Short-term plasticity & temporal precision at the inner hair cell ribbon synapse

短期可塑性

• 批准号: 8720093
• 负责人: ELISABETH GLOWATZKI
• 金额: $ 4.71万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8720093
• 关键词: Acoustic Nerve; Acoustics; Action Potentials; Affect; Affinity; Argentina; Auditory; Auditory system; Behavior; Brain; Buffers; Cells; Characteristics; Chemical Synapse; Cochlear Implants; Code; Collaborations; Companions; Complex; Cytosol; Data; Ear; Environment; Exhibits; Fluorescent Dyes; Frequencies; Goals; Grant; Hearing; Image; Individual; Inner Hair Cells; Kinetics; Measures; Mental Depression; Molecular; Monitor; Nerve Fibers; Neurons; Outcome Study; Pattern; Phase; Physiologic pulse; Preparation; Process; Rattus; Recovery; Relative (related person); Relaxation; Research; Residual state; Role; Sensory; Signal Transduction; Source; Speech Intelligibility; Stimulus; Synapses; Testing; Time; Training; Vertebrates; Vesicle; Work; analog; auditory pathway; base; design; digital; hearing impairment; improved; neurotransmitter release; patch clamp; postsynaptic; presynaptic; relating to nervous system; research study; response; ribbon synapse; sound; speech processing; synaptic depression; voltage

DESCRIPTION (provided by applicant): At the inner hair cell (IHC) ribbon synapse, the first synapse in the auditory pathway, 'analog' sound information is converted into a 'digital' pattern of action potentials at auditory nerve fibers and transmitted to the brain. The relative time of each spike within a train of action potentials carries important information that needs to be faithfully represented in the auditory pathway. A well characterized form of temporal coding is phase locking: auditory neurons are capable of firing at a particular time within each cycle of a low-frequency stimulus. This phenomenon is required for localizing a sound source by computing the small difference in time at which the wave arrives at the two ears. Interaural delays can be as small as 10 microseconds, emphasizing the precision of temporal coding by the auditory periphery. The goal of this proposal is to investigate the mechanisms that allow the IHC ribbon synapse to release neurotransmitter with high precision and over long periods of time. In acutely excised rat cochlear preparations, simultaneous patch-clamp recordings will be performed from IHCs and postsynaptic terminals of auditory nerve fibers. Recently, we have shown that short-term facilitation occurs at this synapse, producing not only an increase in release but also a reduction in latency. Our first aim is to investigate the mechanisms underlying this phenomenon. We will study the role of the residual intracellular Ca2+ concentration by controlling its spread with specific buffers, and by monitoring its decay time course with fluorescent dyes. Facilitation will also be studied by uncaging Ca2+ in the cytosolic space. Secondly, the underlying mechanisms of phase-locked synaptic responses will be investigated. Preliminary experiments show that synaptic responses at the IHC ribbon synapse phase-lock to periodic stimuli. This feature will be further explored by applying stimuli with variable amplitude and by testing whether the preferred phase is conserved. These experiments will be compared with responses to single step depolarizations. We will evaluate the role of short-term facilitation and depression in establishing phase-locking. Finally, the ability of the IHC ribbon synapse to signal continuously with high precision will be studied. It has been shown that in response to steady IHC depolarization, this synapse exhibits short-term depression. The time course of recovery of synaptic responsiveness following a depleting stimulus will be evaluated. Given that neural synchrony is required for complex tasks such as speech intelligibility, the outcome of this study will hopefully provide the basis for potential improvements in cochlear implant design and a better understanding of hearing deficits that originate at the IHC afferent synapse. This research will be done primarily in Argentina, at the Instituto de Investigaciones en Ingenier¿a Gen¿tica y Biolog¿a Molecular (INGEBI) in collaboration with Dr. Juan Goutman, with the companion grant being R01 DC006476, 01-01-2004 to 11-29-2013.

描述（由申请人提供）：在内毛细胞（IHC）带状突触（听觉通路中的第一个突触）处，“模拟”声音信息被转换为听觉神经纤维处动作电位的“数字”模式，并传输到一系列动作电位中每个尖峰的相对时间携带着需要在听觉通路中忠实表示的重要信息，一种明确的时间编码形式是锁相：听觉神经元能够放电。低频刺激的每个周期内的特定时间需要通过计算波到达两耳的时间的微小差异来定位声源，强调这一点。该提案的目的是研究 IHC 带状突触在急性切除的大鼠中高精度地释放神经递质的机制。最近，我们已经证明，在该突触处会发生短期促进作用，不仅会增加释放，还会减少潜伏期。我们的首要目标是研究这种现象背后的机制，我们将通过使用特定缓冲液控制其扩散并通过荧光染料促进其衰减时间过程来研究残留细胞内 Ca2+ 浓度的作用。还将通过在细胞质空间中释放Ca2+来研究锁相突触反应的潜在机制，初步实验表明IHC带状突触的突触反应对周期性刺激具有锁相作用。通过施加可变幅度的刺激并测试首选相位是否保守来探索这些实验将与单步去极化的反应进行比较我们将评估短期促进的作用。 最后，将研究 IHC 带状突触以高精度连续发出信号的能力，结果表明，在响应稳定的 IHC 去极化时，该突触表现出短期的抑制。鉴于语音清晰度等复杂任务需要神经同步，这项研究的结果有望为人工耳蜗的潜在改进提供基础。设计并更好地了解源自 IHC 传入突触的听力缺陷这项研究将主要在阿根廷的 Instituto de Investigaciones en Ingenier¿一代?? tica y Biolog¿ a Molecular (INGEBI) 与 Juan Goutman 博士合作，配套资助为 R01 DC006476，2004 年 1 月 1 日至 2013 年 11 月 29 日。