Neuronal circuit modulation by myelination in the mammalian visual cortex

哺乳动物视觉皮层髓鞘形成对神经​​元回路的调节

• 批准号: 10632809
• 负责人: Wen Xin
• 金额: $ 10.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10632809
• 关键词: Address; Adhesions; Adolescence; Adult; Alzheimer' s Disease; Axon; Behavior; Cell physiology; Cells; Central Nervous System; Central Nervous System Diseases; Cognition; Data; Dendritic Spines; Development; Electrophysiology (science); Foundations; Functional disorder; Genetic; Goals; Individual; Injury; Interneurons; Knowledge; Learning; Link; Memory; Mental disorders; Methods; Mus; Myelin; Myelin Sheath; Nerve Degeneration; Nervous System Physiology; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Ocular Dominance; Oligodendroglia; Parvalbumins; Pathologic; Phase; Play; Population; Process; Property; Research; Role; Schizophrenia; Scientist; Sensory; Shapes; Silicon; Slice; Specificity; Structure; Study models; Synapses; Synaptic plasticity; Testing; Training; V1 neuron; Visual Cortex; Work; area striata; autism spectrum disorder; cell type; critical period; experience; experimental study; genetic approach; hippocampal pyramidal neuron; imaging study; improved; in vivo; in vivo two-photon imaging; life-long learning; monocular deprivation; mouse genetics; myelination; nervous system development; nervous system disorder; neural circuit; neural repair; neuronal circuitry; neuropathology; novel; oligodendrocyte lineage; orientation selectivity; postsynaptic; presynaptic; programs; serial imaging; symptomatic improvement; synaptic function; tool

PROJECT SUMMARY In the past decade, the field of myelination has undergone a conceptual revolution. Long considered a static structure, recent studies have revealed that myelination is continuously shaped by external experiences and plays essential roles in supporting learning and memory. A key question that emerges from these studies is how oligodendrocytes, and the myelin sheaths they produce, influence neuronal circuits to impact behavior. My long-term research goal is to determine how oligodendrocytes and myelin shape neuronal circuit function and plasticity during development, learning, and memory. This work will crucially advance our knowledge of the cellular processes underlying neural circuit maturation and lifelong plasticity, particularly considering the numerous recent studies identifying myelination deficits as a common pathological hallmark of neurodevelopmental and neurodegenerative disorders with cognitive symptoms, including autism spectrum disorders, schizophrenia, and Alzheimer’s disease. Given its well-characterized developmental windows for experience-induced neuronal plasticity and accessibility for in vivo readouts of neuronal activity, the mouse visual cortex presents an ideal model for studying the interaction between external experience, myelination, and neuronal plasticity. I will use novel genetic tools in combination with in vivo longitudinal two-photon imaging and in vivo/slice electrophysiology to 1) test the effects of disrupting developmental myelination on the maturation of functional neuronal properties and experience-induced plasticity, 2) determine the synaptic basis for circuit modulation by myelination, and 3) investigate the cell type-specific roles of myelination in circuit function by inhibiting myelination in specific populations of neurons. Results from these experiments will define the specific neuron-myelin interactions underlying neuronal circuit maturation and plasticity with unprecedented rigor and cell specificity, and provide a foundation for studying how these processes are perturbed in pathological contexts. Furthermore, completion of these aims will provide me with rigorous training in in vivo electrophysiology and analysis of large-scale electrophysiology data, which will be critical in the establishment of my independent research program focused on the role of myelination in neuronal circuit maturation and function, as well as how disruptions in myelination can lead to circuit dysfunction in neurodevelopmental and psychiatric disorders.

项目摘要 在过去的十年中，髓鞘形成领域经历了一场概念革命。长期以来被认为是 静态结构，最近的研究表明，髓鞘是不断塑造外部经验 并在支持学习和记忆中发挥重要作用。这些研究中出现的一个关键问题是 少突胶质细胞和它们产生的髓鞘是如何影响神经回路从而影响行为的。我 长期的研究目标是确定少突胶质细胞和髓鞘如何塑造神经元回路功能， 在发育、学习和记忆过程中的可塑性。这项工作将极大地促进我们对 神经回路成熟和终身可塑性的细胞过程，特别是考虑到 许多最近的研究确定髓鞘形成缺陷是一个共同的病理标志， 具有认知症状的神经发育和神经退行性疾病，包括自闭症谱系 精神分裂症和阿尔茨海默病。鉴于其良好的发展窗口， 经验诱导的神经元可塑性和体内神经元活动读数的可及性，小鼠视觉 皮层为研究外部经验、髓鞘形成和神经元之间的相互作用提供了一个理想的模型。 神经可塑性我将使用新的遗传工具结合体内纵向双光子成像， 体内/切片电生理学以1）测试破坏发育性髓鞘形成对 神经元的功能特性和经验诱导的可塑性，2）决定了回路的突触基础 髓鞘形成的调节，和3）研究髓鞘形成在回路功能中的细胞类型特异性作用， 抑制特定神经元群体的髓鞘形成。这些实验的结果将确定具体的 神经元-髓鞘相互作用是神经元回路成熟和可塑性的基础，具有前所未有的严格性， 细胞特异性，并为研究这些过程在病理环境中如何受到干扰提供了基础。 此外，完成这些目标将为我提供严格的体内电生理学培训， 大规模电生理数据的分析，这将是建立我的独立的关键 一项研究计划集中在髓鞘形成在神经元回路成熟和功能中的作用，以及如何 髓鞘形成的破坏可导致神经发育和精神障碍中的回路功能障碍。