Synaptic Determinants of Vestibular Afferent Dynamics

描述（由申请人提供）：在前庭系统中，如在听觉和视觉系统中，刺激被转换，神经信号在传输到大脑之前被处理。我们的研究和其他人的研究已经清楚地表明，从半规管的传入反应偏离运河生物力学，并暗示毛细胞初级传入突触在塑造传入反应的信号处理。我们的总体假设是，空间分布的一个合奏的发射器和受体表型的毛细胞和传入终端乔木形成处理实体，将毛细胞受体电位转换成频率代码中看到的神经放电。拟议的研究的目标是测量和量化这些实体的前庭半规管传入的适应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：GABA能，谷氨酸能和细胞表达这两种递质。我们建议，特定的组合的毛细胞和传入神经末梢在前馈和反馈配置的操作规定的转换到个别初级传入纤维的神经代码的运河生物力学响应。该建议集中于四类突触和/或突触外因子，它们参与信号处理：（1）影响给定末端的毛细胞递质表型，包括多种毛细胞递质表型和突触后受体分布在给定末端相互作用的可能性，（2）花萼和毛细胞之间的潜在反馈，包括从毛细胞释放的递质到毛细胞本身的反馈，（3）递质释放的速率和随后的突触电流动力学，由特定突触处存在的突触前和突触后离子电流控制，和（4）传入树突的整合特性。了解由传入末梢执行的信号处理的复杂性是开发前庭疾病治疗的必要步骤。基础科学增加了理解正常和异常功能的重要信息。一旦更彻底地理解了传入动力学形成的确切机制，就可以开发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。内耳包含听觉、平衡和平衡器官。我们研究了毛细胞（主要的机械传感器）和其受支配的神经纤维之间的化学递质的突触通讯。这些研究的结果有望支持外周前庭疾病（如M <$ni <$re综合征和良性阵发性位置性眩晕）的靶向治疗的发展。

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.