Cochlear Neurotransmitters

耳蜗神经递质

基本信息

批准号：
8577802
负责人：
WILLIAM F SEWELL
金额：
$ 34.85万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8577802
关键词：
AMPA Receptors Acoustic Nerve Acoustic Stimulation Acoustics Address Afferent Neurons Attenuated Auditory Auditory Physiology Biochemical Cochlea Code Complex Coupled Dendrites Excision Failure Fiber Figs - dietary Future Gene Deletion Glutamate Receptor Hair Cells Hearing Inner Hair Cells Kainic Acid Receptors Knowledge Laboratories Lead Mediating Metabotropic Glutamate Receptors Methodology Monitor Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate Natural regeneration Nervous system structure Neurons Neuropathy Neurotransmitters Normal Cell Pathology Pattern Pharmaceutical Preparations Physiological Play Predisposition Process Receptor Activation Receptor Gene Role Sensorineural Hearing Loss Sensory Signal Transduction Stimulus Synapses Synaptic Membranes Synaptic Transmission Testing Time Tinnitus Trauma Work auditory stimulus base computerized data processing desensitization excitotoxicity hearing impairment improved in vivo interest kainate nerve supply neurotransmitter release novel strategies public health relevance receptor receptor recycling response sound spiral ganglion synaptic function tool trafficking transmission process

项目摘要

DESCRIPTION (provided by applicant): We have known for decades that glutamate receptors mediate synaptic transmission between the inner hair cell and its afferent fiber, yet we know astonishingly little about the contributions of the different types of glutamate receptors to stimulus coding and auditory pathology. All 4 basic types of glutamate receptors (AMPA, kainate, metabotropic, and NMDA) are present on afferent terminals but the only one we really understand well is the AMPA receptor, which mediates moment-by-moment transmission at this synapse. Understanding how these different types of glutamate receptors interact to code acoustic signals will illuminate how this synapse achieves some of its extraordinary information transfer capabilities and how its failure modes can lead to excitotoxic hearing loss. The specific aims are: Aim 1: How do different glutamate receptors cooperate to produce sound-evoked responses in the cochlea? Aim 2. Test the hypothesis that kainate receptors are trafficked and regulated at the hair cell synapse. Aim 3: How do different glutamate receptors contribute to excitotoxicity in the cochlea? Understanding the roles of these receptors in cochlear function could also lead to strategies to improve hearing. For example, a greater understanding of the role NMDA receptors play in the cochlea could lead to new tinnitus therapies. Understanding trafficking could lead to drugs that improve hearing by increasing the sensitivity of afferent neurons to auditory stimuli. Knowledge of the roles that the different neurotransmitters play in cochlear function could help in developing strategies for reinnervating hair cells in future therapies based on regenerating hair cells. Finally, understanding the roles of these different glutamate receptors at the hair cell afferent synapse provides an extraordinary opportunity to understand fundamental issues of glutamate receptor coding with relevance to understanding synaptic function in the nervous system in general. The simplicity and extreme organization of the innervation pattern in the cochlea, coupled to the ability to precisely deliver sensory signals and monitor responses while perfusing the synapse with drugs allows us to precisely address the roles of these receptors in signal processing in vivo.

描述（由申请人提供）：几十年来，我们已经知道谷氨酸受体介导内毛细胞与其传入纤维之间的突触传递，但我们对不同类型的谷氨酸受体对刺激编码和听觉病理学的贡献知之甚少。所有 4 种基本类型的谷氨酸受体（AMPA、红藻氨酸、代谢型和 NMDA）都存在于传入末梢，但我们真正了解的唯一一种是 AMPA 受体，它介导突触处的即时传递。了解这些不同类型的谷氨酸受体如何相互作用以编码声音信号将阐明这种突触如何实现其一些非凡的信息传输能力以及其故障模式如何导致兴奋性毒性听力损失。具体目标是：目标 1：不同的谷氨酸受体如何合作在耳蜗中产生声音诱发的反应？目标 2. 检验红藻氨酸受体在毛细胞突触处运输和调节的假设。目标 3：不同的谷氨酸受体如何导致耳蜗的兴奋性毒性？了解这些受体在耳蜗功能中的作用也可能有助于制定改善听力的策略。例如，更好地了解 NMDA 受体在耳蜗中的作用可能会带来新的耳鸣疗法。了解贩运可能会导致药物通过增加传入神经元对听觉刺激的敏感性来改善听力。了解不同神经递质在耳蜗功能中发挥的作用可能有助于在未来基于毛细胞再生的治疗中制定重新支配毛细胞的策略。最后，了解毛细胞传入突触中这些不同谷氨酸受体的作用，为了解谷氨酸受体编码的基本问题提供了一个绝佳的机会，这与了解一般神经系统中的突触功能相关。耳蜗神经支配模式的简单性和极端组织性，与精确传递感觉信号的能力相结合并在用药物灌注突触时监测反应使我们能够精确地确定这些受体在体内信号处理中的作用。