Spontaneous Activity in Development of Auditory Processing Circuitry

项目摘要 发育中的听觉神经元组装成基本的回路， 通过声学经验。由于创伤、耳毒性或先天性，这些回路的发育改变 耳聋可导致听觉超敏反应、深度听力损失或使人衰弱的耳鸣。本质 产生的“自发”神经活动在发作前通过新生的听觉神经回路传播 声音输入，提供了一个早期的训练阶段，被认为是启动关键的发展过程。 然而，自发性听前活动的确切作用仍然知之甚少。本实验室 确定了内支持细胞（ISC）在发育中的耳蜗中的关键作用， 在听前阶段触发内毛细胞动作电位放电的事件。这个过程 关键取决于钙激活的氯离子通道（TMEM 16 A/ANO-1）的开放， 从ISCs的K+。ISCs中TMEM 16 A的基因缺失显著降低了小鼠听前神经活动， TMEM 16 A cKO小鼠在体内的听觉CNS中，但TMEM 16 A cKO小鼠保留了听力阈值和外周听力阈值。 耳道开放后对声音的反应，提供了询问自发活动如何 通过功能和行为评估影响中央声音处理电路的成熟。 地形组织是感觉中枢神经系统的定义特征。开创性的实验， 视觉系统表明，在有限的发育期内， 对于建立、维护和调整外部世界的精确地形图至关重要。预处理 因此，感觉神经活动可能是细化发育粗糙的地形组织的关键。 为了评估发育中的听觉系统中的自发性听前活动是否有助于改善 中枢音调定位图和神经调谐，我将大大减少在听觉中枢神经系统的自发活动 通过在ISCs内删除TMEM 16 A，随后在大鼠脊髓中成像神经Ca 2+对声音的反应， 听觉中脑和皮层。我将确定后续的声音输入是否能够 在没有听前活动的情况下改善听觉皮层音调。最后，我将确定是否自发活动 锐化听觉回路和神经调谐所需的音调辨别通过频率依赖 声音惊吓反应的抑制和自我激励的操作性条件反射行为范例。 这些实验将提供重要的见解如何早期急性损伤的耳蜗和 先天性耳聋导致听觉回路处理和解释能力的长期变化 声音，可能导致新的方法来改善听力受损患者的听觉功能。

Project Summary Developing auditory neurons assemble into rudimentary circuits that are subsequently modulated through acoustic experience. Altered development of these circuits due to trauma, ototoxicity or congenital deafness can lead to acoustic hypersensitivity, profound hearing loss, or debilitating tinnitus. Intrinsically generated, “spontaneous” neural activity propagates through nascent auditory neural circuits prior to the onset of acoustic input, providing an early training period that is thought to initiate key developmental processes. However, the precise roles for spontaneous pre-hearing activity remain poorly understood. Our laboratory has identified a critical role for inner supporting cells (ISCs) within the developing cochlea, which initiate a cascade of events that trigger action potential firing in inner hair cells during the pre-hearing period. This process critically depends upon opening of calcium-activated chloride channels (TMEM16A/ANO-1) that induce efflux of K+ from ISCs. Genetic deletion of TMEM16A from ISCs dramatically reduces pre-hearing neural activity in the auditory CNS in vivo, but TMEM16A cKO mice have preserved hearing thresholds and peripheral responses to sound after ear canal opening, providing the means to interrogate how spontaneous activity influences the maturation of central sound processing circuits via functional and behavioral assessments. Topographic organization is a defining feature of the sensory CNS. Pioneering experiments in the visual system show that the sensory input an organism receives during restricted developmental periods is critical for establishing, maintaining, and modulating precise topographic maps of the external world. Pre- sensory neural activity is therefore likely critical for refining developmentally coarse topographic organization. To assess if spontaneous pre-hearing activity in the developing auditory system contributes to refinement of central tonotopic maps and neural tuning, I will dramatically reduce spontaneous activity in the auditory CNS through deletion of TMEM16A within ISCs and subsequently image neural Ca2+ responses to sound in the auditory midbrain and cortex just after hearing onset. I will determine if subsequent acoustic input is capable of refining auditory cortical tonotopy without pre-hearing activity. Finally, I will identify if spontaneous activity sharpens auditory circuitry and neural tuning required for tone discrimination through frequency-dependent inhibition of the acoustic startle response and self-motivated operant conditioning behavioral paradigms. These experiments will provide important insight into how early acute injury to the cochlea and congenital deafness lead to long-term changes in the capacity of auditory circuits to process and interpret sounds, potentially leading to new approaches for improving auditory function in hearing impaired patients.