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，髓鞘形成领域发生了概念革命。长期认为 静态结构，最近的研究表明，髓鞘形成不断地由外部经验塑造 并在支持学习和记忆中扮演重要角色。这些研究中出现的一个关键问题是 它们产生的少突胶质细胞和髓鞘如何影响神经元电路影响行为。我的 长期研究目标是确定少突胶质细胞和髓鞘如何形成神经元电路功能和 在开发，学习和记忆中的可塑性。这项工作将彻底提高我们对 神经回路成熟和终生可塑性的蜂窝过程，特别是考虑到 鉴定髓鞘化的许多最近的研究将其定义为 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 疾病，精神分裂症和阿尔茨海默氏病。鉴于其特色的开发窗口 经验诱导的神经元可及性和可访问性，可用于神经元活动的体内读数，鼠标视觉 皮质提出了研究外部经验，髓鞘化和 神经元可塑性。我将使用新型的遗传工具与体内纵向二光子成像和 体内/切片电生理学至1）测试破坏发育性髓鞘化对成熟的影响 功能性神经元特性和经验诱导的可塑性，2）确定电路的突触基础 通过髓鞘形成调节，3）研究通过 抑制特定神经元群体的髓鞘形成。这些实验的结果将定义特定 神经蛋白相互作用的神经元电路成熟和可塑性，并具有前所未有的严格性和 细胞特异性，并为研究这些过程在病理环境中如何干扰提供了基础。 此外，这些目标的完成将为我提供体内电生理学和 大规模电生理数据的分析，这对于建立我的独立 研究计划的重点是髓鞘化在神经元电路成熟和功能中的作用，以及如何 髓鞘中的破坏会导致神经发育和精神疾病的电路功能障碍。