3D functional changes in the gap junctional signaling during the age related neurodegeneration in the mammalian inner ear Organ of Corti

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Hearing loss is one of the major health concerns worldwide. Over 50% of individuals older than 75 suffer from permanent hearing loss. Currently, there is no therapeutic agent that can prevent or reduce the progression of hearing loss. The main hallmark of hearing loss is the damage to the auditory inner ear, including loss of various cell types responsible for the process of hearing, such as spiral ganglion neurons, sensory hair cells and stria vascularis. However, functional alterations are observed in the specific cell types before the onset of hearing loss. These cells which show pathological changes before the onset of hearing are functionally coupled with gap junctions. Gap junctions are intercellular connections that directly connect the cytoplasm of two cells, and allow various molecules, ions and electrical impulses to directly pass through a regulated gate between cells. Importantly, alterations in gap junction function is the major cause of hereditary deafness in humans. Probing the role gap junctional intercellular communication in the process of hearing has relied on studies in expression systems and immature inner ear cultures, using invasive techniques which disrupt native cellular composition (such as injecting dyes into the cell to observe the propagation of dye between cells through gap junctions), or using techniques which cause the damage to the cells (such as very high intensity lasers which are used to visualize the dyes injected). In this study, we focus on mature native tissues, to study gap junctional coupling using novel, non-invasive techniques, allowing for preservation of cellular and endogenous metabolites and second messengers, which are established and important modulators of gap junctional signalling. Thus, this would be the first study to explore a direct link between the age related hearing loss and the alterations of gap junction signaling. The main objectives of this pilot study is to understand the functional alterations in the gap junction intercellular communication that contribute to neurodegeneration of the cochlea leading to hearing loss. We will use mice as models for the human cochlea. It has been shown that the mouse and human cochleae function in similar ways and share common underlying sensory processing mechanisms. Mice are most common animal model used for investigation of hearing processes and any possible hearing restoration. The studies of gap junctional coupling will be performed in acutely isolated auditory inner ear using novel high resolution optical techniques and cell permeable dyes which can defuse through gap junctions between cells to study the kinetics of gap junctional coupling. We will also use pharmacological modulators known to affect the gap junctional coupling and function to asses in intact system how these affect the electrical signalling between cells, and how they change in the process of neurodegeneration, such as in age related hearing loss. The results from this project may provide new directions and fresh opportunities to understand the process of hearing loss. Moreover, knowledge gained from these pilot studies would provide novel insights into the workings of cochlea and provide future research directions, which could ultimately contribute to development of future therapeutic treatments for the majority of the hearing impaired community that benefits very little from current treatments for hearing loss.