Circadian mechanisms of myelination

髓鞘--包裹轴突的结构--对于有效的电信号转导和代谢是不可或缺的 神经元的支持。髓鞘缺陷通常在一系列大脑疾病中被发现--从 神经发育到神经退行性变-暗示髓鞘障碍是一种突出的，但往往被低估的， 是许多神经疾病的特征。类似的髓鞘缺乏会导致注意力、记忆力、学习能力下降， 临床前模型中的社会行为和运动功能。为了最终了解这些疾病的髓鞘形成是如何失败的 对于脑部疾病，我们首先要全面了解其扩散和扩散的机制 髓鞘形成前体细胞的维持。出生前和出生后的发育性髓鞘形成 成年期神经元活性依赖的适应性髓鞘形成均依赖于少突胶质前体细胞 (OPC)及其后代，形成髓鞘的少突胶质细胞。仍有一种尚未得到满足的需求来界定这些机制 在这两种类型的髓鞘形成过程中调节OPC动态，并揭示它们在定义和提纯中的作用 发育和疾病中的回路和行为。OPC是大脑中最丰富的有丝分裂细胞，有70- 在给定的时间内，所有分裂细胞的90%是OPC。根据已发表的研究表明，昼夜节律(~24小时) 系统--由主要的昼夜节律分子调节器BMal1驱动--调节许多神经细胞的增殖 前体细胞和干细胞群体以及我们的初步数据证实了BMal1在OPC动力学中的必要性， 我们的目标是研究昼夜节律系统如何调节OPC和随后的髓鞘形成。除了……之外 像BMAL1这样的生物钟基因的髓鞘功能障碍、昼夜相移和多态一直是 记录在患有自闭症、注意力缺陷/多动障碍、多发性硬化症和阿尔茨海默氏症的患者中 疾病，将昼夜节律机制的紊乱与这些疾病的病理生理学联系起来。我们假设昼夜节律 在发育过程中破坏髓鞘形成细胞将为一系列脑部疾病奠定基础。 在这项建议中，我们的目标是提高目前对髓鞘形成的生物学理解。拟议的工作将 研究昼夜节律系统如何通过1)发育两个不同的BUT 以BMal1为靶点的免费遗传小鼠模型在OPC中被击倒以探测发育髓鞘形成2) 环境时间干扰性慢性时差(CJL)模型在发育髓鞘形成中的应用 神经元活动诱导的适应性髓鞘形成的昼夜变化。我们的初步数据证实了基因敲击 在胚胎和出生后发育过程中，OPC中由BMal1驱动的生物钟下调导致 减少1)OPC密度，2)OPC增殖，3)髓鞘形成，4)髓鞘相关行为。一个 全面了解昼夜节律调节与OPC维持和髓鞘形成之间的相互作用 不仅将为大脑健康的机制提供信息，还将建立对潜在治疗策略的见解 针对许多脑部疾病的髓鞘特定的昼夜节律调节过程。

Myelin—the structure that encapsulates axons—is integral to efficient transduction of electrical signals and metabolic support of neurons. Myelin deficits have been commonly identified in a wide range of brain disorders—from neurodevelopmental to neurodegenerative—implicating dysmyelination as a prominent, but often underappreciated, feature of many neurological disorders. Similar myelin deficiencies cause decrements in attention, memory, learning, social behaviors, and motor function in preclinical models. To ultimately understand how myelination fails in these brain disorders, we first must have a comprehensive understanding of the mechanisms driving the proliferation and maintenance of myelin-forming precursor cells. Developmental myelination during pre- and post-natal life and neuronal activity-dependent adaptive myelination in adulthood both depend on oligodendrocyte precursor cells (OPCs) and their progeny, myelin-forming oligodendrocytes. There remains an unmet need to define the mechanisms mediating OPC dynamics during these two types of myelination and to reveal their roles in defining and refining circuits and behavior in development and disease. The OPC is the most abundantly mitotic cell in the brain with 70- 90% of all dividing cells at a given time being OPCs. Based on published work showing that the circadian (~24 hour) system—driven by the principal circadian molecular regulator Bmal1—regulates cell proliferation of numerous neural precursor and stem cell populations and our preliminary data confirming the necessity of Bmal1 in OPC dynamics, we aim to investigate how the circadian system regulates OPCs and consequent myelination. In addition to dysmyelination, circadian phase-shifts and polymorphisms in circadian clock genes like BMAL1 have been documented in individuals with autism, attention deficit/hyperactivity disorder, multiple sclerosis, and Alzheimer’s disease, linking disruptions in circadian machinery with pathophysiology in these disorders. We posit that circadian disruption of myelin-forming cells during development will lay the foundation for a broad range of brain pathologies. In this proposal, we aim to elevate the current biological understanding of myelination. The proposed work will investigate how the circadian system regulates myelination through 1) the development of two distinct but complimentary genetic mouse models targeting Bmal1 knock down in OPCs to probe developmental myelination 2) application of the environmental chronodisruptive chronic jet lag (CJL) model to developmental myelination, and 3) diurnal changes in neuronal activity-induced adaptive myelination. Our preliminary data establish that genetic knock down of the Bmal1-driven circadian clock in OPCs during embryonic and post-natal development results in a reduction in 1) OPC density, 2) OPC proliferation, 3) myelination, and 4) myelin-associated behaviors. A comprehensive understanding of the interplay between circadian modulation and OPC maintenance and myelination will not only inform on mechanisms of brain health but will also establish insights into potential therapeutic strategies targeting myelin-specific circadian regulatory processes in numerous brain disorders.