Project Summary/Abstract The neuronal pathways that connect the ear to the brain are not well understood. For decades, work has focused on understanding how damage to hair cells (the sensory receptors in the inner ear) impacts hearing. We now know that the neuronal circuits that transmit auditory information detected by the hair cells are even more vulnerable to damage. Further, this damage is permanent and has lasting impact on quality of life. Deepening our understanding of how neuronal circuits are established and maintained in normal hearing will be a critical to better understand disease and improve prevention and treatment strategies. The perception of sound begins in the cochlea, where hair cells detect and transmit auditory input to the brainstem via afferent neurons. Efferent neurons provide feedback control allowing tuning of this input. These neurons are born early in development and following differentiation send projections to the cochlea sensory epithelium where they make highly specific connections with two types of hair cell: the inner and outer hair cells (IHCs and OHCs). How these projections track to the appropriate location within the cochlea (either along the cochlear duct, or between inner and outer compartments) is not well understood. The goal of this proposal is to obtain a comprehensive picture of how afferent and efferent innervation patterns are set up in the organ of Corti. Using a recently described Insm1 mouse model, in which IHCs are intermingled with OHCs in the outer compartment (oc-IHCs), I will test the hypothesis that there is a hierarchical model of innervation such that hair cell type dictates afferent innervation which in turn determines the type of efferent innervation received (aim 1). Additionally, using a combination of mouse genetics and cochlear explant cultures combined with viral vectors, I will test novel candidate genes for roles in axonal pathfinding and branching in the cochlea (aim 2 and alternative aim 2/future goals). I believe these aims will materially advance our understanding of the neuronal circuits within the ear and ultimately lead to the development new and improved treatments for hearing loss. My long term career goal is to establish myself as an independent investigator at a top research institution. Given I have recently moved research field (and model system) from transcriptional regulation to neurobiology, this award would allow me to a) gain depth and breadth of knowledge, and technical expertise in the auditory field b) publish my work in reputable journals and c) develop an independent project that can be used to obtain my own independent funding and tenure track position. With the combination of this grant, the expert guidance by my mentoring team and the expertise and resources available to me through the broader auditory community established here at Northwestern University means that I will have every chance of success.