Myelin remodeling in vivo: A longitudinal study of targeted myelination and neuronal control of sparse myelination in mouse cortex

• Applicant: Dr. Nicolas Snaidero, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 426715780

In this proposal, I will explore the principles and mechanisms underlying the discontinuous myelin pattern found in the mammalian cortex and the resilience of this pattern upon demyelination. I will also investigate the role of neuronal identity and activity in the establishment, resilience and plasticity of cortical myelin patterns. Recent discoveries of discontinuous myelin patterns along axons of excitatory and inhibitory cortical neurons, as well as of myelin remodelling during circuit plasticity, have established cortical myelin and its remodelling as a potential regulator of neuronal circuit function. Cortical oligodendrocyte loss and hence demyelination occurs physiologically with age but also in several brain diseases. Hence, the efficiency and quality of remyelination is critical for maintaining axonal and circuit function. Still, the principles and mechanisms of establishing and maintaining cortical myelin patterns are not understood. Similarly, the neuronal cell type and functional axonal cues that determine proper functional myelination and remyelination by guiding local oligodendrocyte precursor cell (OPC) differentiation and axon targeting in the cortex remain elusive. To address these fundamental questions, I now want to explore: 1) whether cortical myelination is a targeted or random process; 2) the effects of axonal signatures on cortical myelination patterns and the efficiency of remyelination; 3) the role of neuronal activity on cortical myelination selectivity, morphological plasticity and remyelination efficiency. For this, I will take advantage of my expertise in longitudinal two-photon imaging, virus- and transgene-based labelling and manipulations, correlated ultrastructural analysis and a newly developed 2-photon laser ablation-based cortical demyelination model. Together these tools allow me to address the points raised above with unique single-cell precision by following cortical de- and remyelination over time. Given the physiological and pathological significance of cortical myelination that is only fully emerging, but already makes cortical myelin a central topic in understanding the cognitive sequels of MS and related cortical myelinopathies. Thus the knowledge that will result from the proposed study will have profound basic and biomedical implications.

• DFG Programme: Research Grants