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 内耳的前庭器官向大脑传递有关头部运动的信号，从而产生运动 保持凝视和平衡以及对平衡和方向的感知的反射。失调症 因此，前庭系统可以很大程度上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，会导致 使眩晕和其他症状的发作失效。要分析这些疾病的病理生理学，它是 对于了解头部运动信号在前庭外周器官中是如何处理的至关重要。 在眉骨，半规管的感觉器官，即感觉性毛细胞，对头部作出反应。 随着发束的偏转而旋转，激活毛细胞感受器潜力。I型毛细胞是 几乎完全被突触后的前庭神经纤维的末端所包裹，这是一种独特的 前庭外周的特点，和II型毛细胞是由纤维接触的，比较常规 鲍顿的结局。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，并导致传入纤维的反应特性不同，例如 它们的静息放电规律、对外界刺激和传出输入的反应特性。 在这里，我们研究了高度专门化的I型毛细胞/肾盏突触的突触传递 目的是了解花萼传入纤维的放电模式背后的机制。我们有 研制了一种用于电生理的2-4周龄啮齿类动物切除的脊骨制备方法。 来自I型毛细胞和花萼传入的录音，同时回答一些问题。使用共焦 分析，我们还表征了花萼传入的形态特征，并评估了 使用抗体标记的特定突触蛋白或荧光偶联标记的实时成像。 在目标1中，我们描述了毛细胞膜电位与传入放电频率的关系。我们有 研究发现，谷氨酸在突触裂隙中的积累和溢出导致膜电位减慢 传入放电率的变化和随后的调制。我们调查了发布的贡献 特性和谷氨酸能突触传递以塑造突触后反应模式。 目的2研究从花萼到I型毛细胞的胆碱能反馈环是否存在 可以调制传入传输。在这里，我们提出了一个新的概念，包括毛细胞的花萼 反馈环路，可以解释体内记录的一些花萼传入放电的反应模式。 综上所述，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， 为此类损伤开发治疗方法的先决条件。