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

临床报告表明，退伍军人中噪声引起的听力损失和平衡障碍之间存在联系（Akin et 例如，2012），但这种联系的结构和生理基础还没有得到很好的理解。此外，动物 模型提供了连接噪声引起的前庭功能障碍和跌倒风险的机制基础， 有限公司前庭系统在检测头部运动和方向方面起着关键作用， 重力，是正常的姿势控制所必需的。由于它们在解剖学上接近耳蜗， 耳石器官暴露在声压下，有噪声过度刺激的风险，这可能有助于 前庭功能障碍最近的研究将噪音过度刺激与前庭神经活动减少联系起来 以及一类特殊的不规则放电前庭传入神经的丢失，这些传入神经对 加速度（Stewart等人，2018年）。很可能这些传入神经在启动姿势性运动中起着重要作用。 补偿由于其生理特征而导致的头部或身体位置的突然变化，并且其具有 已经确定这些传入投射到次级前庭神经元，次级前庭神经元投射到脊髓 (e.g.,波义耳等人，1992年）。虽然在控制头部和身体姿势方面的缺陷可能不明显， 持续的运动，当突然的扰动需要快速重置中心时，缺陷可能变得明显 重力或头部在太空中的位置。这样的扰动可以自然地发生，以避免一个人的路径中的障碍物，或者 在滑倒、急转弯或航向意外改变后恢复姿势稳定。这个目标 一项建议是描述啮齿类动物的跌倒风险，噪声诱导的前庭损伤优先影响 不规则地发射传入神经，并测试在耳蜗中有效的恢复疗法的潜力。 噪声损伤模型。恢复性治疗的发展可能具有重要的临床意义， 退伍军人，谁经常经历激烈的战场噪音的延迟影响，可能不会寻求治疗， 延长时间。根据现有的证据和我们的初步数据，我建议， 优先损害不规则前庭传入，导致对突然扰动的反应能力降低 在太空中的头部。 拟议研究的基本假设是，噪音会引起即时和长期的 前庭功能障碍导致平衡障碍，其成分可以“隐藏”，直到受到挑战。 需要快速补偿以保持重心的突然运动。这将在大鼠中进行测试， 不同时间暴露于噪音后。感觉细胞突触和前庭神经活动的变化将是 与平衡木任务中的跌倒风险相关，平衡木任务测量姿势稳定性和重心。然后我 预测通过将神经再支配诱导神经营养因子（NTF）递送到突触来修复突触， 内耳将产生平衡和康复的功能恢复。 第一个目标将遵循噪声引起的变化的时间过程，从我们以前的噪声暴露 条件和军事相关的小武器火灾样的噪音。我假设感觉细胞突触的丧失 连接和前庭神经活动将导致平衡紊乱， 改变了交叉策略，增加了平衡木上的福尔斯，这种功能障碍将持续到 时间第二个目标是测试一种治疗方法，诱导失去的突触重新连接，我假设， 神经再支配将改善平衡功能并提供康复。根据文献显示， 前庭神经元在耳毒性诱导的去神经支配后仍能很好地存活，我预测NTF治疗诱导的 在噪音诱导的去神经支配（对应于 多年的人）提供潜在的康复与噪音引起的平衡障碍的退伍军人。

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.