Spontaneous activity in the developing auditory sytem

发育中的听觉系统的自发活动

• 批准号: 9249521
• 负责人: DWIGHT E BERGLES
• 金额: $ 53.51万
• 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: 2007-12-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249521
• 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（由申请人提供）：哺乳动物中枢神经系统中的听觉回路在出现听力之前表现出强大的自发活动，这种活动起源于发育中的耳蜗，并且依赖于内毛细胞（IHC）的兴奋；然而，人们对这种活动知之甚少。负责启动自发 IHC 活动的分子机制或该活动对大脑听觉回路发育的影响。本提案中概述的研究将结合该途径关键成分的体内遗传操作。在离体耳蜗中进行电生理学研究，并在未麻醉的小鼠中进行体内成像，以检验 IHC 活性是由内部支持细胞 (ISC) 定期释放 ATP 诱导的假设。这些研究将定义负责检测 ATP 的自身受体和ISC 诱导附近 IHC 去极化的机制，最终触发螺旋状动作电位爆发的事件 神经节神经元 (SGN) 和听觉中枢回路中神经元的同步活动 听觉神经元在听力出现之前表现出的整体活动模式将在正常发育期间和感觉独立活动时在下丘和初级听觉皮层 (A1) 中定义。耳蜗受到破坏，为了解耳蜗依赖性活动在听觉回路成熟中的作用以及这些回路对这一关键发育阶段活动缺陷的反应提供了根本性的新见解。 在响应连接蛋白 26 丢失的网络活动中，连接蛋白 26 的突变是非综合征性耳聋的主要原因，将进行检查以确定耳蜗支持细胞之间间隙连接耦合的破坏如何改变通过新生听觉回路进行的活动模式此外，自发活动在树突细化中的作用。 SGN 的轴突投射将通过对耳蜗细胞进行选择性体内遗传操作进行评估，这些研究将提供对用于塑造处理声音信息的电路的基本机制的更深入的了解。