Spontaneous Activity in Development of Auditory Processing Circuitry

听觉处理电路发展中的自发活动

• 批准号: 10066095
• 负责人: Calvin Jasper Kersbergen
• 金额: $ 5.05万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066095
• 关键词: Acoustics; Action Potentials; Acute; Address; Adult; Auditory; Auditory Brainstem Responses; Auditory Perception; Auditory Threshold; Auditory area; Auditory system; Behavior assessment; Behavioral; Behavioral Assay; Behavioral Paradigm; Calcium; Characteristics; Chloride Channels; Cochlea; Communication; Complex; Development; Developmental Process; Discrimination; Event; External auditory canal; Frequencies; Genetic; Hair Cells; Hearing; Hypersensitivity; Image; In Vitro; Individual; Inferior Colliculus; Injury; Inner Hair Cells; Inner Supporting Cell; Laboratories; Lead; Maps; Midbrain structure; Mus; Neurons; Operant Conditioning; Organ; Organism; Patients; Pattern; Peripheral; Physiological; Play; Positive Reinforcements; Process; Role; Sensory; Shapes; Sound Localization; Startle Reaction; Stimulus; Synapses; Testing; Tinnitus; Training; Trauma; Visual system structure; Work; auditory processing; awake; congenital deafness; critical developmental period; deaf; deafness; experience; experimental study; hearing impairment; hearing preservation; improved; in vivo; in vivo imaging; insight; neural circuit; neurodevelopment; novel strategies; ototoxicity; postnatal; prepulse inhibition; preservation; relating to nervous system; response; sensory input; sound; two photon microscopy

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.

项目概要 发育中的听觉神经元组装成随后被调节的基本电路 由于创伤、耳毒性或先天性而改变了这些电路的发育。 耳聋可导致声音过敏、严重听力损失或使人衰弱的耳鸣。 产生的“自发”神经活动在发病前通过新生的听觉神经回路传播 声输入，提供了一个被认为可以启动关键发育过程的早期训练期。 然而，我们的实验室对自发预听活动的确切作用仍然知之甚少。 确定了发育中的耳蜗内内部支持细胞（ISC）的关键作用，它启动了级联反应 在预听觉期间触发内毛细胞动作电位放电的事件。 关键取决于诱导外流的钙激活氯通道 (TMEM16A/ANO-1) 的开放 ISC 中 TMEM16A 的基因缺失显着降低了 ISC 中的听力前神经活动。 体内听觉中枢神经系统，但 TMEM16A cKO 小鼠保留了听力阈值和外周血 耳道打开后对声音的反应，提供询问自发活动如何的方法 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开创性实验的一个决定性特征。 视觉系统表明，生物体在发育受限时期接收到的感觉输入是 对于建立、维护和调整外部世界的精确地形图至关重要。 因此，感觉神经活动对于完善发育中的粗糙地形组织可能至关重要。 评估发育中的听觉系统中的自发预听活动是否有助于完善听觉系统 中心音调图和神经调谐，我将大大减少听觉中枢神经系统的自发活动 通过删除 ISC 内的 TMEM16A 以及随后的图像神经 Ca2+ 对声音的反应 听觉中脑和皮质在听觉出现后将确定后续的声学输入是否能够。 在没有预听活动的情况下精炼听觉皮层音调最后，我将识别是否有自发活动。 通过频率依赖来锐化音调辨别所需的听觉电路和神经调节 抑制声音惊吓反应和自我激励的操作性条件反射行为范式。 这些实验将为了解早期耳蜗急性损伤和 先天性耳聋会导致听觉回路处理和解释能力的长期变化 声音，可能会带来改善听力受损患者听觉功能的新方法。