Role of Adaptive Myelination in Auditory Brain Plasticity

项目摘要/摘要： 早期的听觉经验对于建立和重塑听觉大脑中的神经回路至关重要。一次损失 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中枢 听觉回路，即使在使用助听器恢复外围声音灵敏度后也是如此。预防和扭转 外周性听力障碍后的中枢听觉功能障碍，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枢听觉处理之间建立了新的联系 中锋。我们以前的研究表明，髓鞘是分辨听觉信号的一个重要特征 为中枢听觉处理提供极高的时间精度。声音输入本身对髓鞘发育至关重要 并在整个生命过程中沿着听觉脑干回路进行维护。然而，听觉的程度 经验调节的髓鞘发育和可塑性对中枢听觉处理的贡献，以及如何 适应性髓鞘形成发生在听觉脑干，目前尚不清楚。这项提案的目标是确定 听觉经验调节听觉脑可塑性和中央加工的细胞机制 适应性髓鞘形成。我们最近的研究开创了一个理解人与人之间交流的新概念 神经元和髓鞘形成细胞，少突胶质细胞(OL)通过定义听性脑干中OL的兴奋性。 一个新的OL亚群表达谷氨酸受体、电压门控钠(Nav)和钙通道，这些通道 OL去极化、钠电流介导的尖峰电流和钙动力学是其基础。因此，这些运营者最理想的状态是 与电活跃的神经元交流，并以更多的髓鞘形成作为奖励。根据这些数据， 我们假设，声音诱发活动的增加增强了电和化学交流 在这类新的可兴奋的OL和神经元之间调节OL的发育和驱动适应性 用于微调听觉脉冲的时间保真度的髓鞘形成。为了验证这一假设，我们将利用声音 修饰(刺激或剥夺)、体内和体外电生理学(听性脑干反应 和膜片钳记录)、细胞内钙成像和解剖分析技术。我们将决定 声音刺激如何调节神经元-OL交流和OL兴奋性(目标1)，OL兴奋性如何 增强适应性髓鞘形成(目标2)，以及Nav1.2介导的OL兴奋性的丧失如何影响适应性 髓鞘形成和听觉脑干回路(目标3)。拟议中的研究将提供新的机械论见解 外周听觉信号如何通过神经元对适应性髓鞘形成和神经可塑性做出贡献- 听觉脑中的少突胶质细胞通讯。声驱动适应机制的研究进展 髓鞘形成对于理解听觉大脑发育过程中的可塑性和发育过程中的听觉可塑性是必不可少的 周围性听力障碍或儿童听觉加工障碍的有效治疗策略 植入了人工耳蜗术。

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.