ONTOGENY OF COCHLEAR NUCLEUS RESPONSES TO AMINO ACIDS

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.