Synaptic Determinants of Vestibular Afferent Dynamics

前庭传入动力学的突触决定因素

• 批准号: 7799211
• 负责人: Stephen Morris Highstein
• 金额: $ 45.38万
• 依托单位: MARINE BIOLOGICAL LABORATORY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-03 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7799211
• 关键词: Auditory; Basic Science; Bathing; Benign paroxysmal positional vertigo; Biomechanics; Brain; Calcium; Calcium Channel; Categories; Cells; Chemicals; Code; Communication; Complex; Dendrites; Detection; Development; Disease; Distal; Electrodes; Elements; Epithelium; Equilibrium; Feedback; Fiber; Frequencies; Glutamate Receptor; Glutamates; Goals; Hair; Hair Cells; Hearing; Immunofluorescence Immunologic; In Situ; Individual; Investigation; Ions; Kinetics; Labyrinth; Light; Location; Maps; Measures; Mechanics; Meniere' s Disease; Methods; Microelectrodes; Microscopic; Nerve; Nerve Fibers; Organ; Peripheral; Phenotype; Population; Potassium; Process; Property; Proteins; Research; Research Design; Semicircular canal structure; Sensory; Severities; Shapes; Signal Transduction; Site; Spatial Distribution; Stimulus; Symptoms; Synapses; Synaptic Receptors; Synaptic Transmission; Syndrome; System; Testing; Transducers; Trees; Type II Hair Cell; Variant; Visual system structure; cell type; computerized data processing; feeding; gamma-Aminobutyric Acid; lucifer yellow; public health relevance; receptor; relating to nervous system; response; sensor; transmission process; voltage; voltage clamp

DESCRIPTION (provided by applicant): In the vestibular system, as in the auditory and visual systems, stimuli are transduced and neural signals processed prior to transmission to the brain. Our research and that of others has clearly shown that the afferent responses from the semicircular canal deviate from canal biomechanics, and has implicated signal processing by the hair cell-primary afferent synapse in shaping the afferent response. Our overarching hypothesis is that the spatial distribution of an ensemble of transmitter and receptor phenotypes on hair cells and the afferent terminal arbors form processing entities that transform hair cell receptor potentials into the frequency code seen in the nerve discharge. The goal of the proposed research is to measure and quantify the contributions of these entities to the adaptation and frequency-dependent responses of vestibular semicircular canal afferents. We have demonstrated that there are three hair cell transmitter phenotypes: GABAergic, glutamatergic and cells that express both transmitters. We propose that specific combinations of hair cells and afferent terminals operating in feed-forward and feedback configurations dictate the transformation of canal biomechanical responses into the neural codes of individual primary afferent fibers. This proposal focuses on four categories of synaptic and/or extrasynaptic factors putatively involved in signal processing: (1) hair cell transmitter phenotype(s) impinging on a given ending, including the possibility of a diversity of hair cell transmitter phenotypes and post-synaptic receptor distributions interacting at a given terminal, (2) potential feedback between the calyx and hair cell, including feedback from hair cell-released transmitter to the hair cell itself, (3) the rate of transmitter release and subsequent synaptic current dynamics, governed by pre- and post-synaptic ionic currents present at a particular synapse, and (4) the integrative properties of the afferent dendrite. Understanding the complexity of the signal processing performed by afferent terminals is a necessary step toward developing treatments for vestibular disorders. Basic science adds information that is important in understanding normal and abnormal function. Once the precise mechanisms involved in shaping afferent dynamics are more thoroughly understood, appropriate and specific pharmacological agents may be developed to reduce abnormal bursts of afferent neural activity, thereby mitigating the severity of vertiginous symptoms in disorders such as M¿ni¿re's syndrome. PUBLIC HEALTH RELEVANCE The inner ear contains the organs of hearing, balance and equilibrium. We study synaptic communication by chemical transmitter between hair cells (the primary mechanical sensors) and their innervated nerve fibers. Results from these investigations are expected to support the development of targeted therapies for peripheral vestibular disorders such as M¿ni¿re's syndrome and benign paroxysmal positional vertigo.

描述（由适用提供）：在前庭系统中，例如在听觉和视觉系统中，刺激被翻译和神经信号在传播到大脑之前。我们的研究和其他研究清楚地表明，半圆形管的传入响应偏离了运河生物力学，并通过毛细胞细胞 - 主要传入突触实施了信号处理，以塑造传入响应。我们的总体假设是，毛细胞上的发射机和受体表型集合的空间分布以及传入的末端arbor形成的加工实体，将毛细胞受体电位转化为神经排放中看到的频率密码。拟议研究的目的是测量和量化这些实体对前庭半圆形管传统的适应和频率依赖性响应的贡献。我们已经证明，有三种毛细胞发射机表型：表达这两种发射机的GABA能，谷氨酸能和细胞。我们提出，在进料前和反馈配置中运行的毛细胞和传入终端的特定组合决定了运河生物力学响应转换为单个主要传入纤维的神经代码的转化。该提议集中于信号处理中涉及的四类合成和/或外部因素：（1）毛状细胞发射器表型撞击给定的结尾，包括毛发细胞发射机表型的多样性的可能性，包括在给定末端的毛细单元之间交互的毛发细胞发射机表型和（2）毛孔的传递（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）毛细胞本身，（3）由特定突触处存在前后突触后离子电流的发射机释放速率和随后的合成电流动力学的速率，以及（4）理解相关终端执行信号处理复杂性的集成特性是开发前庭分端疾病的必要步骤。基础科学添加了对于理解正常和异常功能很重要的信息。一旦更彻底地了解了塑造传入动力学的精确机制，就可以开发出适当和特定的药物，以减少传入神经元活性的异常爆发，从而减轻诸如m¿ni re anddrome的疾病中垂直符号的严重性。公共卫生相关性内耳包含听力，平衡和同等学历的器官。我们研究毛细胞（主要的机械传感器）及其神经神经纤维之间的化学发射机的突触通信。这些投资的结果预计将支持开发针对周围前庭疾病的靶向疗法，例如M ni ni re综合征和良性阵发性阵发性位置眩晕。