Stimulus processing in mammalian vestibular organs

哺乳动物前庭器官的刺激处理

• 批准号: 7849860
• 负责人: Ruth Anne Eatock
• 金额: $ 17.06万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849860
• 关键词: Accounting; Action Potentials; Affect; Afferent Neurons; Binding Proteins; Brain; Buffers; Calcium; Calcium-Binding Proteins; Caliber; Cells; Classification; Complement; Complex; Computer Simulation; Coupling; Crista ampullaris; Data; Disorientation; Epithelium; Equilibrium; Fiber; Frequencies; Ganglia; Gated Ion Channel; Goals; Hair Cells; Head; Head Movements; In Vitro; Individual; Influentials; Injection of therapeutic agent; Ion Channel; Kinetics; Knowledge; Label; Labyrinth; Location; Measures; Mechanics; Mediating; Membrane Potentials; Methods; Modeling; Morphology; Motion; Mus; Myxoid cyst; Nerve; Nerve Fibers; Neurons; Noise; Organ; Otolithic Membrane; Pattern; Perception; Peripheral; Pharmacology; Phase; Physiological; Play; Population; Positioning Attribute; Posture; Potassium Channel; Preparation; Property; Prosthesis; Rattus; Reflex action; Reflex control; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Semicircular canal structure; Sensory; Shorthand; Signal Transduction; Simulate; Stimulus; Synapses; System; Testing; Training; Transgenic Model; Utricle structure; Utricular macula; Variant; Vestibular ganglion; afferent nerve; afterpotential; channel blockers; design; functional restoration; gaze; immunocytochemistry; improved; in vivo; macula; mutant; neuronal cell body; otoconia; patch clamp; research study; response; stimulus processing; tool; voltage; voltage clamp

DESCRIPTION (provided by applicant): Vestibular afferent nerve fibers convey head position and motion signals from the inner ear to the brain, where they drive reflexes controlling gaze, posture and balance and contribute to perceptions of orientation and self-motion. We propose to study how electrical signals are generated in primary vestibular afferents, focusing on the contributions of intrinsic ion channels and calcium binding proteins. We will examine the origins of specific patterns of activity (firing patterns of action potentials, also called spikes) in vestibular afferents. In recordings made in vivo, vestibular afferents vary greatly in the regularity of inter-spike intervals; this variation is highly systematic, co-varying with many morphological and physiological properties. Thus, highly regular afferents tend to carry tonic signals, to have small diameters and extended dendritic arbors, and to innervate peripheral zones of the sensory epithelia. In contrast, highly irregular afferents tend to have phasic signals, to have large diameters and compact dendritic arbors with large, calyceal afferent terminals, to innervate central zones and to express particular Ca2+ binding proteins (CBPs). High regularity may enhance the information content and temporal encoding for head movement frequencies below ~20 Hz; high irregularity may reflect high sensitivity to synaptic currents. Over two decades ago, investigators exploring possible factors in setting firing patterns suggested that intrinsic ion channels in the afferent fibers were likely to be important. We now know that ion channel complements in vestibular ganglion neurons (VGNs), as in many brain neurons, are much more complex than previously imagined, and we have better tools to study this issue. We propose to use the whole-cell patch clamp method on VGNs from rodents to characterize firing patterns and the underlying voltage- and calcium-gated ion channels. VGNs will be studied in vitro as isolated somata and also within a semi-intact preparation that includes sensory epithelia and the ganglion. The two preparations have different advantages: isolated VGNs provide superior voltage clamp, while VGNs in the semi-intact preparation receive synaptic input from hair cells. Preliminary data suggest that VGNs express specific complements of ion channels, giving rise to distinct endogenous firing patterns in response to injected currents. We will test the hypothesis that the endogenous ion channels help establish different patterns of spike regularity in vivo, and the involvement of specific ion channels in setting firing patterns. We will use RT-PCR to screen for candidate ion channels and immunocytochemistry to localize channels according to afferent type, zone within the sensory epithelium, and cellular location (soma vs. afferent terminal). We will investigate whether specific CBPs help set firing patterns by modulating calcium-dependent potassium channels. We will develop computational models to test our comprehensive understanding of how ion channels contribute to firing patterns. A set of five vestibular organs in the inner ear conveys information about head position and head motion to the brain, where it drives reflexes that stabilize gaze, posture and balance, and provide a sense of self-motion and orientation. The proposed research will investigate how vestibular afferent neurons use ion channels to generate patterns of electrical activity with which they encode head motion and position. Detailed knowledge of electrical signaling by vestibular afferents is essential to understand how inner ear damage, which is widespread in the population, causes poor balance and disorientation. Such knowledge will also help us design prosthetics to electrically stimulate the vestibular system in order to restore function.

描述（由申请人提供）：前庭传入神经纤维从内耳到大脑传达头部位置和运动信号，在那里它们驱动反射，以控制视线，姿势和平衡，并有助于对方向和自我运动的感知。我们建议研究如何在主要前庭传入中产生电信号，重点是固有离子通道和钙结合蛋白的贡献。我们将研究前庭传入中活动特定模式的起源（动作电位的射击模式，也称为尖峰）。在体内的录音中，前庭传入在尖峰间隔的规律性方面差异很大。这种变异是高度系统的，与许多形态学和生理特性共同变化。因此，高度规则的传入倾向于携带滋补信号，具有小直径和延伸的树突状乔木，并支配感觉上皮的外围区域。相比之下，高度不规则的传入倾向于具有质量信号，具有较大的直径和紧凑的树突状乔木，具有较大的钙化传入末端，以支配中心区域并表达特定的Ca2+结合蛋白（CBP）。高规律性可以增强信息含量和时间运动频率低于20 Hz的时间；高不规则性可能反映出对突触电流的高灵敏度。二十多年前，研究人员探索了设定发射模式的可能因素，表明传入纤维中的固有离子通道可能很重要。现在，我们知道，与许多脑神经元一样，前庭神经神经元（VGN）中的离子通道补充比以前想象的要复杂得多，并且我们有更好的工具来研究此问题。我们建议在啮齿动物的VGN上使用全细胞贴片夹方法来表征点火模式以及基础电压和钙门控离子通道。 VGN将在体外作为孤立的somata进行研究，并在包括感觉上皮和神经节在内的半独立制剂中进行研究。这两种制剂具有不同的优势：隔离的VGN提供了优质的电压夹，而半独立制剂中的VGN则获得了毛细胞的突触输入。初步数据表明，VGN表达离子通道的特定补充，从而产生了不同的内源性发射模式，以响应注入的电流。我们将检验以下假设：内源离子通道有助于在体内建立不同的峰值规则性模式，并参与特定离子通道在设定射击模式中的参与。我们将使用RT-PCR筛选候选离子通道和免疫细胞化学的筛选，根据传入类型，感觉上皮内的区域和蜂窝位置（SOMA与传入终端）来定位通道。我们将调查特定的CBP是否通过调节依赖钙的钾通道来帮助设置发射模式。我们将开发计算模型，以测试我们对离子渠道如何促进射击模式的全面理解。内耳中的一组五个前庭器官传达了有关头部位置和头部运动的信息，它驱动反射，稳定凝视，姿势和平衡，并提供一种自我动感和方向的感觉。拟议的研究将研究前庭传入神经元如何使用离子通道来生成用它们编码头部运动和位置的电活动模式。前庭传入对电信号传导的详细知识对于了解内耳损害如何在人群中普遍存在会导致不良平衡和迷失方向至关重要。这些知识还将帮助我们设计假肢以电刺激前庭系统以恢复功能。