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.
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