Role of Adaptive Myelination in Auditory Brain Plasticity

适应性髓鞘形成在听觉脑可塑性中的作用

• 批准号: 10210896
• 负责人: Jun Hee Kim
• 金额: $ 50.66万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10210896
• 关键词: Action Potentials; Anatomy; Auditory; Auditory Brainstem Responses; Auditory Perceptual Disorders; Auditory system; Brain; Brain Stem; Cells; Central Auditory Diseases; Chemicals; Child; Cochlear Implants; Communication; Data; Development; Electrophysiology (science); Exhibits; Gene Expression Profile; Glutamate Receptor; Goals; Hearing Aids; Hearing problem; Human; Image; Impairment; Knockout Mice; Life; Maintenance; Mediating; Membrane; Modification; Mus; Myelin; Neuraxis; Neuronal Plasticity; Neurons; Noise; Oligodendroglia; Peripheral; Population; Population Heterogeneity; Presynaptic Terminals; Preventive; Reporter; Rewards; Role; Signal Transduction; Sound Localization; Speed; Structure; Synapses; Techniques; Testing; Therapeutic; Thick; Training; Transcript; Transmission Electron Microscopy; attenuation; auditory deprivation; auditory processing; base; conditional knockout; congenital deafness; deafness; deprivation; early onset; experience; functional plasticity; hearing impairment; improved; in vivo; insight; myelination; neural circuit; neurophysiology; neurotransmission; new therapeutic target; novel; oligodendrocyte lineage; oligodendrocyte myelination; patch clamp; presynaptic; prevent; response; single-cell RNA sequencing; sound; therapeutically effective; transmission process; voltage; white matter

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.

项目摘要/摘要： 早期的听觉体验对于建立和重塑听觉大脑中的神经回路至关重要。亏损 先天性和早发性耳聋的外周声音输入在结构和功能上改变了中枢 即使使用助听器恢复了外围声音敏感性后，听觉回路也会受到影响。预防和扭转 周围听力缺陷后的中枢听觉功能障碍，了解可塑性如何影响中枢听觉功能障碍非常重要 听觉大脑在恢复的声音输入和中枢听觉处理之间建立新的联系 中心。我们之前的研究表明髓磷脂是解析听觉信号的重要特征 中枢听觉处理的极高时间精度。声音输入本身对于髓磷脂的发育至关重要 以及整个一生中听觉脑干回路的维护。然而，听觉的程度 经验调节的髓磷脂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。该提案的目标是确定 听觉体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理解人与人之间沟通的新概念 神经元和髓磷脂形成细胞、少突胶质细胞 (OL)，通过定义听觉脑干中 OL 的兴奋性。 OL 的一个新亚群表达谷氨酸受体、电压门控 Na+ (Nav) 和 Ca2+ 通道， OL 去极化、Na+ 电流介导的尖峰和 Ca2+ 动力学的基础。因此，这些 OL 处于理想状态 与电活性神经元进行交流，并通过增加髓鞘形成来进行奖励。根据这些数据， 我们假设声音诱发的活动增加可以增强电气和化学通讯 这类新型的可兴奋 OL 和神经元之间的关系，以调节 OL 发育并驱动适应性 髓鞘形成用于微调听觉脉冲的时间保真度。为了验证这个假设，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 Ca2+ 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 通讯和 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 兴奋性丧失如何影响适应性 髓鞘形成和听觉脑干电路（目标 3）。拟议的研究将提供新颖的机制见解 研究外周听觉信号如何通过神经元促进适应性髓鞘形成和神经可塑性 听觉脑中的少突胶质细胞通讯。阐明声音驱动的自适应机制 髓鞘形成对于理解大脑发育过程中的听觉可塑性以及发展 周围性听力缺陷或儿童听觉处理障碍的有效治疗策略 带有人工耳蜗。