Spontaneous activity in the developing auditory sytem

发育中的听觉系统的自发活动

• 批准号: 9906210
• 负责人: DWIGHT E BERGLES
• 金额: $ 51.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906210
• 关键词: Action Potentials; Address; Affect; Auditory; Auditory area; Auditory system; Autoreceptors; Axon; Brain; Cells; Cochlea; Cochlear nucleus; Coupling; DNA Sequence Alteration; Dendrites; Development; Disease; Electrophysiology (science); Event; Exhibits; Exposure to; Fire - disasters; GJB2 gene; Gap Junctions; Glutamates; Growth; Hearing; Inferior Colliculus; Injury; Inner Hair Cells; Inner Supporting Cell; Knowledge; Labyrinth; Lead; Life; Mediating; Molecular; Mus; Mutation; Neurons; Organ; Pathway interactions; Pattern; Periodicity; Pharmaceutical Preparations; Play; Prevention; Process; Purinoceptor; Role; Sensory; Sensory Process; Shapes; Signal Pathway; Signal Transduction; Supporting Cell; Synapses; Systems Development; Testing; Trauma; awake; deafness; genetic manipulation; in vivo; in vivo imaging; insight; neuronal survival; ototoxicity; public health relevance; relating to nervous system; response; sound; spiral ganglion

 DESCRIPTION (provided by applicant): Auditory circuits in the mammalian CNS exhibit robust spontaneous activity before the onset of hearing. This activity originates within the developing cochlea and is dependent on excitation of inner hair cells (IHCs); however, little is known about the molecular mechanisms responsible for initiating spontaneous IHC activity or the consequences of this activity for development of auditory circuits in the brain. The studies outlined in this proposal will use in vivo genetic manipulations of key components of this pathway in combination with electrophysiological studies in isolated cochleae and in vivo imaging in unanesthetized mice to test the hypothesis that IHC activity is induced by the periodic release of ATP from inner supporting cells (ISCs). These studies will define the autoreceptor(s) responsible for detecting ATP and the mechanisms by which ISCs induce depolarization of nearby IHCs, events that ultimately trigger bursts of action potentials in spiral ganglion neurons (SGNs) and synchronous activity of neurons in central auditory circuits. The global activity patterns exhibited by auditory neurons before hearing onset will be defined in the inferior colliculus and primary auditory cortex (A1) during normal development and when sensory-independent activity from the cochlea is disrupted, providing fundamental new insight into the role of this cochlea-dependent activity in maturation of auditory circuits and the response of these circuits to deficits in activity during this crucial developmental stage. Changes in network activity in response to the loss of connexin 26, mutations of which are a major cause of non-syndromic deafness, will be examined to determine how disruption of gap junctional coupling among cochlear supporting cells alters the patterns of activity carried through nascent auditory circuits. In addition, the role of spontaneous activity in the refinement of dendritic and axonal projections of SGNs will be assessed through selective in vivo genetic manipulations of cells in the cochlea. These studies will provide greater insight into the fundamental mechanisms used to shape the circuits that process sound information.

 描述（由适用提供）：哺乳动物中枢神经系统中的听觉电路在听证会开始前表现出强大的赞助商 - 可启用活动。该活性起源于发育中的耳蜗，取决于内毛细胞的兴奋（IHC）。然而，对于负责发起赞助商-IHC活性的分子机制或该活动对大脑中听觉电路发展的后果知之甚少。该提案中概述的研究将使用该途径的关键组成部分的体内遗传操纵与分离的耳蜗中的电生理研究结合使用，并在未消除的小鼠中进行了体内成像，以测试IHC活性的假设，即IHC活性是由ATP定期释放从INTER支持细胞中引起的（ISC）。这些研究将定义负责检测ATP的自身受体以及ISC诱导附近IHC沉积的机制，这些事件最终触发了螺旋中的动作电位爆发。 中央听觉圆中神经元的神经神经元（SGNS）和同步活动。在正常发育过程中，以及当与耳蜗的感觉无关的活动中，将在听觉发作前的听觉神经元和原发性听觉皮层（A1）中定义听觉神经元暴露的全球活动模式，从而在这些循环循环中的响应中，从而提供了对这种同志依赖于这种循环范围的作用的基本洞察力，从而提供了基本的新见解。更改 在响应连接蛋白26的丧失的网络活性中，将检查其突变是非综合性死亡性的主要原因，以确定耳蜗支撑细胞之间间隙连接耦合的破坏如何改变通过新生的听觉通行器携带的活动模式。此外，赞助商活动在树突状和树突的完善中的作用 SGNS的轴突项目将通过耳蜗中细胞的体内遗传操纵进行评估。这些研究将对塑造处理声音信息的电路的基本机制提供更深入的了解。