Cellular mechanisms of age related hearing loss

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PROJECT SUMMARY/ABSTRACT Cochlear nucleus (CN) is the first neural station of the central auditory system that processes all sound information from the auditory nerve (AN). Principal neurons of CN encode different aspects of sound, including information about the temporal fine structure (TFS) that is essential for auditory tasks like sound localization and speech detection in noisy environment. During age related hearing loss (ARHL), the central processing of TFS information is compromised, leads to perceptual deficits. The overall hypothesis is that modifications in CN neurons and neural circuits during aging contribute to the malfunction of auditory temporal processing that underlies ARHL. The project investigates the cellular mechanisms of ARHL in CN bushy neurons, which are specialized in processing TFS information, as well as their excitatory inputs from AN and inhibitory inputs from CN interneurons during aging. Our previous studies showed that synaptopathy occurs at AN central terminals during ARHL, specifically the endbulb of Held synapses, which show age related degradation in transmitting auditory information to postsynaptic bushy neurons. The decrease in endbulb function is due to compromised synaptic transmission that is associated with dysregulated calcium signaling at the synaptic terminal. In Aim1, the project investigates the mechanisms of different calcium signaling pathways during aging at the endbulb of Held synapse, including calcium uptake and removal, calcium influx via voltage gated calcium channels, synaptic vesicle replenishment, as well as the expression of different calcium sensors. Our prior study also found that bushy neurons are depolarized and more excitable during aging. In Aim2, the project will test the hypothesis that auditory system enhances central gain in bushy neurons to compensate for the weakened AN input during ARHL. Mechanisms of voltage-gated ion channels during ARHL will be studied by quantifying membrane conductances that underlie neural excitability in bushy neurons during aging. In Aim3, the project will elucidate the mechanisms of inhibition during ARHL by investigating the effect of inhibition on firing property of bushy neurons, assessing synaptic strength of glycinergic inputs, and evaluating the neural excitability of CN interneurons as well as their AN inputs during aging. To achieve these goals, the project utilizes techniques including behavioral hearing test (auditory brainstem response), whole-cell recording under current or voltage clamp mode using acute brain slices, pharmacological manipulation, as well as immunohistochemistry, using CBA/CaJ mice as the animal model for ARHL at ages up to 30 months. These studies will have a significant impact on our understanding of synaptic and cellular mechanisms underlying ARHL, which is fundamental and essential for developing therapeutic approaches to restore neural processing in the central auditory system and eventually reinstate sound perception in patients with hearing impairments.