Author ORCID Identifier
https://orcid.org/0000-0003-0080-0342
Date of Award
Spring 5-2-2024
Document Type
Thesis (Ph.D.)
Department or Program
Integrative Neuroscience
First Advisor
Robert A. Hill
Abstract
Myelin is a complex multilamellar structure, generated by oligodendrocytes, that ensheaths axons and is a vital component for neural processing. Degeneration of both oligodendrocytes and their myelin sheaths is a common pathological feature associated with aging and neurodegenerative diseases. Efficient removal of the cellular and myelin debris is crucial for remyelination and prevention of further degeneration. Microglia, the primary phagocytes of the CNS, are thought to play a key role in this process. To investigate the cellular dynamics underlying microglia-mediated clearance of degenerating oligodendrocytes and myelin sheaths, at the single cell level, we developed a novel model for inducible cortical demyelination called oligodendrocyte 2Phatal. This model activates a non-inflammatory stereotyped degeneration cascade, leading to remyelination by local oligodendrocyte precursor cells. Using this model of single-cell demyelination, I observed microglia engaging with both the targeted oligodendrocyte and its myelin sheaths followed by a stereotyped and efficient removal of both. Following the removal of the myelin sheath, I observed rapid remyelination, suggesting that efficient clearance of the myelin debris plays a vital role in successful remyelination. Deletion of the fractalkine receptor, CX3CR1, delayed microglia engagement with the targeted oligodendrocyte but did not affect the clearance of myelin sheaths. Surprisingly, the deletion of the phosphatidylserine receptor, MERTK, had no impact on the clearance of either the targeted oligodendrocyte or the myelin sheaths. These new findings reveal the underlying cellular dynamics involved in myelin debris clearance and repair and highlight the role of CX3CR1 signaling in the efficient removal of dying oligodendrocytes.
Original Citation
Chapman, T.W., Olveda, G.E., Bame, X. et al. Oligodendrocyte death initiates synchronous remyelination to restore cortical myelin patterns in mice. Nat Neurosci 26, 555–569 (2023). https://doi.org/10.1038/s41593-023-01271-1
Olveda, G. E., Barasa, M. N. & Hill, R. A. Microglial phagocytosis of single dying oligodendrocytes is mediated by CX3CR1 but not MERTK. bioRxiv (2023). https://doi.org/10.1101/2023.12.11.570620
Recommended Citation
Olveda, Genaro E., "Microglial Dynamics and Mechanisms Underlying the Phagocytosis of Dying Oligodendrocytes" (2024). Dartmouth College Ph.D Dissertations. 239.
https://digitalcommons.dartmouth.edu/dissertations/239