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 内耳的前庭器官将头部运动的信号传递给大脑，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，前庭系统可以极大地影响我们日常生活的能力。外围 前庭功能障碍，如良性阵发性位置性眩晕（BPPV）和梅尼埃病，导致 眩晕和其他症状的致残性发作。要分析这类疾病的病理生理， 这对于理解头部运动信号如何在前庭外周器官中处理至关重要。 在脊部，半规管的感觉器官，感觉毛细胞，对头部的反应， 旋转与偏转的头发束，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梢包被，这是一种独特的 前庭外周的特征，和II型毛细胞接触的纤维与更传统的 饰扣结尾。这些毛细胞类型的神经支配模式是相当复杂的，但遵循特定的形态， 生理模式，并导致传入纤维的反应特性不同，例如， 静息放电的规律性，对外部刺激和传出输入的反应特性。 在这里，我们研究了高度特化的I型毛细胞/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 从2 - 4周龄的啮齿动物中开发了一种用于进行电生理检查的切除嵴的制备物， 录音从I型毛细胞和花萼传入，同时为一些问题。使用共聚焦 分析，我们还描述了花萼传入的形态特征，并评估了 使用抗体标记或用荧光偶联标记物的活体成像来检测特异性突触蛋白。 目的1：研究毛细胞膜电位与传入放电频率的关系。我们有 发现谷氨酸在突触间隙中的积累和溢出诱导慢膜电位 变化和随后的传入放电率的调制。我们调查了释放的贡献 性质和突触传递的突触后反应模式的塑造。 目的2研究从毛萼到I型毛细胞是否存在胆碱能反馈回路， 可以调节传入传递。在这里我们提出了一个新的概念，包括一个花萼到毛细胞 反馈回路，可以解释一些在体内记录的反应模式的花萼传入放电。 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外周功能障碍， 这是开发此类损伤治疗方法的先决条件。