Acoustic overexposure is a growing problem, and understanding the long-term consequences is critical to public health. Our recent work in a mouse model of noise and aging shows that moderate exposures, which initially appear reversible and cause no acute or chronic hair cell loss, elicit a slow-onset loss of spiral ganglion cells (SGCs) when followed for months post-exposure. Confocal immunohistochemistry suggests that many SGC peripheral terminals, and their synapses on inner hair cells, disappear within the first days or hours, consistent with acute excitotoxic effects of acoustic overexposure. We hypothesize that this acute dendritic retraction disrupts normal neurotrophin signaling among hair cells, supporting cells and neurons in the cochlear epithelium, and that this interruption initiates the slow cell-death cascade in SGCs. The proposed Aims test this hypothesis by characterizing the nature and time course of neuronal degeneration and associated pathophysiology (Aim 1), and by manipulating acute excitotoxicity (Aim 2) or neurotrophin expression (Aim 3) and assessing the effects on cochlear neurodegeneration. Quantification of neuropathy (Aim 1a), will track degeneration over post-exposure time as it progresses from synapse, to peripheral axon, to cell body. Correlations with pathophysiology at population-response and single-fiber levels (Aim 1b) will verify if we have identified the functionally important structural changes, and will test the hypothesis that noise causes a preferential loss of neurons with low spontaneous rates. To test if acute excitotoxicity is the key upstream elicitor of the neuropathy, we exploit our techniques for cochlear perfusion in mouse to either 1) block noise-induced excitotoxicity with the glutamate antagonist DNQX (Aim 2a), 2) mimic it with the glutamate agonist AMPA (Aim 2b) or 3) enhance it using mice with targeted deletion of the glutamate transporter GLAST (Aim 2c). To test the role of neurotrophins in the slow cascade of cell death, we will assay (via qRT-PCR, immunohistochemistry and a NT3-reporter mouse) gene expression levels of key molecules in the neurotrophin signaling pathway as a function of post-exposure time (Aim 3a), and attempt a rescue experiment (reduce/prevent loss of neurons;promote re-innervation of intact IHCs) using mouse lines with inducible neurotrophin overexpression in either hair cells or supporting cells (Aim 3b). Understanding the nature, etiology and possible prevention of slow-onset neurodegeneration in our noise- exposed mice has important ramifications for human hearing. It suggests that primary neuronal loss is a more common and important aspect of acquired sensorineural hearing loss than previously thought. It also raises important concerns re possible long-term consequences of apparently benign acoustic overexposures: the phenomenon of slow-onset noise-induced neurodegeneration may contribute in a major way to the main hearing-related complaint in aging humans, i.e. problems understanding speech in a noisy environment.
Our recent work in mouse shows that noise-exposures, even those that appear to result in fully reversible threshold shifts, actually set in motion a slow cell death cascade leading to the ultimate loss of roughly half of the neural elements throughout large regions of the cochlea. If generally applicable to the mammalian ear, as there is every reason to believe it will be, the phenomenon of slow-onset, noise-induced, primary, cochlear-nerve loss is potentially a very common problem with significant public health implications. Our proposed experiments provide a powerful platform to study the phenomenon and to probe its mechanisms, using a cochlear insult (i.e. noise) that is highly relevant to the human condition.
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