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

开发芯片上细胞平台来研究可塑性和神经变性中少突胶质细胞-神经元的相互作用

• 批准号: 10753372
• 负责人: Birgitt Schuele
• 金额: $ 42.86万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753372
• 关键词: Acceleration; Action Potentials; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Axon; Biology; Brain; Buffers; Cells; Central Nervous System; Coculture Techniques; Cognition; Disease; Disease Progression; Disease model; Electric Stimulation; Electrophysiology (science); Exhibits; Fluorescent Dyes; Human; Image; Impaired cognition; Impairment; Individual; Induced pluripotent stem cell derived neurons; Laboratories; Learning; Length; Maps; Measures; Mediating; Memory; Memory impairment; Modeling; Morphology; Myelin; Myelin Sheath; Nerve Degeneration; Neural Conduction; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Oligodendroglia; Pattern; Process; Rattus; Reporter; Resolution; Resources; Retinal Ganglion Cells; System; Technology; Time; Transgenic Organisms; Variant; Visualization; age related; cell type; density; extracellular; improved; induced pluripotent stem cell; innovation; insight; live cell imaging; mouse model; multi-electrode arrays; multimodality; myelination; neural circuit; neuronal circuitry; neuronal excitability; optogenetics; patch clamp; pre-clinical; public repository; resilience; response; risk variant; spatiotemporal; synaptic inhibition; tool; vesicular release; voltage

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.

项目总结/文摘