Oligodendroglial Interactions Group

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

The capacity of oligodendrocytes to effect changes in brain function is primarily due to the significant increase in impulse propagation speed and efficiency that occurs when axons are myelinated. Myelination in most white matter tracts is selective, appearing only in a subpopulation of axons, and the structure of individual myelin internodes significantly influences action potential propagation. However, the mechanisms regulating which axons or axonal domains become myelinated, and the functional connectivity between neurons and oligodendrocytes, remain poorly understood. Beyond ligand/receptor-mediated interactions, neuronal activity plays a crucial role in determining which axons become myelinated. ATP release from excited axons stimulates the differentiation of oligodendrocyte progenitor cells (OPCs) via purinergic receptors and indirectly by prompting astrocytes to release the cytokine leukemia inhibitory factor, promoting OPC differentiation. Unmyelinated axons also form synapses with OPCs, and vesicular release of the neurotransmitter glutamate binds to AMPA receptors on OPCs to stimulate myelination. Blocking electrical activity during developmental myelination impairs OPC proliferation and the final stages of oligodendrocyte differentiation. Additionally, studies have shown that increasing the activity of certain axons results in their selective myelination, while decreasing activity reduces myelination. These findings suggest that activity-dependent myelination plays a vital role in defining the repertoire of myelinated and unmyelinated axons generated during development and ongoing plasticity. However, there is still much to learn about how populations of axons that require synchronous activity are myelinated to ensure that signals are received at their post-synaptic targets with appropriate isochronicity. The Oligodendroglial Interactions Group is developing approaches to link structural relationships between neurons and glia to functional outcomes in specific neural networks. Our research utilizes existing and novel transgenic tools to manipulate and record the functional interplay between oligodendroglia and axonal targets. We aim to assess the extent to which oligodendrocytes communicate with each other in executing the myelination of a common set of axons and test the hypothesis that activity-dependent changes in myelin morphology tune axonal properties through persistent bidirectional signaling between oligodendrocytes and their target axons. Another critical area of interest for our group is understanding the cellular and molecular mechanisms orchestrating myelin repair after a demyelinating injury. Demyelination is a common pathological consequence of several neurodegenerative and neurological conditions, including multiple sclerosis, a disease with significant psychological tolls. Previous research has shown that, in addition to OPCs, neural precursor cells (NPCs) from the ventricular-subventricular zone (V-SVZ) also contribute to remyelination following cuprizone-mediated demyelination of the corpus callosum in mice. Our group is developing approaches to probe the relative importance of OPCs and NPCs in the regenerative process, given that these two populations of progenitor cells regenerate myelin with distinct structural differences. They revealed that while OPCs regenerate thin myelin sheaths during remyelination, NPCs regenerate significantly thicker myelin, resembling normal healthy myelin. To explore the functional differences between myelin regenerated from NPCs versus OPCs, our group is developing tools to genetically ablate OPCs from the adult CNS to examine remyelination mediated by NPCs in the absence of OPCs. Existing methods to ablate OPCs in the rodent CNS have been limited in the extent and duration of OPC depletion. Our recent work has demonstrated the development of a pharmacogenetic approach for conditional OPC ablation, eliminating over 98% of OPCs throughout the brain. By combining recombinase-based transgenic and viral strategies for targeting OPCs and V-SVZ-derived NPCs, we found that new PDGFRA-expressing cells born in the V-SVZ repopulated the OPC-deficient brain starting 12 days after OPC ablation. Our data reveal that OPC depletion induces V-SVZ-derived NPCs to generate vast numbers of PDGFRA+/NG2+ cells capable of proliferating and migrating extensively throughout the dorsal anterior forebrain. Further application of this approach to ablate OPCs will advance our knowledge of the functions of both OPCs and oligodendrogenic NPCs in health and disease.