Genetic dissection of auditory circuit assembly

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Project Summary Spiral ganglion neurons (SGNs) encode everything an animal hears and send this information to the brain. In order to achieve rapid and reliable signal transmission, SGNs exhibit a number of specialized properties, including the ability to respond to glutamate via large, AMPA-receptor rich post-synaptic densities. Although all SGNs are glutamatergic, differences in the nature of their synapses and their responses to sound indicate that there are three distinct subtypes. High spontaneous firing rate (SR) SGNs have low thresholds and are likely the first to respond to sound. Low SR SGNs have higher thresholds and are proposed to improve the ability to detect sounds in noise; medium SR SGNs fall in between. These physiological differences are accompanied by parallel changes in the abundance of AMPA receptors and the size of the opposing pre-synaptic ribbon. Low SR SGN synapses are more vulnerable to the effects of noise exposure, which may be why some people have trouble understanding what they hear despite normal auditory thresholds. The long-term goal of this project is to understand how SGNs acquire the properties needed for the perception of sound. More immediately, we will define the intrinsic transcriptional networks that endow SGN subtypes with their distinct properties and functions. This supplement will support a talented Hispanic graduate student, Ms. Cynthia Moncada-Reid, for one year, so that she can receive additional training in mechanisms of gene regulation and collect preliminary data needed for a successful fellowship application. The goal of her dissertation is to dissect how two transcription factors, c- Maf and Mafb, interact with DNA to control different programs of gene expression in different SGN subtypes. To get started, she will perform a set of new experiments that build on findings from Aim 3 of the Parent Grant and that will prepare her to become an expert in the latest techniques used to study gene regulation in the laboratory. Her training will be further complemented by attendance at the ARO Midwinter Meeting, by completing courses on Python and R, and by attending an intensive course on molecular neuroscience. Collectively, these activities will expand her training and put her in an excellent position to make fundamental discoveries about the molecular basis of SGN subtype differentiation during development.