Evaluation of noise-induced injury and restorative agents in the vestibular periphery

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Clinical reports suggest a link between noise-induced hearing loss and balance disorders in Veterans (Akin et al., 2012), but the structural and physiological basis for this linkage is not well understood. Furthermore, animal models which provide a mechanistic basis connecting noise-induced vestibular dysfunction and fall risk are limited. The vestibular system plays a critical role in detection of head movements and orientation with respect to gravity and is essential for normal postural control. Due to their anatomical proximity to the cochlea, the otolith organs are exposed to sound pressure and are at risk for noise overstimulation, which may contribute to vestibular dysfunction. Recent studies have linked noise overstimulation to decreased vestibular nerve activity and loss of a specialized class of irregularly firing vestibular afferents which exhibit enhanced sensitivity to acceleration (Stewart et al., 2018). It is likely that these afferents play an important role initiating postural compensation for abrupt changes in head or body position due to their physiological characteristics and it has been established that these afferents project to secondary vestibular neurons that project to the spinal cord (e.g., Boyle et al., 1992). Although deficits in control of head and body posture may not be obvious during sustained movements, deficits may become apparent when sudden perturbations require rapid resets of center of gravity or head position in space. Such perturbations may naturally occur to avoid obstacles in one’s path or regain postural stability after a slip, abrupt turn, or unexpected change in heading direction. The goal of this proposal is to characterize fall risk in rodents with noise induced vestibular insults that preferentially impact irregularly firing afferents, and to test the potential for restorative therapies that have been effective in cochlear noise-induced injury models. Development of restorative therapies may hold significant clinical relevance for Veterans, who often experience delayed effects of intense battlefield noise and may not seek treatment for an extended period of time. Based on available evidence and our preliminary data, I propose that noise exposure preferentially damages irregular vestibular afferents, resulting in reduced ability to react to abrupt perturbations of the head in space. The underlying hypothesis of the proposed studies is that noise will induce both immediate and long-term vestibular dysfunction resulting in a balance disorder with components that can be “hidden” until challenged by an abrupt motion which requires rapid compensation to maintain center of gravity. This will be tested in rats at different times after exposure to noise. Changes in sensory cell synapses and vestibular nerve activity will be correlated with fall risk in a balance beam task that measures postural stability and center of gravity. I then predict that repairing the synapses by delivery of re-innervation inducing neurotrophic factor(s) (NTF) to the inner ear will produce a functional recovery in balance and rehabilitation. The first aim will follow the time course of noise-induced changes from both our previous noise exposure condition and a military relevant small arms fire-like noise. I hypothesize that loss of sensory cell synaptic connections and vestibular nerve activity will result in a balance disorder evidenced by slower crossing times, altered crossing strategy, and increased falls on the balance beam, and that this dysfunction will persist over time. The second aim will test a treatment that induces reconnection of lost synapses and I hypothesize that the re-innervation will improve balance function and provide rehabilitation. Based on the literature suggesting vestibular neurons persist well after ototoxicity induced de-innervation, I predict NTF treatment induced reconnection and recovery will remain possible well after the noise induced de-innervation (corresponding to many years in people) providing potential for rehabilitation in Veterans with noise-induced balance disorder.