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

短期可塑性

• 批准号: 8411050
• 负责人: ELISABETH GLOWATZKI
• 金额: $ 6.26万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8411050
• 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. PUBLIC HEALTH RELEVANCE: The inner hair cell ribbon synapse is the first synapse in the auditory pathway and is responsible for transmitting information about the acoustic environment to the brain. This study focuses on identifying cellular mechanisms that allow this synapse to perform this task continuously and with highest temporal precision. Facilitation of the synaptic signal and the involvement of calciumdynamics in this process are being studied in depth.

描述（由适用提供）：在内部毛细胞（IHC）色带突触，听觉途径中的第一个突触，“模拟”声音信息将转换为听觉神经纤维处的“数字”动作电位模式，并传播到大脑。动作电位中每个尖峰的相对时间都带有重要的信息，需要在听觉途径中忠实地代表。临时编码的特征形式是相位锁定：听觉神经元能够在低频刺激的每个周期内在特定时间发射。通过计算波浪到达两个耳朵的时间差异的小差异，需要这种现象来定位声源。耳间延迟可能很小至10微秒，这强调了听觉外围的临时编码精度。该提案的目的是研究允许IHC色带突触的机制，以高精度和长时间释放神经递质。在急性优质的大鼠耳蜗制剂中，将从IHC和听觉神经纤维的突触后终端进行简单的贴片钳记录。最近，我们已经表明，短期设施发生在该突触处，不仅会增加释放的增加，而且还会减少潜伏期。我们的第一个目的是研究这种现象的基础机制。我们将通过使用特定的缓冲液控制其扩散，并通过荧光染料监测其衰减时间过程，从而研究残留细胞内Ca2+浓度的作用。还将通过在胞质空间中脱离Ca2+来研究促进。其次，将研究相锁的合成反应的潜在机制。初步实验表明，IHC色带突触锁定对周期性刺激的合成反应。通过使用可变放大器应用刺激以及测试首选相位是否保存，将进一步探索此功能。这些实验将与对单步沉积的响应进行比较。我们将评估短期设施的作用 和建立相锁的抑郁症。最后，IHC色带突触以高精度连续信号的能力将进行研究。已经表明，为了响应稳定的IHC沉积，该突触表现出短期抑郁症。将评估突触刺激后突触反应能力的恢复时间过程。鉴于复杂的任务（例如语音清晰度）需要神经同步，因此这项研究的结果将有望为人工耳蜗设计的潜在改进提供基础，并更好地理解起源于IHC传入突触的听力缺陷。这项研究将主要在阿根廷进行，在Instituto de Investiones en Ingenier€gen` tica tica y tica y tica y tica y tica y分子（Ingebi）与Juan Goutman博士合作，同伴授予的R01 DC006476，01-01-01-2004至11-29-29-29-2013。 公共卫生相关性：内毛细胞色带突触是听觉途径中的第一个突触，负责将有关声学环境的信息传输到大脑。这项研究着重于识别允许该突触连续执行此任务的细胞机制，并具有最高的临时精度。合成信号的促进和钙动力学在此过程中的参与正在深入研究。