Project Summary
Tonotopy is the most fundamental organizing principle of the vertebrate auditory system, meaning neurons at
all levels of the auditory pathway are topographically arranged based on their preferred sound frequency. It
allows animals to separate a complex sound into its frequency components, forming the basis for sound
discrimination. Disruption of tonotopy may result in difficulty processing sound frequencies. Despite its clinical
implications and importance in auditory function, very little is known about the mechanisms that govern the
formation of tonotopy in the auditory system. Knowing how auditory neurons generate tonotopic maps to
process sound information, is, therefore, crucial for understanding auditory functions and dysfunctions such as
central auditory processing disorders. Ephrins and Eph receptors are signaling molecules that play essential
roles in topographic mapping in other sensory systems during neural development. Our previous studies have
demonstrated that ephrin-A3 is required for tonotopic map precision and auditory functions in mouse cochlear
nucleus (CN). In ephrin-A3 mutant mice, although the tonotopic map is degraded, the gross tonotopic
organization is still maintained, suggesting that other ephrin and Eph molecules could also be involved in
tonotopic map formation in the CN. Our preliminary studies indicate that another ephrin molecule, ephrin-B2, is
differentially expressed along the tonotopic axis in the CN. Moreover, ephrin-B2 signaling is sufficient to repel
auditory nerve fibers in region-dependent and developmental stage-dependent manners. Based on these
observations, we hypothesize that that ephrin-B2 signaling works in concert with ephrin-A3 signaling to
regulate tonotopic map formation in the CN. To test our hypotheses and to elucidate the mechanisms that
underlie tonotopic map formation in the CN, we propose three major aims: 1) we will use lipophilic dye tracing
studies and neuronal c-fos induction assays after pure tone stimulation to determine if the tonotopic map
becomes less precise and is degraded in mice lacking ephrin-B2 specifically in the CN; 2) we will use prepulse
inhibition of the acoustic startle response to assess whether mice lacking ephrin-B2 specifically in the CN show
impaired abilities to discriminate sound frequency change; 3) we will use in situ hybridization and ephrin stripe
assays of cochlear explants to identify candidate Eph receptors in the developing spiral ganglion neurons that
mediate the effects of ephrin-A3 and/or ephrin-B2 signaling in the CN. Results from these studies will provide
novel insights into the cellular and molecular basis of how tonotopic maps are formed in the CN and how
Eph/ephrin signaling plays a role in regulating these processes. These studies will also allow us to better
understand how disruption of tonotopy results in auditory dysfunctions.
