Excitability and synaptic function of type II cochlear afferents

II型耳蜗传入神经的兴奋性和突触功能

• 批准号: 8153000
• 负责人: Paul A Fuchs
• 金额: $ 38.12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8153000
• 关键词: ATP Receptors; Acoustic Trauma; Acoustics; Action Potentials; Afferent Neurons; Anatomy; Animals; Apical; Auditory; Behavior; Brain Stem; Calcium; Carrying Capacities; Cell Count; Cochlea; Curiosities; Data; Dyes; Equilibrium; Exposure to; Fiber; Functional disorder; Hair Cells; Hearing; Hyperacusis; Kanamycin; Knowledge; Lead; Length; Maps; Measures; Membrane; Methods; Modeling; Molecular; Motivation; Mus; Nature; Nervous system structure; Neurons; Neuropathy; Outer Hair Cells; Pain; Pathogenesis; Pathology; Pattern; Perception; Peripheral; Permeability; Phantom Limb Pain; Pharmacology; Probability; Process; Property; Purines; Rattus; Receptor Up-Regulation; Role; Signal Transduction; Site; Skin; Stimulus; Structure; Synapses; Synaptic Potentials; Testing; Tinnitus; Transgenic Model; Trauma; hearing impairment; mouse model; nerve supply; new therapeutic target; operation; ototoxin; painful neuropathy; postsynaptic; presynaptic; purine; receptor; response; ribbon synapse; seal; sound; synaptic function; theories

DESCRIPTION (provided by applicant): This is a proposal to determine the functional properties of till-now-mysterious type II afferents of the mammalian cochlea. Although comprising only a small fraction (5-10%) of all cochlear afferents, their unique arborization to outer hair cells, and termination pattern in the auditory brainstem strongly imply a functional role quite distinct from that of the type I afferents. Limited data suggest that type II afferents have a very high acoustic threshold, perhaps signaling only traumatic or painful levels of sound. Further extending an analogy to somatic pain fibers, type II afferents are activated by ATP that can be released during cochlear trauma, as it is in damaged skin. This project will involve giga-ohm-seal intracellular recording from type II afferents in cochlear segments ex vivo to characterize the excitability and synaptic function of type II afferents. Basic membrane properties, action potential threshold and initiation site, and the size and distribution of synaptic inputs will be determined. Quantal analysis will determine outer hair cell synaptic strength. Pre- and postsynaptic structures associated with recorded fibers will be immunolabeled posthoc. These data will be incorporated into an anatomically-correct, compartmental model to obtain an estimate of the acoustic stimulus required to activate the type II afferent. To explore further a possible role in cochlear trauma, type II recordings will be made in cochleae that have been damaged by loud sound and/or exposure to ototoxins. Hearing loss can lead to hyperacusis and the phantom percept of tinnitus. The analogy to peripheral sensitization and 'phantom limb pain' prompts parallels with somatic neuropathy. Delineation of the functional role of type II afferents adds essential, long-missing information on cochlear function that will enhance theories of auditory pathogenesis, and may provide new therapeutic targets. PUBLIC HEALTH RELEVANCE: Hearing loss and the associated pathologies of hyperacusis and tinnitus result from loss of cochlear hair cells, and altered activity in cochlear afferent neurons. This proposal will determine the responsiveness, signaling and pharmacology of type II cochlear afferents that have until recently been entirely mysterious. Auditory pathogenesis may result from an altered balance of activity between small type II, and large type I afferents, by analogy to neuropathic pain in the somatic nervous system, thus providing the type II afferent as a novel therapeutic target.

描述（由申请人提供）：这是一项确定哺乳动物耳蜗至今仍神秘的 II 型传入神经功能特性的提案。尽管仅占所有耳蜗传入神经的一小部分（5-10%），但其独特的外毛细胞树状结构以及听觉脑干的终止模式强烈暗示其功能作用与 I 型传入神经截然不同。有限的数据表明，II 型传入神经具有非常高的声学阈值，可能仅发出创伤性或痛苦性的声音信号。进一步将类比延伸到躯体疼痛纤维，II 型传入神经由 ATP 激活，ATP 可以在耳蜗创伤期间释放，就像在受损皮肤中一样。该项目将涉及离体耳蜗节段 II 型传入神经的千兆欧姆密封细胞内记录，以表征 II 型传入神经的兴奋性和突触功能。基本膜特性、动作电位阈值和起始位点以及突触输入的大小和分布将被确定。定量分析将确定外毛细胞突触强度。与记录的纤维相关的突触前和突触后结构将被事后免疫标记。这些数据将被纳入解剖学上正确的隔室模型中，以获得激活 II 型传入神经所需的声刺激的估计。为了进一步探索耳蜗创伤中可能的作用，将对因大声喧哗和/或暴露于耳毒素而受损的耳蜗进行 II 型录音。 听力损失会导致听觉过敏和耳鸣幻觉。周围敏化和“幻肢痛”的类比提示与躯体神经病相似。对 II 型传入神经功能作用的描述增加了有关耳蜗功能的重要且长期缺失的信息，这将增强听觉发病机制的理论，并可能提供新的治疗靶点。 公共卫生相关性：听力损失以及听觉过敏和耳鸣的相关病理是由于耳蜗毛细胞的丧失以及耳蜗传入神经元的活动改变造成的。 该提案将确定 II 型耳蜗传入神经的反应性、信号传导和药理学，而这些传入神经直到最近还是完全神秘的。听觉发病机制可能是由于小 II 型传入神经和大 I 型传入神经之间的活动平衡改变所致，类似于躯体神经系统中的神经性疼痛，从而将 II 型传入神经提供为新的治疗靶点。