Cellular and circuit effects of genetic ablation of adult-born oligodendrocytes

About This Grant

PROJECT SUMMARY Oligodendrocytes (OLs), glial cells in the central nervous system, critically contribute to neuronal conduction and health. OLs wrap axons in insulating myelin sheaths – increasing conduction speed – and shuttle metabolites to the local axon to provide necessary energetic support. OLs generate throughout life, deriving from a dedicated pool of OL progenitor cells (OPCs) that tile the brain. Oligodendrogenesis, or the differentiation of OLs from OPCs, is modulated in adulthood by neuronal activity; new OLs and myelin form at increased rates on circuits activated by artificial stimulation or learning and memory tasks. This activity-dependent oligodendrogenesis is consequential for circuit function; across a variety of paradigms, the irreversible genetic blockade of oligodendrogenesis prior to learning results in significantly impaired behavioral performance. Furthering our understanding of the roles adult-born OLs play on neuronal circuits will greatly expand our understanding of neural-glial interactions and assist in determining the extent of functional benefits potentially garnered by therapeutics that induce oligodendrogenesis. This study investigates the cellular biology and circuit interactions of adult-born OLs, using a novel knock-in mouse line enabling the selective labeling and delayed ablation of new OLs generated after a designated time. We first propose to use in vivo two-photon imaging through cranial windows to track and visualize the generation, loss, and replacement dynamics of OLs and myelin in this model, determining the timeline of events occurring after ablation is induced and whether OLs demonstrate cellular age- related resistance to ablation. Data acquired in this aim will provide interesting insight into the cellular and subcellular changes adult-born OLs undergo in response to ablation. To elucidate the functional contribution of activity-generated OLs on neuronal circuitry, we will use a contextual fear conditioning paradigm to induce oligodendrogenesis. Rather than blocking the generation of new OLs after learning, a common model in the field, we will permit OLs to generate and integrate onto neuronal circuitry before ablation and use post-ablation freezing behavior to determine whether the sustained integration of OLs is required for fear memory. The data and knowledge gathered from successful completion of these aims will provide valuable insight into the cellular and circuit dynamics of adult-born OLs.