Role of Adaptive Myelination in Auditory Brain Plasticity

项目概要/摘要： 早期听觉经验对于听觉脑神经回路的建立和重塑至关重要。亏损 先天性和早发性耳聋患者的外周声音输入在结构和功能上改变了中枢神经系统 听觉回路，即使在使用助听器恢复周边声音灵敏度之后。防止和扭转 中枢听觉功能障碍后，周边听力障碍，重要的是要了解可塑性如何在 听觉大脑在恢复的声音输入和中央听觉处理之间建立了新的联系 中心.我们以前的研究表明，髓鞘是一个重要的特征，在解决听觉信号， 中央听觉处理的极端时间精确度。声音输入本身对髓鞘发育至关重要 并在整个生命中保持沿着听觉脑干回路。然而，在多大程度上， 经验调节的髓鞘发育和可塑性有助于中枢听觉处理，以及如何 适应性髓鞘形成发生在听觉脑干，目前尚不清楚。本提案的目的是确定 听觉经验调节听觉大脑可塑性和中枢处理的细胞机制， 适应性髓鞘形成我们最近的研究开创了一个新的概念，在理解之间的沟通 神经元和髓鞘形成细胞，少突胶质细胞（OL）的定义在听觉脑干的OL兴奋性。 一种新的OLs亚群表达谷氨酸受体、电压门控Na+（Nav）和Ca 2+通道， 在OL去极化，Na+电流介导的尖峰和Ca 2+动力学的基础。因此，这些OL在理想状态下 与电活跃的神经元交流，并以增加髓鞘形成作为奖励。根据这些数据， 我们假设声音诱发的活动增加， 这类新的可兴奋的OL和神经元之间的调节OL的发展和驱动适应性 髓鞘形成用于微调听觉脉冲的时间保真度。为了验证这一假设，我们将利用声音 修饰（刺激或剥夺）、体内和离体电生理学（听觉脑干反应 和膜片钳记录）、细胞内Ca 2+成像和解剖分析技术。我们将确定 声音刺激如何调节神经元-OL通信和OL兴奋性（目的1），OL兴奋性如何 增强适应性髓鞘形成（目的2），以及Nav1.2介导的OL兴奋性丧失如何影响适应性髓鞘形成（目的2）。 髓鞘形成和听觉脑干回路（Aim 3）。拟议的研究将提供新的机制见解 研究外周听觉信号如何通过神经元促进自适应髓鞘形成和神经可塑性， 听觉脑中的少突胶质细胞通讯。阐明声音驱动自适应机制 髓鞘形成对于理解发育过程中听觉脑的可塑性和发展听觉神经元是必不可少的。 儿童周围性听力障碍后听觉加工障碍的有效治疗策略 人工耳蜗

Project Summary/ Abstract: Early auditory experience is crucial for establishing and remodeling neural circuits in the auditory brain. A loss of peripheral sound input in congenital and early-onset deafness structurally and functionally alters central auditory circuits, even after peripheral sound sensitivity is restored with hearing aids. To prevent and reverse central auditory dysfunctions following peripheral hearing deficits, it is important to understand how plasticity in the auditory brain creates new connections between restored sound input and central auditory processing centers. Our previous studies showed that myelin was an important feature in resolving auditory signals with extreme temporal precision for central auditory processing. Sound input itself is critical for myelin development and maintenance along auditory brainstem circuitry throughout life. However, the extent to which auditory experience-regulated myelin development and plasticity contribute to central auditory processing, and how adaptive myelination occurs in the auditory brainstem, are unclear. The goal of this proposal is to determine the cellular mechanisms whereby auditory experiences regulate auditory brain plasticity and central processing via adaptive myelination. Our recent studies pioneered a new concept in understanding communication between neurons and myelin-forming cells, oligodendrocytes (OLs) by defining OL excitability in the auditory brainstem. A new subpopulation of OLs expresses glutamate receptors, voltage-gated Na+ (Nav), and Ca2+ channels, which underlie OL depolarization, Na+ current-mediated spiking and Ca2+ dynamics. Thus, these OLs are ideally poised to communicate with electrically active neurons and reward with increased myelination. Based on these data, we hypothesize that increased sound-evoked activity enhances electrical and chemical communication between this novel class of excitable OLs and neurons to regulate OL development and drives adaptive myelination for fine-tuning temporal fidelity of auditory impulses. To test this hypothesis, we will utilize sound modification (stimulation or deprivation), in vivo and ex vivo electrophysiology (auditory brainstem responses and patch-clamp recordings), intracellular Ca2+ imaging, and anatomical analysis techniques. We will determine how sound stimulation modulates neuron-OL communication and OL excitability (Aim 1), how OL excitability enhances adaptive myelination (Aim 2), and how loss of Nav1.2-mediated OL excitability impacts adaptive myelination and auditory brainstem circuitry (Aim 3). The proposed study will provide novel mechanistic insights into how peripheral auditory signals contribute to adaptive myelination and neural plasticity via neuron- oligodendroglia communication in the auditory brain. Elucidating the mechanisms of sound-driven adaptive myelination is essential for understanding auditory brain plasticity during development and for developing an effective therapeutic strategy for auditory processing disorders following peripheral hearing deficits or in children with cochlear implants.