Synaptic mechanisms underlying vestibular nerve fiber activity

前庭神经纤维活动的突触机制

• 批准号: 8791310
• 负责人: ELISABETH GLOWATZKI
• 金额: $ 37.83万
• 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/8791310
• 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; Health; 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; receptor; receptor coupling; response; signal processing; transmission process

DESCRIPTION (provided by applicant): 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.

描述（申请人提供）：内耳的前庭器官将头部运动的信号传递给大脑，产生运动反射，维持凝视和平衡，以及平衡和方向的感知。因此，前庭系统的功能障碍会严重影响我们日常生活的能力。外周前庭功能障碍，如良性阵发性位置性眩晕（BPPV）和梅尼埃病，可导致致残性眩晕发作和其他症状。为了分析这些疾病的病理生理，了解头部运动信号如何在前庭周围器官中处理是至关重要的。在嵴中，半圆管的感觉器官，感觉毛细胞，对头部旋转作出反应，其毛束偏转，激活毛细胞受体电位。I型毛细胞几乎完全被前庭传入神经纤维的突触后花萼末端包裹，这是前庭周围的一个独特特征，II型毛细胞被更传统的钮扣末梢的纤维接触。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，并导致传入纤维在其反应特性方面存在差异，例如静息放电的规律性，对外部刺激的反应特性