Our research addresses the development of circuitry in the auditory system. Information from the cochlea is transmitted to the brainstem through the auditory nerve. This input is arranged in a tonotopic manner, so that at each level of processing there is an orderly representation of best frequencies. In addition, precision in auditory circuitry is used in sound localization. In birds, the auditory nerve contacts nucleus magnocellularis (NM). Axons emanating from neurons in NM bifurcate and innervate nucleus laminaris (NL) on both sides of the brain. NL neurons have symmetric dorsal and ventral dendrites. The dorsal dendrites receive input from ipsilateral NM while the ventral dendrites receive input from contralateral NM. NL neurons thus have binaurally segregated input, which is used to compute interaural time differences for low frequency sound localization. How do these precise connections form during development?

	Auditory pathways in avian (A) and rodent (B) brainstem.		Misexpression of EphA4 in NL produces targeting errors in the NM-NL projection.

We have previously shown that proteins in the Eph family of receptor tyrosine kinases and their ligands are expressed in the auditory brainstem nuclei. These proteins are involved in the regulation of axon outgrowth and are necessary for the formation of topographic maps in the visual system. One family member, EphA4, is highly expressed in dorsal, but not ventral, NL dendrites during the formation of synaptic connections between NM and NL. Because we have identified the locations of precursors for auditory nuclei in the early chick hindbrain, in ovo electroporation can be used to introduce genes focally into the developing auditory system. Misexpression studies of EphA4 followed by in vitro labeling of axonal projections demonstrate that this protein has an important role in establishing binaurally segregated inputs. Our work is currently aimed at understanding the role of Eph receptors in the formation of tonotopic connections in the auditory system. These studies assess the extent to which topography forms using similar mechanisms in different sensory modalities. In addition, we are examining the interactions between different members of this large family of proteins in auditory development.

Finally, we are studying the potential relationship between mechanisms of development and mechanisms of plasticity when connections in the auditory brainstem are altered following deafferentation. Do the same molecules serve to establish appropriate connections in both cases? How does neuronal activity influence the expression of these molecules? These studies will provide insight into brain reorganization, and may contribute to our understanding of how the brain repairs itself in response to injury.