The role of microglia in developmental myelination

The National Institute of Neurological Disorders and Stroke awarded $152,300 to The Regents of The University of Colorado (University of Colorado-Denver) on May 1, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to conduct research on the role of microglia in developmental myelination.

The research investigates how microglial cells target and remove myelin sheaths during normal brain development to refine the amount and placement of myelin on specific neural circuits. The project addresses the molecular mechanisms governing microglial regulation of myelin, the specificity and plasticity of developmental myelination, and whether dysregulated microglia activity contributes to neurodegenerative diseases. The work employs in vivo imaging and investigates how neuronal activity influences oligodendrocyte differentiation, axon selection for myelination, and myelin coverage patterns.

Performance is located in Aurora, Colorado. The period of performance runs from May 1, 2026, to June 30, 2028. The funding is classified as a Project Grant, an assistance type supporting discrete, time-limited research projects under peer review.

Abstract

Myelin facilitates rapid and efficient conduction of action potentials and promotes the long-term health of axons. The absence or loss of myelin consequently has tremendous effects on nervous system function as seen in neurodegenerative diseases. Notably, myelin pathology and microglia activation often are coupled in neurological diseases. Knowing how microglia activation alters myelin and how this affects brain development and function would significantly improve our understanding of human health. A major unanswered question is how specific amounts of myelin are targeted only to select axons in development. Myelination is highly selective and plastic; not all axons are myelinated. Neuronal activity can influence oligodendrocyte differentiation, the probability of axon selection for myelination, the number, length and thickness of myelin internodes produced by oligodendrocytes and the total myelin coverage on axons. Furthermore, under normal circumstances, myelin forms mostly on axons of the dorsal and ventral tracks of the spinal cord, with very little myelination occurring in the axons of the region in between. What mechanisms account for this remarkable specificity and plasticity? In vivo imaging studies using zebrafish revealed that a substantial number of nascent myelin sheaths are removed from axons, raising the possibility that selective myelin sheath removal contributes to plasticity and target specificity. Microglia remove myelin in disease and injury. Recent work by our lab uncovered they also remove myelin in normal development to refine the amount and placement of myelin on specific neural circuits, but the molecular cues and mechanisms for microglial regulation of myelin are still unknown. How do microglia target myelin for phagocytosis and can dysregulated microglia activity contribute to neurodegenerative diseases? Developmental myelination is a dynamic process engaging precise multicellular interactions, but most experimental models do not permit direct and simultaneous observation of oligodendrocytes, their myelinating targets and microglia in living animals. Thus, we do not know how microglia engage with myelin as IT forms. Consequently, we lack insight to how microglia selectively remove myelin under non-pathological conditions. By establishing methods for imaging oligodendrocytes, microglia and axons in living zebrafish, we have created powerful assays to test the mechanistic basis of myelin refinement. By harnessing genetic, and pharmacogenetic tools, we have the ability to precisely test hypotheses aimed at uncovering the mechanisms that mediate myelin surveillance and refinement by microglia. Altogether, we now have the conceptual framework, experimental tools and expertise to significantly advance our understanding of developmental myelination. Our experimental plan is designed to investigate the mechanistic basis of myelin refinement in development, with a particular focus on how microglia contribute to myelin plasticity and myelin integrity.