Spontaneous activity in the developing auditory system

项目摘要 发育中的听觉系统中的神经元在听觉活动开始之前经历高度刻板的活动爆发。 感官体验这种活动是在耳蜗内启动时，非感觉内支持细胞 释放ATP，触发级联反应，最终在螺旋神经节中诱导一连串动作电位 神经元（SGN）在整个听觉系统中传播。ATP触发物的空间限制性释放 SGN组中的相关发射，稍后将编码类似的声音频率，提供了一种方法， 诱导听觉前大脑中声音处理回路的活动依赖性成熟和完善 发病尽管在这一关键的发育时期，模式化活动很突出，但它在 听觉系统的成熟仍然知之甚少，部分原因是由于无法选择性地干扰 自发活动，同时保持耳蜗中的声音传导。在这里，我们建议利用新的 开发了小鼠模型，允许耳蜗支持内的自发活动的选择性中断， 细胞仍保留耳蜗结构和听神经的完整性。我们将显式地测试 假设听觉神经元的爆发性放电对于启动听觉神经元的结构和功能成熟至关重要， 新生的声音处理电路这些研究将利用P2ry1和Tmem16a的遗传破坏， 在耳蜗支持细胞中产生自发活动所需的组件， 神经元活动的双光子成像、RNA表达谱和听觉功能的行为分析 来严格检验这个假设我们将扩展我们最近的发现，即下丘的星形胶质细胞 (IC)在自发事件期间，听觉前小鼠的神经元与周围的神经元共同激活， 协调三部分突触的空间和时间成熟的手段（兴奋性突触被 星形胶质细胞）。目标1将集中在耳蜗，确定P2RY1和TMEM16A的丢失如何影响耳蜗的功能。 SGN的特性和发展轨迹。目标2将定义耳蜗和 耳蜗外听觉皮层（AC）的自发活动，确定耳蜗来源的破坏 自发活动改变了IC和AC中神经元激活的空间模式，并最终影响 听觉辨别目标3将定义诱导钙升高所需的神经元活动模式 在星形胶质细胞中，并确定星形胶质细胞mGluR5表达的选择性遗传破坏， 必要的检测神经元爆发放电，影响星形胶质细胞的成熟和逐步完善， 声音在体内的音调位置表示。这些研究将提供更深入的了解基本的 用于定义处理声音信息的电路的机制，并建立一个框架来探索如何 基因突变，创伤和暴露于耳毒性药物在生命早期改变的处理能力， 中枢听觉回路从这些研究中获得的信息最终可能有助于制定新的战略， 补偿耳蜗输出的发育中断并改善耳蜗的性能 植入物.

Project Summary Neurons in the developing auditory system experience highly stereotyped bursts of activity prior to the onset of sensory experience. This activity is initiated within the cochlea when non-sensory inner supporting cells release ATP, triggering a cascade of events that ultimately induces trains of action potentials in spiral ganglion neurons (SGNs) that propagate throughout the auditory system. The spatially restricted release of ATP triggers correlated firing in groups of SGNs that will later encode similar frequencies of sound, providing a means to induce activity-dependent maturation and refinement of sound processing circuits in the brain prior to hearing onset. Despite the prominence of patterned activity during this critical developmental period, its role in maturation of the auditory system remains poorly understood, in part, due to an inability to selectively disrupt spontaneous activity while preserving sound transduction in the cochlea. Here, we propose to leverage newly developed mouse models that allow selective disruption of spontaneous activity within cochlear supporting cells yet preserve cochlear structure and the integrity of the auditory nerve. We will explicitly test the hypothesis that burst firing of auditory neurons is critical to initiate structural and functional maturation of nascent sound processing circuits. These studies will leverage genetic disruption of P2ry1 and Tmem16a, two components required to generate spontaneous activity in cochlear supporting cells, with in vivo widefield and two photon imaging of neuronal activity, RNA expression profiling and behavioral analyses of auditory function to rigorously test this hypothesis. We will extend our recent discovery that astrocytes in the inferior colliculus (IC) of pre-hearing mice are co-activated with surrounding neurons during spontaneous events, providing a means to coordinate spatial and temporal maturation of tripartite synapses (excitatory synapses ensheathed by astrocytes). Aim 1 will focus on the cochlea, determining how loss of P2RY1 and TMEM16A influence the properties and developmental trajectory of SGNs. Aim 2 will define the relationship between cochlear and extra-cochlear spontaneous activity in auditory cortex (AC), determine how disruption of cochlea-derived spontaneous activity alters spatial patterns of neuronal activation in the IC and AC and ultimately influence auditory discrimination. Aim 3 will define the patterns of neuronal activity required to induce calcium elevation in astrocytes and determine how selective genetic disruption of astrocyte mGluR5 expression, which is necessary to detect neuronal burst firing, influences astrocyte maturation and progressive refinement of tonotopic representation of sounds in vivo. These studies will provide greater insight into the fundamental mechanisms used to define circuits that process sound information and establish a framework to explore how genetic mutations, trauma and exposure to ototoxic drugs during early life alter the processing capabilities of central auditory circuits. Information gained from these studies may ultimately help establish new strategies to compensate for developmental disruptions in cochlear output and improve the performance of cochlear implants.