Synaptic Processing in the Vestibular System

前庭系统中的突触处理

• 批准号: 8273812
• 负责人: Ruth Anne Eatock
• 金额: $ 36.71万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-16 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8273812
• 关键词: Address; Affect; Age; Attention; Attenuated; Cells; Cleaved cell; Clinical; Complex; Data; Dependence; Development; Disorientation; Distal; Dizziness; Employee Strikes; Epithelial; Epithelium; Equilibrium; Face; Fiber; Financial compensation; Frequencies; Goals; Hair; Hair Cells; Head; Incidence; Individual; Ion Channel; Labyrinth; Location; Membrane; Methods; Molecular; Motion; Nerve Fibers; Neurobiology; Neurons; Noise; Organ; Pathway interactions; Patients; Perception; Performance; Periodicity; Peripheral; Pharmacologic Substance; Phase; Physiological; Population; Positioning Attribute; Posture; Potassium; Potassium Channel; Preparation; Process; Property; Prosthesis; Rana; Reaction Time; Reflex action; Reflex control; Research; Resistance; Rodent; Saccule structure; Sensory; Sensory Process; Signal Transduction; Site; Sodium; Speed; Stimulus; Stream; Swelling; Synapses; Synaptic Cleft; Synaptic Transmission; Synaptic Vesicles; System; Testing; Time; Type I Hair Cell; Type II Hair Cell; Ursidae Family; Variant; Vestibular Hair Cells; Work; afferent nerve; base; cost; gaze; improved; insight; loss of function; macula; novel strategies; otoconia; patch clamp; postsynaptic; prevent; receptor; research study; response; ribbon synapse; synaptic function; transmission process; vestibular reflex; voltage; voltage gated channel

DESCRIPTION (provided by applicant): Vestibular hair cells transduce head position and motion into electrochemical signals which they transmit across synapses to afferent nerve fibers. The signals drive reflexes that control gaze, posture and balance and also contribute to perception of orientation and self-motion. Loss of function in the vestibular inner ear is likely responsible for many cases of dizziness and disorientation that require clinical attention, and the synapses between hair cells and afferents may be the most vulnerable site, based on work in both vestibular and cochlear parts of the inner ear. Thus, the synapses are a clinically important subject. In addition, they present a unique neurobiological opportunity because of their striking morphological and molecular features. In mammalian vestibular organs, primary afferents form small bouton terminals opposite pre-synaptic ribbons in type II hair cells plus large calyceal terminals that engulf one or more type I hair cells. These uniquely postsynaptic calyces may receive transmitter released from synaptic vesicles arrayed around dozens of synaptic ribbons. Recent work has shown that calyces in the central (striolar) zone of the epithelium bear especially dense concentrations of voltage-gated sodium (Na) and potassium (K) channels. Variations in boutons and calyces with epithelial zone are likely to contribute to spontaneous and evoked firing differences between striolar and extrastriolar (peripheral-zone) afferent populations. We will study transmission from hair cells to afferents in excised, semi-intact sensory epithelia of rodent otolith organs. In Aim 1, we will record pre- and post-synaptic responses to deflection of hair bundles (single or as ensembles) to characterize how the synapse affects timing, tuning and level dependence of the mechanosensory signal. Preliminary results show that vesicular (quantal) transmission has a significant delay and that calyceal synapses can transmit non-quantal signals in addition to quantal signals. We hypothesize that striolar synapses have multiple mechanisms to improve the temporal performance of the synapse and that extrastriolar synapses integrate spatially and temporally to enhance sensitivity at low stimulus frequencies. In Aim 2, we will investigate the impact of low-voltage-activated (LV) Na and K channels in calyces and boutons. We hypothesize that immature terminals transmit bursty activity driven by hair cell electrical resonances and spikes, which are eliminated from maturing striolar synapses by KLV channels. We know that adding KLV channels to striolar type I hair cells during differentiation greatly broadens the bandwidth and reduces phase lag of the receptor potential and hypothesize that adding KLV channels to striolar terminals similarly affects postsynaptic potentials. We will test whether: KLV channels enhance non-quantal signals and NaLV channels increase the excitability of striolar calyces. Such maturational changes may create phase leads that offset the phase lags of the reflex pathway, allowing compensation by vestibular reflexes for head motions even above 20 Hz. PUBLIC HEALTH RELEVANCE: Head motions stimulate vestibular sensory cells to make electrical signals that drive stabilizing reflexes. The proposed research will investigate how signals are transmitted across specialized synaptic contacts between the sensory cells and neurons. Damage to the synapses is likely to contribute to the high incidence of dizziness and disorientation requiring clinical attention. Our experiments should provide insight into this vulnerability and help identify pharmaceutical and prosthetic therapies to restore balance and mobility to patients.

描述（由申请人提供）：前庭毛细胞将头部位置和运动转换为电化学信号，它们在突触中传播到传入的神经纤维。信号驱动反射，以控制凝视，姿势和平衡，并有助于对方向和自我运动的感知。前庭内耳的功能丧失可能导致许多需要临床关注的头晕和迷失方向的情况，并且 毛细胞和传入之间的突触可能是最脆弱的部位，基于内耳的前庭和耳蜗部分的工作。因此，突触是临床上重要的主题。此外，由于它们具有惊人的形态和分子特征，它们也带来了独特的神经生物学机会。在哺乳动物的前庭器官中，初级传入形成了II型毛细胞中突触前丝带的小胸部末端，以及吞噬一个或多个I型毛细胞的大型钙化末端。这些独特的突触后钙可能接收从数十个突触丝带的突触囊泡中释放出的发射器。最近的工作表明，上皮熊的中央（Striolar）区域特别密集的电压门控钠（NA）和钾（K）通道。带有上皮区域的胸子和钙的变化可能会导致自发和引起诱发的发射差异，而骨膜外（周围区）传入群体之间的差异。我们将研究从啮齿动物耳道器官切除的半直觉感觉上皮中的传播到传入的传播。在AIM 1中，我们将记录对头发束（单个或作为合奏）偏转的突触前和突触后反应，以表征突触如何影响机械感觉信号的时间，调谐和水平依赖性。初步结果表明，囊泡（量子）传输具有显着的延迟，并且钙化突触还可以传递非量化信号，此外还可以传输非量化信号。我们假设Striolar突触具有改善突触的时间性能的多种机制，并且外层突触会在空间和时间上积分以增强低刺激频率下的灵敏度。在AIM 2中，我们将调查在钙和胸子中低压激活（LV）Na和K通道的影响。我们假设未成熟的末端传递了由毛细胞电共振和尖峰驱动的爆发活动，这些活动被消除了 来自KLV通道成熟的Striolar突触。我们知道，在分化过程中向Striolar I型毛细胞中添加KLV通道会极大地拓宽带宽并减少受体电位的相位滞后，并假设将KLV通道添加到Striolar末端会类似地影响突触后电位。我们将测试：KLV通道是否增强非量化信号，而NALV通道会增加Striolar Calyces的兴奋性。这种成熟的变化可能会产生相位导线，以抵消反射途径的相位滞后，从而可以通过前庭反射补偿头部运动，甚至超过20 Hz。 公共卫生相关性：头部运动刺激前庭感觉细胞，以使电信号驱动稳定反射。拟议的研究将研究如何在感觉细胞和神经元之间的专门突触接触之间传输信号。突触的损害可能导致您的头晕和迷失方向的高发生率，需要临床关注。我们的实验应洞悉这种脆弱性，并有助于识别药物和假肢疗法，以恢复对患者的平衡和流动性。