Mechanisms of capillary-associated microglial interactions

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Project Summary The brain requires a significant amount of energy compared to other organs. This high energy demand is met by a dense network of blood vessel that deliver oxygen and nutrients and facilitates the removal of waste products. Therefore, the interactions between the neurovasculature and brain cells are important. While extensive work has been done to elucidate contributions by astrocytes and pericytes to vascular integrity, less work has been done to understand microglial interactions with the vasculature. Multiple lines of evidence suggest that microglia facilitate the development of the vasculature early in life and following injury or in disease. However, the extent of microglial interactions with the vasculature in homeostasis has not been adequately clarified. As resident immune cells, microglia are the brain’s first line of defense and it is possible that they could help detect pathogens or abnormalities in the circulation, but this would perhaps require stable physical interactions with the vasculature. In our preliminary studies for this project, we used in vivo two photon and electron microscopy approaches to document robust physical interactions between a subpopulation of microglial somata and the microvasculature (capillaries) across brain regions and brain age. Remarkably, even with pharmacological elimination and subsequent repopulation of microglia, the density of these capillary-associated microglia (CAM) was maintained suggesting that capillary association is a critical feature of microglial residence in the brain. In our proposed studies, we will: (1) attempt to differentiate CAMs from parenchymal microglia by using morphological, functional and transcriptional approaches; and (2) test the hypothesis that CAM interactions are facilitated by purine release from endothelial pannexins that recruit microglia through P2Y12 receptor sensing. This project is a first to thoroughly characterize capillary associated microglia and elucidate salient molecular mechanisms governing these interactions to understand microglia-vascular interactions in homeostasis.