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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要在过去的十年中，髓鞘形成领域经历了一场长期被认为是概念的革命。静态结构，最近的研究表明髓鞘形成不断受到外部经验的影响这些研究中出现的一个关键问题是：少突胶质细胞及其产生的髓鞘如何影响神经回路从而影响行为。长期研究目标是确定少突胶质细胞和髓磷脂如何塑造神经元回路功能和这项工作将至关重要地增进我们对发育、学习和记忆过程的可塑性的了解。神经回路成熟和终生可塑性的细胞过程，特别是考虑到最近的许多研究将髓鞘形成缺陷视为常见的病理标志具有认知症状的神经发育和神经退行性疾病，包括自闭症谱系鉴于其明确的发育窗口，因此可能会导致疾病、精神分裂症和阿尔茨海默病。经验诱导的神经元可塑性和神经元活动体内读数的可及性，小鼠视觉皮质为研究外部经验、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。我将结合体内纵向双光子成像和神经元可塑性使用新颖的遗传工具。体内/切片电生理学 1) 测试破坏发育髓鞘形成对成熟的影响功能性神经特性和经验诱发的可塑性，2）确定电路的突触基础通过髓鞘形成进行调节，3）通过以下方式研究髓鞘形成在电路功能中的细胞类型特异性作用抑制特定神经元群中的髓鞘形成，这些实验的结果将定义特定的神经元。神经元-髓磷脂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和细胞特异性，并为研究这些过程在病理环境中如何受到干扰提供基础。此外，完成这些目标将为我提供体内电生理学和分析大规模电生理学数据，这对于建立我的独立性至关重要研究计划的重点是髓鞘形成在神经回路成熟和功能中的作用，以及如何髓鞘形成的破坏可能导致神经发育和精神疾病的回路功能障碍。