Regeneration of Cochlear Synapses after Excitotoxic Trauma

In mammals, the ability to hear sound from the external world requires the rapid transformation of incoming acoustic signals into electrical impulses. This sub-millisecond transformation takes place at a highly specialized junction between two cells called a synapse, and is driven by a cascade of molecular events, ultimately giving rise to the sensory experience of hearing. The cells responsible for carrying these signals from the inner ear, or the cochlea, to the next relay center in the neural circuitry of the auditory system in the brainstem are called spiral ganglion neurons (SGNs). SGNs are bipolar neurons that project one of their processes into the periphery, forming synapses with the sensory cells of the cochlea, whilst the other projection carries this signal centrally toward the brain, forming the auditory nerve (AN). Damage to the peripheral synaptic connections of the AN, "synaptopathy", can result from overexposure to noise, causing difficulties hearing speech amid background noise, and goes undetected on clinical audiograms. The work of my thesis has been to investigate the underlying biological mechanisms that govern the loss, maintenance, and restoration of these synapses. Using ex-vivo techniques I describe experiments that led to the discovery of a drug that can block the damage that occurs during noise from occurring completely. Additionally, I demonstrate a new functional role for two molecules: CNTF, a neurotrophic factor, and progesterone, a female steroid sex hormone, showing that their ability to promote regeneration of synapses after trauma that results in synaptopathy.