Spontaneous activity in the developing auditory system

发育中的听觉系统的自发活动

• 批准号: 10604276
• 负责人: DWIGHT E BERGLES
• 金额: $ 52.07万
• 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 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604276
• 关键词: Acoustic Nerve; Acoustics; Action Potentials; Acute; Adult; Astrocytes; Auditory; Auditory area; Auditory system; Behavioral; Brain; Calcium; Cells; Cochlea; Cochlear Implants; Compensation; Coupling; DNA Sequence Alteration; Development; Discrimination; Electrophysiology (science); Event; Excitatory Synapse; Exhibits; Exposure to; Expression Profiling; Frequencies; Genetic; Genetic Transcription; Hearing; Image; Inferior Colliculus; Inner Supporting Cell; Knowledge; Lead; Life; Mediating; Membrane; Midbrain structure; Monitor; Morphology; Mus; Neurons; Output; Pattern; Performance; Peripheral; Pharmaceutical Preparations; Process; Property; Role; Sensory; Shapes; Signal Induction; Signal Transduction; Specific qualifier value; Stereotyping; Structure; Supporting Cell; Synapses; Testing; Training; Trauma; auditory discrimination; critical developmental period; electrical property; experience; hearing impairment; improved; in vivo; in vivo imaging; insight; mouse model; neuronal circuitry; neuronal excitability; neuronal patterning; neurotransmission; ototoxicity; preservation; reconstruction; sound; sound frequency; spiral ganglion; tool; two-photon

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.

项目摘要 在发展中的听觉系统中的神经元在开始之前经历了高度定型的活动爆发 感官体验。当非敏感性内部支撑细胞时，该活动是在耳蜗内开始的 释放ATP，引发一系列事件，最终引起螺旋神经节的动作电位 在整个听觉系统中传播的神经元（SGNS）。 ATP触发器的空间限制释放 与SGN的组相关触发，后来将编码类似的声音频率，从而提供了一种手段 在听到之前，诱导活动依赖性依赖性成熟和大脑的声音处理电路的完善 发作。尽管在这个关键发展时期，图案活动的突出是显着的，但它的作用 听觉系统的成熟程度仍然很少，部分原因是无法选择性破坏 自发活动，同时保存耳蜗中的声音转导。在这里，我们建议新的 开发的鼠标模型，可以选择性破坏人工耳蜗中的自发活动 细胞仍然保留耳蜗结构和听觉神经的完整性。我们将明确测试 假设听觉神经元爆发对启动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，两个 在人工耳蜗支撑细胞中产生自发活动所需的组件，并具有体内广场和 神经元活性的两个光子成像，RNA表达分析和听觉功能的行为分析 严格检验这一假设。我们将扩展我们最近发现的，即属丘丘中的星形胶质细胞 （IC）在自发事件中与周围神经元共激活（IC） 用于协调三方突触的空间和时间成熟（兴奋性突触 星形胶质细胞）。 AIM 1将重点放在耳蜗上，确定P2RY1和TMEM16A的损失如何影响 SGN的性质和发育轨迹。 AIM 2将定义人工耳蜗与 听觉皮层（AC）中的周期外的自发活动，确定耳蜗衍生的破坏 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 听觉歧视。 AIM 3将定义诱导钙升高所需的神经元活动的模式 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如何 检测神经元爆发的必要 体内声音的吨位表示。这些研究将提供对基本的更深入的洞察力 用于定义电路的机制来处理声音信息并建立一个框架以探索如何 早年的基因突变，创伤和暴露于耳毒性药物改变了加工能力 中央听觉电路。从这些研究中获得的信息最终可能有助于建立新的策略 弥补人工耳蜗产量的发育破坏并提高人工耳蜗的性能 植入物。