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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC001007-04
Application #
3217746
Study Section
Hearing Research Study Section (HAR)
Project Start
1990-06-01
Project End
1995-05-31
Budget Start
1993-06-01
Budget End
1994-05-31
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Father Flanagan's Boys' Home
Department
Type
DUNS #
City
Boys Town
State
NE
Country
United States
Zip Code
68010
Sprenkle, P M; McGee, J; Bertoni, J M et al. (2001) Prevention of auditory dysfunction in hypothyroid Tshr mutant mice by thyroxin treatment during development. J Assoc Res Otolaryngol 2:348-61
Sprenkle, P M; McGee, J; Bertoni, J M et al. (2001) Consequences of hypothyroidism on auditory system function in Tshr mutant (hyt) mice. J Assoc Res Otolaryngol 2:312-29
Sprenkle, P M; McGee, J; Bertoni, J M et al. (2001) Development of auditory brainstem responses (ABRs) in Tshr mutant mice derived from euthyroid and hypothyroid dams. J Assoc Res Otolaryngol 2:330-47
Cai, Y; McGee, J; Walsh, E J (2000) Contributions of ion conductances to the onset responses of octopus cells in the ventral cochlear nucleus: simulation results. J Neurophysiol 83:301-14
Fitzakerley, J L; McGee, J A; Walsh, E J (1998) Paradoxical relationship between frequency selectivity and threshold sensitivity during auditory-nerve fiber development. J Acoust Soc Am 103:3464-77
Sanes, D H; McGee, J; Walsh, E J (1998) Metabotropic glutamate receptor activation modulates sound level processing in the cochlear nucleus. J Neurophysiol 80:209-17
Cai, Y; Walsh, E J; McGee, J (1997) Mechanisms of onset responses in octopus cells of the cochlear nucleus: implications of a model. J Neurophysiol 78:872-83
Tubach, M; McGee, J; Walsh, E J (1996) Distortion generated by the ear: its emergence and evolution during development. Laryngoscope 106:822-30
McFadden, S L; Walsh, E J; McGee, J (1996) Onset and development of auditory brainstem responses in the Mongolian gerbil (Meriones unguiculatus). Hear Res 100:68-79
Riggs, G H; Walsh, E J; Schweitzer, L (1995) The development of glycine-like immunoreactivity in the dorsal cochlear nucleus. Hear Res 89:172-80

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