The role of ion channels in shaping the function of inner ear neurons

离子通道在塑造内耳神经元功能中的作用

• 批准号: 10170312
• 负责人: RADHA KALLURI
• 金额: $ 35.06万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170312
• 关键词: Acoustic Nerve; Adult; Afferent Neurons; Auditory; Biophysical Process; Brain Stem; Calcium-Binding Proteins; Cause of Death; Cells; Classification Scheme; Code; Complement; Complex; Critical Pathways; Data; Dendrites; Development; Electrophysiology (science); Equilibrium; Fiber; Ganglia; Hair Cells; Head Movements; Hearing; Heterogeneity; Immunohistochemistry; Intervention; Ion Channel; Label; Labyrinth; Lead; Link; Maps; Measures; Membrane; Methodology; Methods; Modeling; Morphology; Neuronal Differentiation; Neurons; Pathway interactions; Pattern; Peripheral; Pharmacology; Preparation; Presynaptic Terminals; Property; Role; Sensory; Shapes; Stimulus; Subgroup; Synapses; System; Testing; Theoretical model; Vestibular Nerve; Vestibular ganglion; Vulnerable Populations; Work; base; biophysical properties; critical developmental period; critical period; equilibration disorder; experimental study; hearing impairment; in vivo; nerve supply; neuroepithelium; neuronal cell body; patch clamp; relating to nervous system; response; selective expression; sound; spiral ganglion

SUMMARY Vestibular and auditory afferent neurons are the primary conduits for information transfer from the sensory periphery to the brainstem. Many hearing and balance impairments are caused by death or damage to these neurons or their partner hair cells. In both vestibular and auditory afferents some functionally distinct neuronal sub-groups are more susceptible to damage than others. By understanding the mechanisms that shape the function of these sensory neurons, we hope to better understand why this is the case. We hypothesize that heterogeneity in the composition of neuronal ion channels is important for shaping their function. We base our hypothesis on the observation that the cell bodies of vestibular and auditory afferents are remarkably heterogeneous in their intrinsic firing patterns and ion channels. Previous studies could not reliably link ion channel properties to afferent function because the isolated cell bodies lacked the necessary morphological markers that would allow functional identification. To deal with this problem, we will perform patch-clamp recordings together with single cell labeling in semi-intact neuro-epithelium preparations in which neurons are still connected to their hair cells. We will link ion channel properties with neuronal function by exploiting established associations between function and patterns of afferent connectivity with hair cells. Combined with pharmacological manipulation of candidate ion channels and theoretical modeling, our experiments will test if and how specific groups of ion channels influence neuronal function. Alternatively, the approach will offer new candidate ion channels for consideration. These experiments will also contribute to our understanding of neuronal differentiation by mapping ion channel properties onto afferent connectivity during critical developmental periods when afferent innervation patterns are forming and stabilizing. By taking a developmental approach we will disentangle the significance of ion channel diversity as an indication of neuronal maturation versus its importance for adult function. Our focus on vestibular and auditory afferents within one study, using similar methodology, will reveal ion channel specializations that are unique to each system and specializations that are common across both systems. In defining how ion channels differ among functionally distinct neuronal groups, our work may identify the mechanisms that render some neurons more susceptible to damage, which could lead to pharmacological interventions for protecting vulnerable neuronal groups.

概括 前庭和听觉传入神经元是信息转移的主要管道 脑干的感觉外围。许多听力和平衡障碍是由 这些神经元或其伴侣毛细胞的死亡或损害。在前庭和听觉 传入某些功能上不同的神经元子组比损害更容易受到伤害 其他的。通过了解塑造这些感觉神经元功能的机制， 我们希望更好地理解为什么是这种情况。我们假设在 神经离子通道的组成对于塑造其功能很重要。我们以我们的为基础 关于观察的假设是，前庭和听觉传入的细胞体是 其内在的射击模式和离子通道非常异质。先前的研究 由于孤立的细胞体 缺乏将允许功能识别的必要形态标记。交易 有了这个问题，我们将执行补丁钳记录以及单个单元格在 半独立性神经上皮制剂，其中神经元仍连接到其毛细胞。 我们将通过利用已建立的关联将离子通道属性与神经元功能联系起来 在与毛细胞的传入连通性的功能和模式之间。与 候选离子通道和理论建模的药理学操纵，我们 实验将测试离子通道的特定组是否以及如何影响神经元功能。 另外，该方法将提供新的候选离子渠道以供考虑。这些 实验还将通过绘制离子来有助于我们对神经元分化的理解 在关键发展期间，渠道属性在传入的连接上 神经支配模式正在形成和稳定。通过采用发展方法，我们将 将离子通道多样性的重要性解散为神经元成熟的指示 与其对成人功能的重要性相比。我们专注于前庭和听觉传入 一项使用类似方法的研究将揭示离子通道的特殊化 每个系统中常见的每个系统和专业。定义离子如何 在功能不同的神经元组之间的渠道不同，我们的工作可能会识别 使一些神经元更容易受到损害的机制，可能导致 保护脆弱神经元组的药理干预措施。