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.

项目概要 发育中的听觉系统中的神经元在听觉开始之前会经历高度刻板的活动爆发。 感官体验。当非感觉内部支持细胞出现时，该活动在耳蜗内启动 释放 ATP，引发一系列事件，最终在螺旋神经节中诱发一系列动作电位 在整个听觉系统中传播的神经元（SGN）。 ATP 触发器的空间限制释放 SGN 组中的相关发射随后将编码相似的声音频率，从而提供了一种方法 在听觉之前诱导大脑中声音处理电路的活动依赖性成熟和完善 发病。尽管模式活动在这个关键的发育时期很突出，但它在 听觉系统的成熟仍然知之甚少，部分原因是无法选择性地干扰 自发活动，同时保留耳蜗中的声音传导。在这里，我们建议利用新的 开发的小鼠模型可以选择性破坏耳蜗支持内的自发活动 细胞仍保留耳蜗结构和听神经的完整性。我们将明确测试 假设听觉神经元的突发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 的基因破坏，这两个 在耳蜗支持细胞中产生自发活动所需的成分，具有体内宽场和 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，即下丘中的星形胶质细胞 预听小鼠的（IC）在自发事件期间与周围神经元共同激活，提供了 协调三方突触（由兴奋性突触包裹的兴奋性突触）的空间和时间成熟的手段 星形胶质细胞）。目标 1 将重点关注耳蜗，确定 P2RY1 和 TMEM16A 的缺失如何影响耳蜗 SGN 的特性和发展轨迹。目标 2 将定义耳蜗与 听觉皮层 (AC) 的耳蜗外自发活动，决定耳蜗衍生的破坏方式 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。目标 3 将定义诱导钙升高所需的神经元活动模式 并确定如何选择性地遗传破坏星形胶质细胞 mGluR5 的表达，即 检测神经元爆发放电所必需的，影响星形胶质细胞的成熟和逐步细化 体内声音的音调表征。这些研究将提供对基本原理的更深入的了解 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、创伤和早年接触耳毒性药物会改变大脑的处理能力 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策略 补偿耳蜗输出的发育中断并提高耳蜗的性能 植入物。