The Peripheral Vestibular System in Congenital Vestibular Disorders

先天性前庭疾病的周围前庭系统

• 批准号: 10366081
• 负责人: Kenna D Peusner
• 金额: $ 33.33万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366081
• 关键词: Address; Adult; Affect; Age; Animal Model; Animals; Anterior; Aromatase; Auditory; Basic Science; Birds; Brain; Brain Stem; Cell Count; Cell Nucleus; Cells; Chick; Chick Embryo; Chick model; Child; Childhood; Clinic; Clinical; Clinical assessments; Data; Development; Developmental Delay Disorders; Disease; Dizziness; Electrophysiology (science); Embryo; Epithelial; Equilibrium; Fiber; Foundations; Functional disorder; Goals; Hair Cells; Image; Label; Laboratories; Labyrinth; Lead; Life; Link; Membrane; Modeling; Motor; Musculoskeletal Equilibrium; Neurons; Neurotransmitters; Operative Surgical Procedures; Organ; Outcome; Pathologic; Pathology; Patients; Pattern; Peripheral; Phenotype; Physical therapy; Planet Earth; Pregnancy; Procedures; Property; Quality of life; Reflex action; Reporting; Reproducibility; Research; Role; Rotation; Semicircular canal structure; Sensory; Side; Signal Transduction; Site; Stains; Structure; Symptoms; Synapses; Synaptic Transmission; System; Testing; Thinking; Time; Tissue Stains; Tissues; Vestibular Nerve; Vestibular ganglion; Vestibular nucleus structure; Walking; Work; X-Ray Computed Tomography; base; biocytin; disability; experience; experimental study; ganglion cell; hatching; improved; inner ear development; malformation; neural circuit; new therapeutic target; novel strategies; novel therapeutic intervention; otoconia; patch clamp; ribbon synapse; signal processing; vestibular pathway; vestibular reflex; vestibulo-ocular reflex; visual tracking

ABSTRACT In the US, an estimated 3.3 million children experience dizziness and balance problems (19). Children with congenital vestibular disorders (CVDs) show delayed motor development and challenges in maintaining posture and balance, indicating that the vestibular neural circuitry is affected. Computed tomography (CT) shows that children with CVDs most commonly form a sac-like inner ear with the semicircular canals missing or truncated. It is not known how their vestibular connectivity is altered. We hypothesize that formation of a sac-like inner ear during early gestation results in a reduced number of vestibular ganglion cells forming fewer primary vestibular synapses on hair cells peripherally and on vestibular nuclei neurons centrally, leading to underconnectivity in the vestibular system. We further hypothesize that the sac-like inner ear pathology results in abnormal convergence of canal and otolith fibers onto vestibular nuclei neurons, or anomalous connectivity, contributing to abnormal signal processing in these neurons. The proposed work will establish a framework to test the overarching hypothesis that formation of a congenitally-malformed, sac-like inner ear alters the peripheral and central vestibular neural circuitry. To address these questions, our laboratory has implemented and validated a new chick embryo model. We can produce a reproducible animal model in 85% of cases by surgically rotating the developing inner ear or “otocyst” 180° on one side in two-day old chick embryos (E2). Since the procedure involves Anterior-posterior axis Rotation of the Otocyst to produce a Sac-like inner ear, the model is called the ARO/s chick. The sac-like inner ear of ARO/s chicks resembles the sac-like inner ear in children with CVDs. After hatching (H), ARO/s chicks experience challenges in maintaining balance and walking. As a first step in understanding the consequences of the sac-like inner ear on the developing vestibular neural circuitry, in Specific Aim 1 we will further analyze the vestibular epithelium and quantify vestibular ganglion cells to determine to what extent primary vestibular afferent synapses are decreased in ARO/s chicks. In Specific Aim 2, we will combine imaging and electrophysiological approaches to determine whether a structurally-uniform class of vestibular nuclei neurons, the principal cells of the tangential nucleus (TN), acquire the orderly inputs from canal and otolith fibers, passive and active membrane properties, and synaptic transmission found in normal chicks. In Specific Aim 3, we will perform ethological tests to characterize posture and balance in H5 ARO/s chicks, followed by the horizontal vestibuloocular reflex (hVOR) using Earth vertical axis rotation (EVAR) to test canal function and the static tilting platform test to evaluate otolith function. The experimental outcomes will provide a foundation to better understand the pathological changes occurring in the vestibular neural circuitry of CVD patients, and modify our thinking on how to treat these disorders.

抽象的 在美国，估计有330万儿童遇到头晕和平衡问题（19）。有孩子 先天性前庭疾病（CVD）表明运动发展延迟，并在保持位置方面挑战 平衡，表明前庭神经回路受到影响。计算机断层扫描（CT）表明 CVD的儿童最常见的是囊状内耳，半圆形管丢失或截断。 尚不清楚其前庭连通性如何改变。我们假设形成了类似囊的内耳 在早期妊娠期间，导致前庭神经节细胞数量减少，形成较少的原发性前庭 毛细胞在外围和前庭核神经元上的突触中心，导致连接不足 前庭系统。我们进一步假设，类似囊的内耳病理学会导致异常收敛 在前庭核神经元或异常连通性上的运河和耳石纤维的纤维 这些神经元中的信号处理。拟议的工作将建立一个测试总体的框架 假说形成先天性的，类似囊的内耳会改变外围和 中央前庭神经回路。为了解决这些问题，我们的实验室已经实施和验证 一种新的小鸡胚胎模型。我们可以通过外科手术旋转85％的病例中生产可再现的动物模型 在两天老的小鸡胚胎（E2）中，一侧的内耳或“耳细胞” 180°（E2）。由于该过程 涉及耳囊的前轴旋转以产生类似囊的内耳，该模型称为 aro/s小鸡。 aro/s小鸡的囊状内耳类似于CVD儿童的囊状内耳。 孵化（H）后，Aro/S小鸡在保持平衡和步行方面面临挑战。作为第一步 了解类似囊的内耳在发育中的前庭神经回路上的后果， 具体目的1我们将进一步分析前庭上皮并将前庭神经节细胞定量 确定ARO/S雏鸡的主要前庭传入突触在多大程度上减少。在特定目标中 2，我们将结合成像和电生理方法，以确定结构均匀 切向核（TN）的主要细胞（TN）的前庭核神经元类别获取有序的输入 从运河和耳石纤维，被动和活性膜特性以及​​正常的突触传播 小鸡。在特定目标3中，我们将进行伦理测试以表征H5 ARO/S中的姿势和平衡 小鸡，然后使用地球垂直轴旋转（EVAR）进行水平前庭反射（HVOR）进行测试 运河功能和静态倾斜平台测试，以评估耳石功能。实验结果将 提供一个基础，以更好地了解在前庭神经回路中发生的病理变化 CVD患者，并修改我们对如何治疗这些疾病的思考。