Cochlear Neurotransmitters

耳蜗神经递质

• 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
• 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

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及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）都存在于传入终末上，但我们真正了解的唯一一种是AMPA受体，它介导该突触的瞬间传递。了解这些不同类型的谷氨酸受体如何相互作用以编码声学信号将阐明这种突触如何实现其非凡的信息传递能力，以及其故障模式如何导致兴奋性听力损失。具体目标是：目标1：不同的谷氨酸受体如何合作，以产生声音诱发的反应在耳蜗？目标2.检验红藻氨酸受体在毛细胞突触处被运输和调节的假设。目的3：不同的谷氨酸受体如何促进耳蜗兴奋性毒性？了解这些受体在耳蜗功能中的作用也可能导致改善听力的策略。例如，更好地了解NMDA受体在耳蜗中的作用可能会导致新的耳鸣疗法。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的作用，有助于在未来基于毛细胞再生的治疗中开发毛细胞神经再支配的策略。最后，了解这些不同的谷氨酸受体在毛细胞传入突触的作用提供了一个非凡的机会，了解谷氨酸受体编码的基本问题，了解神经系统中的突触功能。耳蜗中神经支配模式的简单和极端组织，加上精确传递感觉信号的能力 并在用药物灌注突触的同时监测反应，使我们能够精确地解决这些受体在体内信号处理中的作用。