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Disabling hearing loss represents a global public health concern. At least 33% of adults aged 65 and above have age-related hearing deficits. In recent years, there is also an increasing prevalence for acoustic trauma in young adults; 19% of adults aged 20 to 29 have evidence of early noise-induced damage. Unfortunately, age-related (AHL) and noise-induced (NIHL) hearing loss can result in permanent synaptopathy and axonopathy in spiral ganglion neurons (SGNs), the primary auditory neurons of the inner ear. Loss of these synapses can lead to social isolation, tinnitus, and a drop in a patient’s quality of life. Prior work has shown that AHL and NIHL target a subpopulation of differentially vulnerable SGN synapses. However, the molecular basis for this heterogeneity remains unknown. To address this challenge, I leveraged our group’s single-cell RNAseq database of adult Type I SGNs and showed that Lypd1, a nicotinic acetylcholine receptor modulator, and Calb2, an intracellular calcium buffer, define differentially vulnerable populations of SGNs. In particular, Lypd1+ SGNs share neuroanatomical features with low spontaneous firing rate (SR) SGNs, a functional SGN subtype previously shown to be susceptible to AHL and NIHL. SmFISH analysis of aged mice cochlea also showed that AHL preferentially targets Lypd1+ SGNs. At 108 weeks, the density of surviving Lypd1+ SGNs is severely attenuated, while the density of Calb2+ SGNs remains largely unchanged. Traditional therapies for hearing loss fail to fully compensate for SGN synapse loss and lack the ability to protect against future damage. To protect Lypd1+ SGNs from AHL and NIHL, I investigated the therapeutic potential of Bclw, an anti-apoptotic protein previously shown to be critical for the long term survival of sensory neuron axons. I injected adeno-associated viruses packaged with Bclw into the inner ears of early postnatal and adult mice and showed that overexpression of Bclw protected the SGNs from noise-induced synaptopathy. I also found that the viral treatment led to functional auditory protection, suggesting that Bclw overexpression can act as a prophylactic therapy against future acoustic trauma. As a result, we propose that Bclw is an attractive drug target for the prevention of AHL and NIHL.

With a global prevalence of 3.54% for a population aged 40-80 years and projections indicating worldwide affliction numbers increasing to 76 million people by 2020, glaucoma undoubtedly remains the leading cause of irreversible blindness worldwide (Tham et al., 2014). The research I have conducted over the past five years in the field of glaucoma has demonstrated that anterograde axonal transport loss occurs before retrograde transport deficits are seen and semifunctional RGC axons persist in the DBA/2J mouse model of glaucoma for much longer than previously thought (Dengler-Crish et al., 2014). While axons and synapses of the retinal projection are present after transport loss (Dengler-Crish et al., 2014; Crish et al., 2013), it is unclear from an ultrastructural perspective how morphologically intact and/or different these connections are. Furthermore, axonal elements such as nodes of Ranvier (NOR), and synaptic elements such as active zones, maintain strict morphometric and molecular composite standards. Apparent minor modifications to any of these elements can have major ramifications on normal function of the neural unit. However, very little is known about the relationship between axonal abnormalities and synaptic structure defects, in glaucoma. To clarify these relationships, my thesis work has examined the ultrastructure of RGC terminals in the neuropil of the superior colliculus, the morphometry and composition of NORs, as well as, axon size and cytoskeletal matrices in the optic nerve of a naturally occurring glaucomatous mouse model.