Neuronal circuit modulation by myelination in the mammalian visual cortex

项目总结 在过去的十年里，髓鞘形成领域经历了一场概念革命。长期以来一直被认为是 静态结构，最近的研究表明髓鞘形成是由外部经验持续塑造的 在支持学习和记忆方面起着至关重要的作用。从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元回路，从而影响行为。我的 长期的研究目标是确定少突胶质细胞和髓鞘如何形成神经元回路功能和 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 最近的大量研究发现，髓鞘形成缺陷是骨髓瘤的共同病理特征 有认知症状的神经发育和神经退行性疾病，包括自闭症 精神障碍、精神分裂症和阿尔茨海默氏症。鉴于其具有良好特征的发展窗口 经验诱导的神经元可塑性和可获得性用于体内神经元活动的读数，小鼠视觉 大脑皮层为研究外部经验、髓鞘形成和 神经元的可塑性。我将使用新的基因工具结合体内纵向双光子成像和 体内/切片电生理学：1)检测髓鞘发育受阻对胚胎成熟度的影响 功能神经元的特性和经验诱导的可塑性，2)决定回路的突触基础 髓鞘形成的调节，以及3)研究细胞类型特定的髓鞘形成在电路功能中的作用 抑制特定神经元群体的髓鞘形成。这些实验的结果将定义具体的 神经元-髓鞘相互作用以前所未有的严密性和可塑性支持神经元回路成熟和可塑性 细胞特异性，并为研究这些过程如何在病理背景下受到干扰提供了基础。 此外，这些目标的完成将为我提供体内电生理学和 分析大规模的电生理数据，这将是我独立建立的关键 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 髓鞘形成障碍可导致神经发育和精神障碍中的回路功能障碍。

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.