Glial mechanisms governing the removal and repair of degenerating myelin

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PROJECT SUMMARY Myelin has evolved to speed up, finely tune, and increase the metabolic efficiency of electrical signal transmission in the brain. In numerous human diseases however, myelin degenerates, ultimately resulting in devastating motor and cognitive impairment. Importantly, in order for tissue repair to proceed after myelin damage has occurred, the many layers of compacted cell membrane that constitute the myelin sheath must be rapidly and efficiently removed by resident phagocytic cells in the brain. Defective removal of these debris has been implicated in a number of degenerative conditions, including but not limited to, multiple sclerosis and aging, yet we know little about the cellular dynamics and molecular mechanisms governing these processes. In order to study these critical cellular events and answer questions centered on which cell populations are involved and what roles these different cell types play, we have developed advanced techniques for imaging and manipulating these discrete events in the live animal over a wide range of temporal scales from seconds to months. These techniques include intravital imaging of new combinations of fluorophore-based multicolor transgenic labels of distinct populations of neurons and glia together with label-free imaging modalities specific for compact myelin. In addition to these powerful labeling and optical imaging strategies, we have also developed a new technique for targeted induction of single-cell death, which we have recently established as a model of on-demand and titratable demyelination in the mouse cortical gray matter. Combining these techniques now allows dynamic investigation of demyelination and remyelination in the context of targeted genetic manipulations and animal models of human disease. Using these powerful tools this project will investigate three central aims. First, there is increasing evidence that in addition to microglia, the primary phagocytes of the brain, other resident glial cell types, namely astrocytes and NG2 glia, are also involved and play important roles in the phagocytosis and repair process. We will determine the precise contribution of each glial cell type in the dynamic detection and clearance of degenerating myelin debris. Next, we and others have shown the importance of phosphatidylserine receptors in the efficient detection and clearance of dying neurons and other cells in different organs. We will determine the role and consequences of both defective phagocytic receptors and debris digestion signaling on the dynamic response by NG2 glia to cortical demyelination and the resulting remyelination success and myelin patterning. Finally, there is evidence that neuronal activity and/or sensory experience can modify remyelination, but less is known about the roles of neuronal activity on phagocytic function in the context of demyelination. We will determine the consequences of bidirectional neuronal activity changes on the response by phagocytic cells to single-cell demyelination. Ultimately, these studies will reveal which cells are involved in myelin debris clearance, the role of major cell debris recognition pathways in successful clearance and repair, and how neuronal activity and sensory experience modify the response of phagocytic glia to a demyelinating event.