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（由申请人提供）：在前庭系统中，与听觉和视觉系统一样，刺激被转导，神经信号在传递到大脑之前被处理。我们和其他人的研究已经清楚地表明，来自半圆形管道的传入反应偏离了管道生物力学，并且暗示了毛细胞初级传入突触在形成传入反应中的信号处理。我们的主要假设是，毛细胞和传入终端乔木上的递质和受体表型集合的空间分布形成了将毛细胞受体电位转化为神经放电中所见的频率编码的处理实体。本研究的目的是测量和量化这些实体对前庭半规管传入的适应性和频率依赖性反应的贡献。我们已经证明有三种毛细胞递质表型：氨基丁酸能，谷氨酸能和表达这两种递质的细胞。我们提出毛细胞和传入终端在前馈和反馈配置下的特定组合决定了管道生物力学反应转化为单个初级传入纤维的神经编码。本研究主要关注四类可能参与信号处理的突触和/或突触外因子：(1)影响特定末端的毛细胞递质表型，包括毛细胞递质表型多样性和在特定末端相互作用的突触后受体分布的可能性；(2)花萼和毛细胞之间的潜在反馈，包括毛细胞释放的递质对毛细胞本身的反馈；(3)递质释放的速率和随后的突触电流动态；受特定突触中存在的突触前和突触后离子电流的支配，以及(4)传入树突的整合特性。了解传入终端信号处理的复杂性是开发前庭疾病治疗的必要步骤。基础科学为理解正常和异常功能提供了重要的信息。一旦对形成传入神经动力学的确切机制有了更彻底的了解，就可以开发出适当和特定的药理学药物来减少传入神经活动的异常爆发，从而减轻诸如M¿ni¿re综合征等疾病中眩晕症状的严重程度。内耳包含听力、平衡和平衡器官。我们研究了毛细胞（主要的机械传感器）和受支配的神经纤维之间的化学递质突触通讯。这些研究结果有望支持周围前庭疾病（如M¿ni¿re综合征和良性阵发性位置性眩晕）靶向治疗的发展。