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电路，然后进行调制 通过声学体验。由于创伤、耳毒性或先天原因导致的这些回路的发育改变 耳聋会导致听觉过敏、严重的听力损失或衰弱的耳鸣。从本质上讲 在发病前，产生的“自发”神经活动通过新生的听觉神经回路传播 声学输入，提供被认为启动关键发展过程的早期训练期。 然而，自发的听前活动的确切作用仍然知之甚少。我们的实验室有 确认了发育中的耳蜗内支持细胞(ISCs)的关键作用，它启动了级联反应 在听前阶段触发内毛细胞动作电位激发的事件。这一过程 关键依赖于钙激活的氯离子通道(TMEM16A/ANO-1)的开放，从而导致外流 来自ISCs的K。ISCs TMEM16A基因缺失显著降低听前神经活动 但TMEM16A CKO小鼠听阈和外周血细胞数均未受影响 耳道打开后对声音的反应，提供了询问自发活动的手段 通过功能和行为评估影响中央声音处理电路的成熟。 地形图的组织是感觉中枢神经系统的一个重要特征。具有开创性的实验 视觉系统显示，有机体在受限的发育时期接受的感觉输入是 对于建立、维护和调整外部世界的精确地形图至关重要。Pre- 因此，感觉神经活动可能是精炼发育粗糙的地形组织的关键。 评估发育中的听觉系统中自发的听前活动是否有助于改善 中枢张力图和神经调节，I将极大地减少听觉中枢神经系统的自发活动 通过缺失ISCs内的TMEM16A，随后在脑内成像对声音的神经钙反应 听力发作后的听觉中脑和大脑皮质。我会确定后续的声音输入是否能够 在听前活动的情况下，精炼听觉皮质强直。最后，我将确定自发的活动是否 通过频率依赖增强音调辨别所需的听觉电路和神经调谐 声学惊吓反应的抑制和自我激励的操作性条件反射行为范式。 这些实验将提供重要的洞察，以了解早期的急性耳蜗损伤和 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.