Understanding the fundamental principles of normal and abnormal brain development requires knowledge of the cellular events whereby differential experience influences the ontogeny of neural structure and function. In the auditory system, this area of research has achieved new and immediate clinical importance with the increasing use of cochlear implants in congenitally and prelingually hearing impaired infants. This application seeks continued funding for a research program aimed at understanding the cellular events underlying the influence of inner ear integrity and activity on development of brainstem auditory pathways. Four separate lines of investigation will be either continued or initiated. 1. We will continue to investigate the hypothesis that intracellular calcium homeostasis plays a key role in regulating the initiation of events leading to transneuronal cell death of brainstem neurons in young animals following damage to the inner ear or deprivation of acoustically driven inner ear activity. 2. We will investigate activity-dependent regulation of a specific molecule, a potassium channel (Kv1.1), thought to play a uniquely important role in the temporal coding of auditory information. Afferent regulation of the expression of this molecule will be examined at the levels of gene transcription, protein, and functional properties of cochlear nucleus cells. 3. We will use normal and mutant mice to examine the biological principles underlying differential susceptibility of the developing and mature brains to deprivation-induced degeneration. 4. We will combine single cell labeling, electrophysiology and calcium imaging methods to study the cellular mechanisms of afferent regulation of dendritic structure.
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