Circadian mechanisms of myelination

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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.