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: 8291983
• 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/8291983
• 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.

描述(由申请人提供)：这是一项确定哺乳动物耳蜗二型传入神经的功能特性的提案。虽然只有很小一部分(5%-10%)的耳蜗神经传入，但它们独特的外毛细胞树枝状分支和听性脑干的终止模式强烈暗示着一种与I型传入截然不同的功能作用。有限的数据表明，II型传入具有非常高的声学阈值，可能只发出创伤或痛苦的声音。进一步扩展到躯体疼痛纤维的类比，II型传入由ATP激活，在耳蜗伤期间可以释放，就像在受损的皮肤中一样。该项目将涉及吉欧姆细胞内记录的II型传入耳蜗节在体外，以表征兴奋性和突触功能的II型传入。基本的膜特性，动作电位阈值和起始位置，以及突触输入的大小和分布将被确定。量化分析将决定外毛细胞突触的强度。与记录到的纤维相关的突触前和突触后结构将被免疫标记。这些数据将被合并到一个解剖学上正确的隔室模型中，以获得激活II型传入所需的声刺激的估计。为了进一步探索在耳蜗伤中的可能作用，将对因大声和/或暴露于耳毒素而受损的耳蜗进行II型录音。听力损失会导致听力亢进和耳鸣的幻觉。外周敏感症和幻肢痛的类比与躯体神经病有相似之处。对第二类传入神经功能作用的描述增加了有关耳蜗功能的基本信息，这将加强听觉发病机制的理论，并可能提供新的治疗靶点。