Synaptic mechanisms underlying vestibular nerve fiber activity

前庭神经纤维活动的突触机制

• 批准号: 8652148
• 负责人: ELISABETH GLOWATZKI
• 金额: $ 38.21万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-13 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652148
• 关键词: Acetylcholine; Action Potentials; Affect; Afferent Pathways; Antibodies; Benign paroxysmal positional vertigo; Brain; Cell membrane; Cholinergic Receptors; Complex; Coupled; Crista ampullaris; Data; Disease; Equilibrium; Excitatory Postsynaptic Potentials; Feedback; Fiber; Frequencies; Functional disorder; Generations; Glutamates; Hair; Hair Cells; Head; Image; Impairment; Label; Labyrinth; Lead; Life; Membrane; Membrane Potentials; Meniere' s Disease; Motion; Motor; Negative Reinforcements; Nerve Fibers; Organ; Pattern; Perception; Peripheral; Physiological; Play; Positive Reinforcements; Potassium Channel; Preparation; Property; Proteins; Rattus; Reflex action; Research Design; Rest; Rodent; Role; Rotation; Semicircular canal structure; Sensory; Sensory Hair; Shapes; Signal Transduction; Stimulus; Symptoms; Synapses; Synaptic Cleft; Synaptic Transmission; System; Type I Hair Cell; Type II Hair Cell; Vertigo; Vestibular Nerve; cell type; cholinergic; controlled release; gaze; in vivo; nerve supply; patch clamp; postsynaptic; public health relevance; receptor; receptor coupling; response; signal processing; transmission process

Project Summary The vestibular organs of the inner ear convey signals about head motions to the brain, resulting in motor reflexes that maintain gaze and balance as well as the perception of balance and orientation. Dysfunction of the vestibular system can therefore substantially affect the ability to lead our everyday lives. Peripheral vestibular dysfunctions, like benign paroxysmal positional vertigo (BPPV) and Meniere's disease, lead to disabling episodes of vertigo and other symptoms. To analyze the pathophysiology of such diseases, it is crucial to understand how head motion signals are processed in the vestibular peripheral organs. In the crista, the sensory organ of the semicircular canals, the sensory hair cells, respond to head rotations with a deflection of their hair bundles, activating hair cell receptor potentials. Type I hair cells are close to completely ensheathed by a postsynaptic calyx ending of the afferent vestibular nerve fiber, a unique feature of the vestibular periphery, and type II hair cells are contacted by fibers with the more conventional bouton endings. The innervation pattern of these hair cell types is quite complex, yet follows a specific morpho- physiological pattern, and results in afferent fibers with differences in their response properties, for example in their regularity of resting discharge, their response properties to external stimuli and efferent inputs. Here we investigate synaptic transmission at the highly specialized type I hair cell/calyx synapse with the aim to understand the mechanisms that underlie firing patterns of the calyx afferent fibers. We have developed a preparation of excised cristae from 2-4 week old rodents to perform electrophysiological recordings from type I hair cells and calyx afferents, for some questions simultaneously. Using confocal analysis, we also characterize the morphological features of calyx afferents and assess the localization of specific synaptic proteins using antibody labeling or live imaging with fluorescently coupled markers. In Aim 1, we characterize the relation of hair cell membrane potential and afferent firing rate. We have found that glutamate accumulation and spillover in the synaptic cleft induces slow membrane potential changes and subsequent modulation of the afferent firing rate. We investigate the contribution of release properties and glutamatergic synaptic transmission to shaping the postsynaptic response pattern. Aim 2 investigates whether a cholinergic feedback loop from the calyx to the type I hair cell exists that may modulate afferent transmission. Here we put forward a new concept, including a calyx to hair cell feedback loop that may explain some of the in vivo recorded response patterns of calyx afferent firing. In Summary, we investigate the cellular mechanisms underlying calyx afferent firing properties. These studies are designed to gain a better understanding of possible vestibular peripheral dysfunctions, a prerequisite for developing treatments for such impairments.

项目摘要 内耳的前庭器官传达有关大脑头部运动的信号，导致运动 保持凝视和平衡的反射以及对平衡和方向的感知。功能障碍 因此，前庭系统可以实质上影响过我们日常生活的能力。外围 前庭功能障碍，例如良性阵发性位置眩晕（BPPV）和Meniere病，导致 禁用眩晕和其他症状的发作。为了分析此类疾病的病理生理学，这是 了解如何在前庭外围器官中处理头部运动信号至关重要。 在Crista中，半圆形管的感觉器官，感觉毛细胞对头部有反应 旋转偏转的毛发束，激活毛细胞受体电位。 I型毛细胞是 接近传入前庭神经纤维的突触后花萼结束，完全靠近 前庭外围和II型毛细胞的特征通过更常规的纤维接触 胸部结尾。这些毛细胞类型的神经支配模式非常复杂，但遵循特定的形态 生理模式，并导致传入纤维的反应特性差异，例如 它们的静止放电的规律性，对外部刺激和传出输入的反应特性。 在这里，我们研究了高度专业的I型毛细单元/花萼突触的突触传播 旨在了解花萼传入纤维的发射模式的机制。我们有 开发了从2-4周大的啮齿动物中切除的Cristae的准备工作，以进行电生理 I型毛细胞和花萼传入的录音，同时进行一些问题。使用共聚焦 分析，我们还表征了花萼传入的形态特征，并评估了 使用抗体标记或带有荧光耦合标记的实时成像的特定突触蛋白。 在AIM 1中，我们表征了毛细胞膜电位和传入的发射速率的关系。我们有 发现突触裂口中的谷氨酸积聚和溢出会诱导慢膜电位 变化和随后调节传入率。我们调查释放的贡献 性质和谷氨酸能突触传播，以塑造突触后反应模式。 AIM 2调查了是否存在从花萼到I型毛细胞的胆碱能反馈回路 可能调节传入传输。在这里，我们提出了一个新概念，包括毛细胞的花萼 反馈循环可能解释了一些体内记录的花萼传入射击的响应模式。 总而言之，我们研究了花萼传入的发射特性的细胞机制。这些 研究旨在更好地了解可能的前庭外围功能障碍，A 为这种损害开发治疗方法的先决条件。