Human hearing loss is most often attributed to the loss of hair cells in the cochlea. Hair cells function as auditory receptors and are the sole afferent input to the spiral ganglion neurons (SGNs). Hair cells also provide survival-promoting neurotrophic factors for the SGNs. Genetic disorders, noise trauma, aging, and ototoxic drugs may all cause death of the hair cells. This loss of hair cells results in deafferentation of the SGNs, eventually causing loss of the peripheral axon and death of the neuron. SGNs die gradually over a period of time, ranging from months in rats, to decades in humans. It is not yet known what provides trophic support for the SGNs during this period nor why it is ultimately insufficient in preventing SGN death. Answering these questions might suggest means of maintaining SGN survival indefinitely after deafening. It is also unknown why some SGNs die shortly after loss of hair cells while others persist. Knowing the differences between these populations of SGNs may result in treatments to maintain their survival. Goals of the proposed study include localization of an alternative source for neurotrophic support and identification of the neurotrophic factors provided. Additionally, I wish to understand what distinguishes SGNs still surviving many weeks after hair cell loss from the initial population of SGNs. Alternative sources for neurotrophic support include supporting cells of the organ of Corti, the cochlear nucleus, and spiral ganglion Schwann cells. Examination of these sources, along with the spiral ganglion, through gene expression analysis in the forms of quantitative PCR and microarrays will be completed. Rats will be deafened with daily injections of kanamycin from postnatal days 8 (P8) through P16 and euthanized at 23, 32, 60, and 88 along with age-matched hearing controls. These time points were chosen based on the course of SGN death: P23 corresponds to the onset of SGN death, a statistically significant amount of SGN degeneration has occurred by P32, P60 is midway through the period of degeneration, and at P90 few SGNs remain. RNA will be isolated and converted to cDNA to be used for gene expression analysis. Emphasis during analysis will be on neurotrophic factors, apoptotic and pro-survival factors, and genes associated with neural survival and physiology.
Sensorineural hearing loss affects about 20,000,000 Americans and the only current means to replace the function of the lost sensory cells is the cochlear implant, which directly stimulates cochlear neurons. My research focuses on improving the survival and function of surviving neurons in order to improve the long-term efficacy of cochlear implants, currently used by over 40,000 Americans.
|Bailey, Erin M; Green, Steven H (2014) Postnatal expression of neurotrophic factors accessible to spiral ganglion neurons in the auditory system of adult hearing and deafened rats. J Neurosci 34:13110-26|