Spontaneous activity in the developing auditory sytem

 描述（由申请人提供）：哺乳动物CNS中的听觉回路在听力开始之前表现出稳健的自发活动。这种活动起源于发育中的耳蜗，并依赖于内毛细胞（IHC）的兴奋;然而，很少有人知道的分子机制，负责启动自发的IHC活动或这种活动的后果，在大脑中的听觉回路的发展。本提案中概述的研究将使用该途径关键组分的体内遗传操作，结合分离耳蜗中的电生理学研究和未麻醉小鼠中的体内成像，以检验IHC活性由内支持细胞（ISC）定期释放ATP诱导的假设。这些研究将确定负责检测ATP的自身受体，以及ISC诱导附近IHC去极化的机制，这些事件最终触发螺旋细胞中动作电位的爆发。 神经节神经元（SGN）和中枢听觉回路中神经元的同步活动。听觉神经元在听力开始之前表现出的整体活动模式将在正常发育期间的下丘和初级听觉皮层（A1）中定义，并且当来自耳蜗的感觉独立活动被破坏时，提供了基本的新的见解，这种耳蜗依赖的活动在听觉回路的成熟和这些回路的反应，在这个关键的发展阶段的活动赤字的作用。变化 连接蛋白26的突变是非综合征性耳聋的主要原因，将检查连接蛋白26的缺失引起的网络活动，以确定耳蜗支持细胞之间缝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，自发活动的作用，在细化的树突状和 SGN的轴突投射将通过耳蜗中细胞的选择性体内遗传操作来评估。这些研究将提供更深入的了解用于塑造处理声音信息的电路的基本机制。

 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.