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成电化学信号，并通过突触传输至传入神经纤维。这些信号驱动控制凝视、姿势和平衡的反射，也有助于感知方向和自我运动。前庭内耳功能丧失可能是导致许多头晕和定向障碍病例的原因，需要临床关注，并且 根据内耳前庭和耳蜗部分的工作情况，毛细胞和传入神经之间的突触可能是最脆弱的部位。因此，突触是临床上重要的课题。此外，由于其显着的形态和分子特征，它们提供了独特的神经生物学机会。在哺乳动物的前庭器官中，初级传入神经形成与 II 型毛细胞中的突触前带相对的小布顿末端，以及吞噬一个或多个 I 型毛细胞的大肾盏末端。这些独特的突触后肾盏可以接收从排列在数十个突触带周围的突触小泡释放的递质。最近的研究表明，上皮中央（纹状体）区域的肾盏具有特别密集的电压门控钠 (Na) 和钾 (K) 通道。上皮区的纽扣和肾盏的变化可能会导致纹状体和纹状体外（外周区）传入群体之间自发和诱发的放电差异。我们将研究啮齿动物耳石器官切除的半完整感觉上皮中从毛细胞到传入神经的传递。在目标 1 中，我们将记录突触前和突触后对发束（单个或整体）偏转的反应，以表征突触如何影响机械感觉信号的时序、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，并且肾盏突触除了传输量子信号外还可以传输非量子信号。我们假设纹状体突触具有多种机制来改善突触的时间性能，并且纹状体突触在空间和时间上整合以增强低刺激频率下的敏感性。在目标 2 中，我们将研究低电压激活 (LV) Na 和 K 通道对肾盏和纽扣的影响。我们假设未成熟的末端传输由毛细胞电共振和尖峰驱动的突发活动，这些活动被消除 来自 KLV 通道成熟的纹状体突触。我们知道，在分化过程中向纹状体 I 型毛细胞添加 KLV 通道可以极大地拓宽带宽并减少受体电位的相位滞后，并假设向纹状体末端添加 KLV 通道同样会影响突触后电位。我们将测试：KLV 通道是否增强非量子信号，NaLV 通道是否增加纹状花萼的兴奋性。这种成熟的变化可能会产生相位超前，抵消反射通路的相位滞后，从而允许前庭反射对头部运动进行补偿，甚至高于 20 Hz。 公共健康相关性：头部运动刺激前庭感觉细胞产生驱动稳定反射的电信号。拟议的研究将调查信号如何通过感觉细胞和神经元之间的专门突触接触传递。突触损伤可能会导致头晕和定向障碍的高发，需要临床关注。我们的实验应该能够深入了解这种脆弱性，并帮助确定药物和假肢疗法，以恢复患者的平衡和活动能力。