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.

项目概要 内耳的前庭器官将有关头部运动的信号传递给大脑，从而产生运动信号 保持凝视和平衡的反射，以及平衡和方向的感知。功能障碍 因此，前庭系统可以极大地影响我们日常生活的能力。周边 前庭功能障碍，如良性阵发性位置性眩晕 (BPPV) 和梅尼埃病，会导致 眩晕和其他症状的发作。为了分析此类疾病的病理生理学， 对于理解前庭周围器官如何处理头部运动信号至关重要。 在嵴中，半规管的感觉器官，感觉毛细胞，对头部做出反应 旋转并偏转毛束，激活毛细胞受体电位。 I 型毛细胞是 接近完全被传入前庭神经纤维的突触后萼末端包裹，这是一种独特的 前庭周边的特征，II 型毛细胞通过纤维与更传统的毛细胞接触 布顿结局。这些毛细胞类型的神经支配模式相当复杂，但遵循特定的形态 生理模式，并导致传入纤维的响应特性存在差异，例如 它们的静息放电规律、它们对外部刺激和传出输入的反应特性。 在这里，我们研究高度专业化的 I 型毛细胞/花萼突触的突触传递 目的是了解花萼传入纤维放电模式的机制。我们有 开发了一种从 2-4 周龄啮齿动物身上切除的嵴制备物，用于进行电生理学检查 来自 I 型毛细胞和花萼传入神经的录音，同时回答一些问题。使用共焦 分析中，我们还描述了花萼传入神经的形态特征并评估了 使用抗体标记或荧光耦合标记的实时成像来检测特定的突触蛋白。 在目标 1 中，我们描述了毛细胞膜电位与传入放电速率的关系。我们有 发现突触间隙中谷氨酸的积累和溢出会导致膜电位减慢 传入放电频率的变化和随后的调制。我们调查发布的贡献 特性和谷氨酸突触传递来塑造突触后反应模式。 目标 2 研究是否存在从花萼到 I 型毛细胞的胆碱能反馈回路 可以调节传入传输。这里我们提出了一个新的概念，包括花萼到毛细胞 反馈回路可以解释一些体内记录的花萼传入放电的反应模式。 总之，我们研究了花萼传入放电特性的细胞机制。这些 研究旨在更好地了解可能的前庭周围功能障碍， 开发治疗此类损伤的先决条件。