OPPOSING ROLES FOR MICROGLIA IN THE YOUNG AND AGED NEUROGENIC NICHE

Neural stem cell/progenitors cells give rise to mature neurons, astrocytes and oligodendrocytesthroughout life. However, neurogenesis rapidly declines during aging and the mechanism forage-dependent neural stem cell dysfunction is not clear. The ventricular-subventricular zone (V-SVZ), lining the lateral ventricle, is home to the largest pool of neural stem cells in the murinebrain. We have found that microglia, the innate immune cells of the brain, are prominentlypositioned throughout the young and aged V-SVZ niche. During aging, microglia undergo amorphological and phenotypical shift from a resting state to a pro-inflammatory state.Preliminary data suggest that secreted molecules from young microglia support proliferation andneuronal differentiation in vitro. In contrast, microglia isolated from aged mice appear to losethis influence on proliferation in vitro. Together, these data suggest microglia play a critical age-dependent role in regulating neurogenesis. Although microglia are known to be important inphagocytosis of neuroblasts, their influence on type B neural stem cells, type C transitamplifying cells and niche cytoarchitecture is essentially unknown. Using 3-dimensional imageanalysis of niche cytoarchitecture and flow activated cell sorting (FACS), we will test thehypothesis that microglia have opposing roles in the young and aged neurogenic niche.In aim 1, we will pharmacologically and genetically deplete microglia from the young neurogenicniche and interrogate the impact on neurogenesis, Type B, C and neuroblast cell survival aswell as number, proliferation and position near the vascular compartment. In aim 2, we will useheterochronic infusion of secreted molecules from young and aged microglia to directly test ifthese molecules have opposing roles in neurogenesis. In aim 3, we will test if mitigating theinflammatory phenotype of aged microglia restores neural stem/progenitor cell function. We willalso explore novel molecular candidates for microglia derived secreted molecules that supportor hinder neurogenesis. Understanding how the microglia activation state regulatesneurogenesis will have far-reaching consequences. It is widely accepted that V-SVZ neuralstem cells and their progeny contribute to brain repair. Thus, understanding how microgliacontribute to neurogenesis during tissue homeostasis and aging will not only further our basicunderstanding of neurogenesis but will help in the eventual goal of using neural stem/progenitorcells in brain therapeutics.