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

临床报告表明，退伍军人中噪音导致的听力损失和平衡障碍之间存在联系(Akin et Al.，2012)，但这种联系的结构和生理基础尚不清楚。此外，动物 提供连接噪音引起的前庭功能障碍和跌倒风险的机制基础的模型是 有限的。前庭系统在检测头部运动和方位方面起着关键作用。 对重力，对正常的姿势控制是必不可少的。由于它们在解剖学上与耳蜗很接近， 耳石器官暴露在声压下，存在噪音过度刺激的风险，这可能会导致 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。 以及丧失一类特殊的不规则放电前庭传入，这些传入表现出对 加速(Stewart等人，2018年)。很可能这些传入在启动姿势时起着重要作用。 对头部或身体位置因其生理特征而突然改变的补偿，它具有 已经证实，这些传入神经投射到投射到脊髓的二级前庭神经元 (例如，Boyle等人，1992)。尽管在控制头部和身体姿势方面的缺陷在 持续的运动，当突然的扰动需要快速重置中心时，赤字可能会变得明显 指重力或头部在空间中的位置。这样的扰动可能会自然地发生，以避开道路上的障碍或 在滑行、突然转弯或意外改变航向后恢复姿势稳定。这样做的目的是 建议是用噪声引起的前庭侮辱来表征啮齿类动物的跌倒风险，这些前庭侮辱优先影响 不规律地发射传入神经元，并测试对耳蜗病有效的恢复性治疗的可能性 噪声性损伤模型。恢复性疗法的发展可能对 退伍军人，他们经常经历激烈战场噪音的延迟效应，可能不会寻求治疗 延长了一段时间。根据现有证据和我们的初步数据，我认为噪音暴露 优先损害不规则的前庭传入，导致对突然干扰的反应能力降低 在太空中的头部。 拟议研究的基本假设是，噪音将导致即时和长期的 前庭功能障碍导致平衡障碍，这些成分可以被“隐藏”，直到受到 需要快速补偿以保持重心的突然运动。这将在老鼠身上进行测试， 暴露于噪声后的不同时间。感觉细胞突触和前庭神经活动的变化将是 在衡量姿势稳定性和重心的平衡木任务中，与跌倒风险相关。然后我 预测神经再支配诱导神经营养因子S对突触的修复作用 内耳将在平衡和康复中产生功能恢复。 第一个目标将跟踪与我们之前的噪声暴露相比，噪声引起的变化的时间进程 情况和军事相关的小武器开火般的噪音。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障碍，表现为穿越时间较慢， 改变了传中策略，在平衡木上摔倒的次数增加，这种功能障碍将持续下去 时间到了。第二个目标将测试一种诱导丢失突触重新连接的治疗方法，我假设 神经的再支配将改善平衡功能，并提供康复。基于文献显示的 前庭神经元在耳毒性诱导的去神经支配后存活良好，我预测NTF治疗会诱导 在噪声引起的去神经后，重新连接和恢复将保持良好的可能性(对应于 为患有噪音引起的平衡障碍的退伍军人提供了康复的潜力。

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.