Cellular and Molecular Basis of Tonotopic Map Formation in the Mouse Cochlear Nucleus

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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.