Cholinergic Response of Cochlear Hair Cells

耳蜗毛细胞的胆碱能反应

• 批准号: 8756481
• 负责人: Paul A Fuchs
• 金额: $ 46.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8756481
• 关键词: Acetylcholine; Acoustic Trauma; Acoustics; Aging; Amino Acids; Birds; Brain Stem; Calcium; Calcium Signaling; Cessation of life; Cholinergic Receptors; Cochlea; Comparative Study; DNA Sequence Rearrangement; Dendrites; Denervation; Development; Efferent Neurons; Employee Strikes; Engineering; Feedback; Frequencies; Hair; Hair Cells; Hearing; Homeostasis; Inner Hair Cells; Knock-in Mouse; Knowledge; Laboratories; Mammals; Measures; Membrane; Modeling; Molecular; Mus; Neurons; Nitric Oxide; Nitric Oxide Synthase; Noise; Outer Hair Cells; Permeability; Physiology; Play; Potassium Channel; Presbycusis; Process; Protocols documentation; Regulation; Relative (related person); Role; Sensory Hair; Shapes; Shunt Device; Signal Transduction; Structure; Synapses; Synaptic Membranes; Synaptic plasticity; Tail; Testing; Therapeutic Agents; Trauma; Variant; Work; age related; aged; base; cholinergic; gain of function; hearing impairment; improved; inhibitor/antagonist; interest; mouse model; nerve supply; operation; prevent; public health relevance; release of sequestered calcium ion into cytoplasm; research study; response; synaptogenesis; therapeutic target; tool; voltage

DESCRIPTION (provided by applicant): "Cholinergic inhibition of cochlear hair cells" is aimed at understanding the basic molecular mechanisms by which efferent neurons of the brainstem release acetylcholine (ACh) to inhibit hair cells and suppress cochlear sensitivity. This central feedback mechanism is particularly highly specialized in the mammalian cochlea where it is proposed to provide gain adjustment, improved signal to noise ratio, extended dynamic range and perhaps to protect from acoustic overstimulation. During development, temporary efferent contacts on inner hair cells are thought to modulate and shape spontaneous activity to help shape central connectivity. Finally, emerging evidence shows that efferent synaptic contacts return to aged or damaged inner hair cells, a process of great interest but presently unknown functional significance. The molecular mechanisms of inhibition may provide clues to these developmental and age-related changes. The hair cell's ACh receptor allows calcium entry that activates nearby potassium channels. This process is regulated by a near-membrane synaptic cistern. Ongoing work suggests that this cistern acts as a calcium sink during normal operation, but during periods of high activity executes calcium-induced calcium release that extends and prolongs cytoplasmic calcium signals. One consequence of prolonged calcium signaling is the activation of nitric oxide synthase to produce the diffusible messenger, nitric oxide (NO). NO causes retrograde facilitation of efferent transmitter release, thereby strengthening these contacts. Mechanisms that regulate efferent synaptic strength are of interest in the context of development, and the changes in synaptic organization that take place in aged or damaged cochleas. In addition to frank hair cell loss, it is clear that afferent denervation of inner hair ells is an important pathogenic change. The adventitious re-innervation of inner hair cells by efferent neurons may prevent afferent dendrites from re-claiming their territory on the hair cell. Understanding the determinants of efferent synapse formation provides tools for manipulating that process, perhaps to ameliorate one consequence of cochlear trauma.

描述（由申请人提供）：“对耳蜗细胞的胆碱能抑制作用”旨在理解脑干释放乙酰胆碱（ACH）抑制毛细胞并抑制人群敏感性的基本分子机制。这种中央反馈机制在哺乳动物的耳蜗中特别高度专业化，在此提议提供增益调节，改善信号与噪声比，扩展动态范围，甚至可以防止声学过度刺激。在开发过程中，内部毛细胞上的暂时传出接触被认为可以调节并塑造自发活动，以帮助塑造中心连通性。最后，新兴的证据表明，传出突触接触返回到老化或受损的内毛细胞，这是一个引起人们关注但目前未知的功能意义的过程。抑制的分子机制可以为这些发育和年龄相关的变化提供线索。毛细胞的ACH受体允许钙进入，以激活附近的钾通道。该过程受近膜突触箱的调节。正在进行的工作表明，这种水箱在正常运行期间充当钙下水道，但是在高活动期间，钙诱导的钙释放延伸并延长了细胞质钙信号。延长钙信号传导的结果之一是一氧化氮合酶的激活以产生扩散的信使一氧化氮（NO）。没有导致传出发射器释放的逆行促进，从而加强了这些接触。调节传出突触强度的机制在发育的背景下以及在老年或受损的耳蜗发生的突触组织的变化中引起了人们的关注。除了坦率的毛细胞损失外，很明显，内毛的传入神经eLLS是一个重要的致病性变化。通过传出神经元对内毛细胞的不定重新引起可能会阻止传入的树突将其领土重新宣称在毛细胞上。了解传出突触形成的决定因素为操纵该过程提供了工具，也许可以改善人工耳蜗创伤的结果。