Developing a cell-on-chip platform to study oligodendrocyte-neuron interactions in plasticity and neurodegeneration

项目总结/摘要 髓鞘加速动作电位沿沿着轴突的传导，赋予髓鞘调节动作的能力 潜在的定时和电路功能。生成新的髓鞘是学习和记忆形成所必需的， 这一过程被称为活性依赖性髓鞘形成。尽管髓鞘有更新的能力， 随着年龄的增长，神经退行性疾病，包括阿尔茨海默病（AD）加剧。损失 髓鞘可能直接导致与年龄相关的认知能力下降，因为有证据表明， 在临床前小鼠模型的老化和AD改善记忆和认知。神经元活动是如何 调节髓鞘的形成，以及这些动力学在神经退行性变中是如何改变的？目前， 对活性依赖性髓鞘形成的研究仅限于少数神经元细胞类型， 使用光遗传学或膜片钳电生理学的刺激范例。这些发现集中在 活跃的轴突有髓鞘的一般原理。然而，根本问题仍然是如何 髓鞘形成模式-通过鞘长度和数量的变化沿沿着轴突-坐标网络 同步和促进高级大脑过程（如学习和记忆）中回路功能 阵重要的是，在神经退行性变的背景下，髓鞘形成模式是如何改变的， 不清楚我们建议开发一个模块化的系统来研究高密度的活动依赖性髓鞘形成。 使用少突胶质细胞-神经元共培养物的多电极阵列芯片 刺激，ii）记录细胞外活性，和iii）用细胞分辨率对髓鞘形态成像。 开发这个系统将使我们能够确定诱发的神经元活动如何调节轴突鞘， 鞘管长度和/或鞘管编号（Aim 1）。这种可编程的，时空控制的诱发活动将 解锁系统地改变电压刺激的时间和幅度的方法， 增强或抑制髓鞘形成的活动模式。此外，该系统还将适用于研究人类 诱导多能干细胞衍生的神经元和少突胶质细胞共培养，使我们能够确定如何 神经元活性和髓鞘形成在神经变性疾病模型中改变（目的2）。我们将分享 记录的神经元活动和MEA芯片上相应的髓鞘-轴突图， 资料库，提供一个开放获取的资源，用于查明时间和活动相关的参数， 研究不同神经元细胞类型的髓鞘形成和神经变性的背景。我们一起， 拟议的研究将建立一个模块化平台，以询问活动依赖性髓鞘形成如何影响不同的神经元， 神经元回路，揭示了神经退行性疾病的选择性脆弱性以及总体 神经可塑性的原理

PROJECT SUMMARY/ABSTRACT Myelin sheaths accelerate action potential conduction along axons, conferring myelin the ability to tune action potential timing and circuit function. Generating new myelin is necessary for learning and memory formation, a process known as activity-dependent myelination. Despite its capacity for renewal, myelin gradually reduces with age, which is exacerbated by neurodegenerative disorders including Alzheimer’s disease (AD). Loss of myelin may directly contribute to age-related cognitive decline, given the evidence that enhancing myelination in preclinical mouse models of aging and AD improves memory and cognition. How does neuronal activity regulate myelin sheath formation, and how are these dynamics altered in neurodegeneration? Thus far, current studies on activity-dependent myelination have been limited to a handful of neuronal cell types and few stimulation paradigms using optogenetics or patch-clamp electrophysiology. These findings converge on the general principle that active axons get myelinated. However, fundamental questions remain on how myelination patterns—through variations in sheath length and number along axons—coordinate network synchrony and promote circuit function in higher-order brain processes such as learning and memory formation. Importantly, how myelination patterns may be altered in the context of neurodegeneration remains unclear. We propose to develop a modular system to study activity-dependent myelination on a high-density multielectrode array chip using oligodendrocyte-neuron co-cultures that enable i) fine-tuning of neuronal stimulation, ii) recording of extracellular activity, and iii) imaging of myelin morphology with cellular resolution. Developing this system will allow us to determine how evoked neuronal activity modulates axon ensheathment, sheath length, and/or sheath number (Aim 1). This programmable, spatiotemporal control of evoked activity will unlock the means to systematically vary the timing and amplitude of voltage stimulation and elucidate neuronal activity patterns that enhance or inhibit myelination. Moreover, this system will also be adapted to study human induced pluripotent stem cell-derived neuron and oligodendrocyte co-cultures to enable us to determine how neuronal activity and myelination are altered in models of neurodegenerative disease (Aim 2). We will share the recorded neuronal activity and corresponding myelin-axon maps on MEA chips on publicly accessible repositories, providing an open-access resource for pinpointing temporal and activity-dependent parameters to study myelination of different neuronal cell types and in the context of neurodegeneration. Together, our proposed studies will establish a modular platform to ask how activity-dependent myelination affects different neuronal circuits, revealing insight into selective vulnerabilities in neurodegeneration as well as overarching principles in neuroplasticity.