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.

该申请在康复研究与开发服务局中包括一个研究计划 全面研究周围前庭功能低下的状况，它如何在前庭中表现出来 相关行为，以及它是否与前庭毛细胞中突触病的诱导有关。 出于两个主要原因，对前庭功能障碍的知识增强至关重要。首先，它出现 在美国服务人员和退伍军人之间表现出广泛的外观，主要是因为前庭功能不全 可能与脑外伤有关。其次，有强有力的证据表明多种形式 前庭功能功能低下可能与突触病有关，康复策略可能是 对于治疗特别有效。因此，鉴于美国服务的风险因素增加 人员可能会暴露，研究前庭功能障碍的诊断和治疗 突触疗法有可能对我们的退伍军人的生活产生广泛的影响。 虽然对人工耳蜗功能低下的调查提供了有关有关的大量有价值的信息 他们的病因学，诊断和治疗，有关前庭功能障碍的信息处于新生状态。一个 最近对衰老小鼠的研究表明，突触病是与年龄有关的组成部分 前庭性功能低下，从而表明突触病影响了所有内耳感觉上皮。 轻度氨基糖苷治疗也诱导耳蜗功能低下和突触病，导致 与轻度声学创伤引起的突触病相似的特征功能障碍。这 提出的研究计划努力全面研究低剂量引起的前庭功能低下 庆大霉素在正常的前庭功能的良好动物模型中，直接实施 腹腔内给药以精确控制输送给迷宫的剂量。初步数据 证明前庭性功能低下是由于留下前庭感觉上皮的条件而引起的 在形态上完整，这种情况与人工耳蜗病中的发现相似。功能障碍是 在传入神经元排出时刺激与反应之间的相干性表示， 表明沿前庭传入途径的信噪比和信息传输的妥协。 有了这些证据，我们提出了四个假设和相关目标。在目的中，我将建立直接 庆大霉素的条件下，前庭功能低下与突触密度变化的关联 我们拥有从单个指标中的潜在突触病的功能证据 神经元电生理学。直接测量突触密度，通过定量评估 免疫组织化学将通过细胞内标记与传入生理学直接相关 生理表征的传入神经元。 AIM II下的研究针对发展 动态头部稳定测定法，我们提出的行为测试为您提供了一个窗口 我们在传入神经元记录中观察到的功能障碍。我们认为此行为测试需要集成 受感官不确定性与条件的增加影响的多模式CNS电路 突触病。通过AIM III，我们将阐明分级功能低下的剂量依赖性结果，并 建立突触性发展的时间过程。 AIM IV致力于测试的功效 使用动态稳定法作为训练工具，以提高头部稳定功能并有可能提供 突触康复。总而言之，这项研究代表了改善条件的全面努力 可能会影响大量的退伍军人，并为将来的疗法奠定基础，以恢复突触 功效和损害退伍军人和美国人口活动的条件。