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）：这是一项建议，以确定哺乳动物耳蜗的耕种至今的II型传入的功能性能。尽管仅包含所有人工耳蜗的一小部分（5-10％），但它们对外毛细胞的独特化，而听觉脑干中的终止模式强烈暗示了与I型传入的功能作用完全不同。有限的数据表明，II型传入具有很高的声学阈值，也许仅表示声音的外伤或痛苦水平。进一步扩展了与躯体疼痛纤维的类比，II型传入被ATP激活，该传入可以在人工耳蜗创伤期间释放，因为它处于受损的皮肤中。该项目将涉及来自人工耳蜗段中II型传入的Giga-Ohm-seal细胞内记录，以表征II型传入的兴奋性和突触功能。将确定基本的膜特性，动作电位阈值和起始位点以及突触输入的大小和分布。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结构和后结构将是后体内的。这些数据将纳入解剖学上的隔室模型中，以获得激活II型传入所需的声刺激的估计。为了进一步探索在人工耳蜗创伤中的可能作用，将在耳蜗中进行II型记录，这些记录被大声的声音和/或暴露于耳毒素损坏。 听力损失可能导致超源和耳鸣的幻影感知。与周围敏化和“幻影肢体疼痛”的类比促使与体细胞病变相似。 II型传入的功能作用的描述增加了有关人工耳蜗功能的必需，长期失误的信息，该信息将增强听觉发病机理的理论，并可能提供新的治疗靶标。