalian auditory development that will support biomedical research designed to determine the influence of environmental hazards on the development of auditory function in humans, as well as the development of pharmaceuticals engineered to ameliorate congenital and environmentally induced auditory pathology. Based upon results from previous research, several hypotheses are to be tested in proposed experiments: (1) on the basis of known innervation time courses, that the development of excitatory function subserved via glutamatergic membrane receptors precedes the development of functional GABA and glycine mediated inhibition, (2) that extrinsic influences (cochlear, other neural networks, etc.),, rather than intrinsic properties of CN neurons, underlie observed response immaturities and (3) that the development of presynaptic elements rate limits 'functional synaptogenesis' in CN. The frequency-dependent aspects of the development of GABA and glycine mediated inhibition among CN neurons will be studied directly for the first time in an auditory structure, among a population of neurons never before studied. Also, changes associated with concentrations and function of endogenous amino acids will be studied during developmental periods exhibiting extensive synaptogenic and neurotrophic activity. To achieve the stated objectives, experiments involving standard single neuron electrophysiology in combination with microionophoresis procedures will be performed and standard physiological and pharmacological procedures will be utilized (i.e., current/or dose/response curve analyses, amino acid modulation of discharge rate vs. sound level functions, acoustically-evoked temporal discharge patterns, etc.) to characterize neurons in this brainstem nucleus. In addition, high performance liquid chromatography (HPLC) and combined electrochemical detection methods will be used to determine the concentrations of GABA and glycine available in specific CN regions throughout postnatal development. Their concentrations will be analyzed in relation to electrophysiology and pharmacology results, particularly with regard to experimental paradigms designed to illuminate our understanding of the relevance of developmental changes associated with endogenous ligand actions. Results of proposed research will provide a firm understanding of certain key molecular events underlying central auditory system development.