In vivo three-photon microscopy of the cortical gray and white matter

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PROJECT SUMMARY Multiple Sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system that afflicts nearly 1 million people in the United States alone. While MS is classically regarded as a white matter disease, gray matter lesion load may exceed that of the white matter in patients with MS. The pathological features of lesions differ between gray and white matter lesions. Interestingly, in lesions that span white and gray matter regions, display pathological hallmarks of white matter-only lesions, suggesting that cellular environments distinctly regulate oligodendrocyte loss and regeneration. Furthermore, attempts at remyelination are more frequent in cortical versus white matter lesions regardless of patient age or disease duration. These findings suggest that remyelination of gray matter regions may be specifically limited by decreased functional integration of new oligodendrocytes compared to white matter regions. Understanding the regional differences in oligodendrocyte loss and regeneration represents a clear unmet need in the MS research community. A major limitation to understanding these regional differences is the inability to monitor the dynamics of oligodendrocytes in white matter in the living brain. To overcome this obstacle, we will use new optical methodologies to determine regional variability in oligodendrocyte cell behavior. We propose to use the superior penetration depth of three- photon excitation fluorescence and longitudinal in vivo imaging to determine the effects of circuit-specific neuronal activity and demyelinating injury on oligodendrocyte lineage cells in both superficial and deep areas of the adult brain. The objectives of this proposal are: 1) evaluate how behaviorally-relevant neuronal activity regulates gray and white matter oligodendrogenesis, 2) to elucidate whether behavioral interventions can equally promote oligodendrocyte regeneration of the gray and white matter. The overall hypothesis of this proposal is region-specific rates of oligodendrocyte precursor differentiation and integration govern the proportion of myelination in healthy, adaptive, and regenerative contexts. This proposal represents a novel synthesis of cutting-edge approaches in optical physics and oligodendrocyte biology, and breaks new ground in understanding the mechanisms underlying the regulation of gray and white matter oligodendrocyte plasticity and regeneration.