Wnt Signaling in Growth Cone Mediated Neurite Outgrowth from Spiral Ganglion Neurons in the Adult Mouse

Profound sensorineural hearing loss affects nearly 700,000 people in the United States and cannot be treated with hearing aids. Many listeners receive cochlear implants that can restore hearing by directly stimulating spiral ganglion neurons with electrodes implanted in the inner ear. However, the success of cochlear implants in older patients is limited by the reduced availability of surviving neurons that can be targeted with electrical stimulation, the distance between the implanted electrode array and the neuron cell bodies, and the formation of scar tissue at the interface between the remaining nerve fibers and the implanted electrodes. An approach to improving the performance of cochlear implants is to stimulate and guide neurite outgrowth from spiral ganglion neurons toward electrodes to form private channels of communication between the cochlear implant and the targeted neuronal populations. To date, there has been little investigation into the roles of Wnt proteins signaling through their Frizzled receptors in neuro-regeneration in the adult inner ear despite their involvement in axon guidance, dendrite morphogenesis, and synapse formation throughout the developing nervous system. In Chapter II, I show the differential expression of several Frizzled receptors in the spiral ganglion neurons of the adult mouse cochlea in an apical-to-basal gradient, as well as the expression of Frizzled 9 protein in growth cones of regenerating neurites in vitro. Then, in Chapter III, I demonstrate that the activation of canonical Wnt signaling by lithium modulates growth cone mediated neurite outgrowth from adult spiral ganglion neurons by altering the neuronal cytoskeleton. This dissertation research demonstrates that Frizzled-Wnt signaling represents a potential regenerative pathway for the restoration of neuronal connections in the adult inner ear after injury