Neurobiology and Behavioral Consequences of Peripheral Vestibular Synaptopathy andRehabilitation

这项对康复研究和发展处的申请包括一项研究计划，以 全面调查外周前庭功能减退的情况，它是如何在前庭表现的- 相关行为，以及它是否与前庭毛细胞突触的诱导有关。 增强对前庭功能减退的认识是至关重要的，主要有两个原因。首先，它似乎 在美国服役人员和退伍军人中表现出广泛的外观性，主要是因为前庭功能低下 可能与创伤性脑损伤有关。第二，有强有力的证据表明，许多形式的 前庭功能减退可能与突触病变有关，对此康复策略可能是 对治疗特别有效。因此，鉴于美国军队面临的高风险因素 前庭功能减退的诊断和治疗研究及其与人员暴露的关系 突触疗法有可能对我们退伍军人的生活产生广泛影响。 虽然对耳蜗功能低下的调查提供了丰富的有价值的信息， 他们的病因、诊断和治疗，关于前庭功能减退的信息还处于萌芽状态。一个 最近对衰老小鼠的研究表明，突触病变是年龄相关的一个组成部分 前庭功能减退，从而表明突触病变影响所有内耳感觉上皮细胞。 轻微的氨基糖苷类治疗也会导致耳蜗功能减退和突触病变，导致 与轻微声损伤引起的突触病变类似的标志性功能障碍。这个 拟议的研究计划致力于全面调查低剂量引起的前庭功能减退 庆大霉素在已建立的前庭功能正常的动物模型中直接实施 外淋巴管内给药，精确控制给药至迷路的剂量。初步数据 证明前庭功能减退是由于离开前庭感觉上皮的状况所致 形态完好，这一情况与耳蜗性突触病的发现相似。功能减退是 表现为传入神经元放电中刺激和反应之间的一致性减弱， 表明信噪比和前庭传入通路的信息传递的折衷。 有了这个证据，我们提出了四个假设和相关的目标。在AIM I中，我们将建立直接 庆大霉素条件下前庭功能减退与突触密度变化的关系 管理，我们有功能证据的潜在突触的指标源自单一 神经电生理学。突触密度的直接测量，通过定量评估 免疫组织化学，将直接与传入生理相关的细胞内标记 具有生理特征的传入神经元。AIM II下的研究是针对这一发展而进行的。 我们提出的动态头部稳定测量的行为测试提供了了解以下形式的窗口 我们在传入神经元记录中观察到功能减退。我们认为，此行为测试需要集成 受感觉不确定性增加影响的多模式中枢神经系统回路伴随着 突触疗法。通过AIM III，我们将阐明分级功能减退的剂量依赖结果，以及 建立突触发育的时间进程。目标IV旨在测试 使用动态稳定测量作为一种训练工具来改善头部稳定功能，并有可能提供 突触康复。总而言之，这项研究代表了一项全面的努力，以改善 可能会影响大量退伍军人，并为未来恢复突触的疗法奠定基础 影响退伍军人和美国民众活动的效力和条件。

This application to the Rehabilitation Research and Development Service includes a research plan to comprehensively investigate the condition of peripheral vestibular hypofunction, how it manifests in vestibular- related behaviors, and whether it is associated with the induction of synaptopathy in vestibular hair cells. Enhanced knowledge of vestibular hypofunction is critically important for two primary reasons. First, it appears to exhibit broad penetrance among US service personnel and veterans, largely because vestibular hypofunction may be associated with traumatic brain injury. And second, there is strong evidence that many forms of vestibular hypofunction may be associated with synaptopathies, for which rehabilitation strategies may be particularly effective for treatment. Therefore, in view of the heightened risk factors to which US service personnel may be exposed, research into diagnosis and treatment of vestibular hypofunction and the association with synaptopathies has the potential for broad impact on the lives of our Veterans. While investigations into cochlear hypofunction have provided a wealth of valuable information regarding their etiology, diagnosis, and treatment, information regarding vestibular hypofunction is in a nascent state. A recent investigation of aging mice has demonstrated that synaptopathies are a component of age-related vestibular hypofunction, thereby demonstrating that synaptopathies impact all inner ear sensory epithelia. Cochlear hypofunction and synaptopathies are also induced by mild aminoglycoside treatment, resulting in similar signature dysfunction as demonstrated for synaptopathies induced by mild acoustic trauma. The proposed research plan endeavors to comprehensively investigate vestibular hypofunction induced by low-dose gentamicin in a well-established animal model of normal vestibular function, implementing direct intraperilymphatic administration to precisely control the dose delivered to the labyrinth. Preliminary data demonstrated that vestibular hypofunction results from conditions that leave the vestibular sensory epithelia morphologically intact, a condition that parallels the findings in cochlear synaptopathy. The hypofunction is represented by attenuated coherence between stimulus and response in the discharge of afferent neurons, indicating compromise to signal-to-noise ratios and information transmission along vestibular afferent pathways. With this evidence, we proposed four hypotheses and associated Aims. In Aim I we will establish the direct association of vestibular hypofunction with changes in synapse density, under conditions of gentamicin administration for which we have functional evidence of potential synaptopathy from metrics derived from single neuron electrophysiology. Direct measures of synapse densities, assessed through quantitative immunohistochemistry, will be directly correlated with afferent physiology by intracellular labeling of physiologically characterized afferent neurons. The research under Aim II is directed toward the development of dynamic head stabilometry, a behavioral test of that we propose provides a window into the form of hypofunction we observe in afferent neuron recordings. We submit that this behavior test requires integration of multimodal CNS circuits that are affected by the increase in sensory uncertainty concomitant with conditions of synaptopathy. Through Aim III we will elucidate the dose-dependent outcomes of graded hypofunction, and establish the temporal course of synaptopathy development. Aim IV is directed toward testing the efficacy of using dynamic stabilometry as a training tool to improve head stabilization function and potentially provide synaptic rehabilitation. In summary, this study represents a comprehensive effort to ameliorate conditions that are likely to impact a large number of Veterans, and lay the groundwork for future therapies restoring synaptic efficacy and the conditions that compromise the activity of Veterans and the US population.