Developmental Determination of Central Auditory Physiology by the Inner Ear

Project Summary:
A longstanding and fundamental question of neural development in sensory pathways is: What is the
role of the organization of the sensory epithelium in establishing central topographic organization? In the
auditory system a direct approach to addressing this question has been elusive because it has not been
possible to manipulate the input to the brain from the auditory periphery without either complete ablation of the
inner ear or induction of hearing dysfunction. The proposed experiments will establish for the first time, a model
of repatterned frequency representation in the chick inner ear by utilizing a new genetic manipulation in
embryos. This manipulation takes advantage of the known genetic factors that establish the organization of the
ear at a very early developmental stage that precedes the auditory nerve innervation of the central nervous
system. By overexpressing one of these factors, bone morphogenic protein 7 (BMP7), inner ears develop
almost exclusively low frequency hair cell phenotypes. In the first brain structure to receive auditory nerve
input, the cochlear nucleus, neurons express a number of well characterized biophysical and morphological
specializations for processing sound in specific frequencies. Frequency specific tuning is topographically
mapped in both the ear and auditory brain regions, a feature known as 'tonotopy.' Thus, neural specialization
occurs along an orderly tonotopic map in the cochlear nucleus. The central hypothesis of this proposal is that
tonotopic refinement of specializations in the cochlear nucleus is developmentally determined by patterned
input from the inner ear, and is not independently induced by local cues in the developing brain. This
hypothesis is now testable using animals with tonotopically altered inner ears. The first aim of this proposal is
to examine whether the BMP7 manipulation indeed induces repatterning of hair cell tuning mechanism in the
inner ear. The second aim investigates the electrical input response properties of cochlear nucleus neurons in
animals that have developed with tonotopically altered inner ears. Finally, the third aim will investigate the
dependence of cochlear nucleus structure on normal topographic innervation from the auditory nerve. These
research objectives, if successful, will provide new insights into the mechanisms that establish the functional
organization of auditory structures. Revelation of these mechanisms may be informative to optimization
strategies for therapeutic interventions in early deafness or hearing loss that aim to preserve normal function
and capacity in auditory circuitry.

Grant Number: 5U01DC018537-04
NIH Institute/Center: NIH
Principal Investigator: R. Burger