Neurobiology and Behavioral Consequences of Peripheral Vestibular Synaptopathy andRehabilitation

周围前庭突触病的神经生物学和行为后果及康复

• 批准号: 10539243
• 负责人: LARRY F HOFFMAN
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539243
• 关键词: Acoustic Trauma; Address; Affect; Afferent Neurons; Afferent Pathways; Aging; Aminoglycoside Antibiotics; Aminoglycosides; Animal Model; Animals; Architecture; Attenuated; Behavior; Behavioral; Bilateral; Cells; Characteristics; Clinical; Cochlea; Code; Confocal Microscopy; Country; Crista ampullaris; Data; Detection; Development; Diagnosis; Diagnostic; Dizziness; Dose; Duct (organ) structure; Electrophysiology (science); Epithelial; Etiology; Evaluation; Exhibits; Exposure to; Foundations; Functional disorder; Future; Gentamicins; Hair Cells; Head; Head Movements; Human Resources; Immunohistochemistry; Investigation; Ipsilateral; Knowledge; Label; Labyrinth; Liquid substance; Locomotion; Measures; Morphology; Mus; Neurobiology; Neurons; Noise; Outcome; Outcome Measure; Penetrance; Performance; Peripheral; Physiological; Physiology; Population; Rehabilitation therapy; Research; Resolution; Response to stimulus physiology; Rewards; Risk; Risk Factors; Running; Secondary to; Sensory; Services; Signal Transduction; Stimulus; Structure; Synapses; Testing; Time; Training; Translating; Traumatic Brain Injury; Treadmill Tests; Uncertainty; Vestibular Function Tests; Vestibular Hair Cells; Veterans; age related; behavior test; cochlear synaptopathy; cohort; density; design; effective therapy; efficacy testing; experimental study; functional decline; improved; kinematics; loss of function; multimodality; novel; ototoxicity; postsynaptic; rehabilitation research; rehabilitation strategy; research and development; response; ribbon synapse; sedentary; tool; transmission process; treadmill; vapor; vestibulo-ocular reflex

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.

本康复研究与开发服务申请包括一项研究计划 全面探讨周围性前庭功能减退的情况，以及在前庭功能减退中的表现 相关行为，以及是否与前庭毛细胞突触病的诱导有关。 出于两个主要原因，增强对前庭功能减退的了解至关重要。首先，出现 在美国服役人员和退伍军人中表现出广泛的外显率，主要是因为前庭功能减退 可能与脑外伤有关。其次，有强有力的证据表明，多种形式的 前庭功能减退可能与突触病有关，针对这种情况，康复策略可能是 对治疗特别有效。因此，鉴于美国服务业面临的风险因素加大 可能暴露的人员、前庭功能减退的诊断和治疗及其关联性的研究 突触病有可能对我们退伍军人的生活产生广泛影响。 虽然对耳蜗功能减退症的研究提供了有关以下方面的大量有价值的信息： 其病因、诊断和治疗方面，有关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，突触病是与年龄相关的神经元的一个组成部分。 前庭功能减退，从而证明突触病影响所有内耳感觉上皮。 温和的氨基糖苷类治疗也会引起耳蜗功能减退和突触病变，从而导致 与轻度声损伤引起的突触病相似的特征功能障碍。这 拟议的研究计划致力于全面研究低剂量引起的前庭功能减退 庆大霉素在正常前庭功能的成熟动物模型中，实施直接 外淋巴内给药以精确控制输送至迷路的剂量。初步数据 证明前庭功能减退是由离开前庭感觉上皮的情况引起的 形态上完整，这种情况与耳蜗突触病的发现相似。功能减退是 以传入神经元放电中刺激和反应之间的一致性减弱为代表， 表明信噪比和沿前庭传入通路的信息传输受到损害。 有了这些证据，我们提出了四个假设和相关目标。在目标 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 对于这一管理，我们从单一的指标中获得了潜在突触病的功能证据 神经元电生理学。通过定量评估直接测量突触密度 免疫组织化学，将通过细胞内标记与传入生理学直接相关 具有生理特征的传入神经元。目标 II 下的研究旨在开发 动态头部稳定性测量，我们提出的行为测试提供了一个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。我们认为该行为测试需要整合 多模态中枢神经系统回路受到感觉不确定性增加以及条件的影响 突触病。通过目标 III，我们将阐明分级功能减退的剂量依赖性结果，以及 建立突触病发展的时间过程。目标 IV 旨在测试功效 使用动态稳定测量作为训练工具来改善头部稳定功能并可能提供 突触康复。总之，这项研究代表了改善条件的全面努力 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 功效以及损害退伍军人和美国民众活动的条件。