The Peripheral Vestibular System in Congenital Vestibular Disorders

先天性前庭疾病的周围前庭系统

基本信息

  • 批准号:
    10610409
  • 负责人:
  • 金额:
    $ 33.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
摘要 在美国,估计有330万儿童出现头晕和平衡问题(19)。患有以下疾病的儿童 先天性前庭疾病(CVD)表现为运动发育延迟和保持姿势的挑战 和平衡,表明前庭神经回路受到影响。计算机断层扫描(CT)显示 患有心血管疾病的儿童通常形成囊状内耳,半规管缺失或被截断。 目前尚不清楚它们的前庭连接是如何改变的。我们假设形成一个囊状的内耳 在妊娠早期导致前庭神经节细胞数量减少,形成较少的初级前庭 外周毛细胞和中央前庭核神经元上的突触,导致 前庭系统。我们进一步假设囊状内耳病理导致异常会聚。 神经管和耳石纤维连接到前庭核神经元,或连接异常,导致异常 这些神经元中的信号处理。拟议的工作将建立一个框架来测试总体 假设先天性畸形、囊状内耳的形成会改变外周和 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并验证了 一种新的鸡胚模型。我们可以通过手术旋转在85%的病例中制造出可复制的动物模型。 2日龄雏鸡胚胎(E_2)一侧发育的内耳或“耳囊”为180°。因为这个程序 涉及耳囊的前后轴旋转以产生囊状内耳,该模型被称为 ARO/S小鸡。ARO/S雏鸡的囊状内耳与心血管病儿童的囊状内耳相似。 孵化(H)后,ARO/S雏鸡在保持平衡和行走方面面临挑战。作为第一步, 了解囊状内耳对发育中的前庭神经回路的影响 具体目标1我们将进一步分析前庭上皮细胞并对前庭神经节细胞进行量化,以 确定ARO/S雏鸡初级前庭传入突触减少的程度。以特定的目标 2,我们将结合成像和电生理方法来确定结构均匀的 前庭核神经元是切线核(TN)的主要细胞,获得有序的输入 正常耳道和耳石纤维、被动和主动膜特性以及突触传递 小鸡。在具体目标3中,我们将进行行为学测试,以表征H5ARO/S的姿势和平衡 然后用水平前庭眼反射(HVOR)用地球垂直轴旋转(EVAR)进行测试 采用耳道功能和静态倾斜台试验评价耳石功能。实验结果将会是 为更好地了解前庭神经回路中发生的病理变化提供了基础 CVD患者,并改变我们对如何治疗这些疾病的想法。

项目成果

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Kenna D Peusner其他文献

Kenna D Peusner的其他文献

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{{ truncateString('Kenna D Peusner', 18)}}的其他基金

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
  • 财政年份:
    2021
  • 资助金额:
    $ 33.33万
  • 项目类别:
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:
    10183006
  • 财政年份:
    2021
  • 资助金额:
    $ 33.33万
  • 项目类别:
Synaptic Transmission During Neuronal Differentiation
神经元分化过程中的突触传递
  • 批准号:
    7735748
  • 财政年份:
    2009
  • 资助金额:
    $ 33.33万
  • 项目类别:
Synaptic Transmission During Neuronal Differentiation
神经元分化过程中的突触传递
  • 批准号:
    7924218
  • 财政年份:
    2009
  • 资助金额:
    $ 33.33万
  • 项目类别:
DEVELOPMENT OF VESTIBULAR NUCLEI NEURONS
前庭核神经元的发育
  • 批准号:
    6937094
  • 财政年份:
    2003
  • 资助金额:
    $ 33.33万
  • 项目类别:
DEVELOPMENT OF VESTIBULAR NUCLEI NEURONS
前庭核神经元的发育
  • 批准号:
    6679020
  • 财政年份:
    2003
  • 资助金额:
    $ 33.33万
  • 项目类别:
DEVELOPMENT OF VESTIBULAR NUCLEI NEURONS
前庭核神经元的发育
  • 批准号:
    6797433
  • 财政年份:
    2003
  • 资助金额:
    $ 33.33万
  • 项目类别:
SYNAPTIC TRANSMISSION DURING NEURONAL DIFFERENTIATION
神经元分化过程中的突触传递
  • 批准号:
    2126169
  • 财政年份:
    1991
  • 资助金额:
    $ 33.33万
  • 项目类别:
SYNAPTIC TRANSMISSION DURING NEURONAL DIFFERENTIATION
神经元分化过程中的突触传递
  • 批准号:
    2126168
  • 财政年份:
    1991
  • 资助金额:
    $ 33.33万
  • 项目类别:
SYNAPTIC TRANSMISSION DURING NEURONAL DIFFERENTIATION
神经元分化过程中的突触传递
  • 批准号:
    6342317
  • 财政年份:
    1991
  • 资助金额:
    $ 33.33万
  • 项目类别:

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