Microglia are the resident immune cells of the brain. However, under certain circumstances, other myeloid cells — including bone marrow-derived myeloid cells — can infiltrate the brain parenchyma. These cells, along with border-associated macrophages (BAMs), have important roles in immune surveillance and defence, but how they interact and enter the brain is poorly understood. Hohsfield and colleagues reveal a specific leptomeningeal structure, the velum interpositum (VI), as an important route of entry for myeloid cells into the mouse brain.

Colony-stimulating factor 1 receptor (CSF1R) signalling is crucial for the survival and function of microglia and many BAMs. The authors used irradiation and bone marrow transplantation from green fluorescent protein-expressing (GFP+) donor mice, followed by CSF1R inhibition to deplete microglia. This protocol resulted in rapid infiltration of GFP+ myeloid cells from bone marrow sources and enabled the authors to track myeloid cell infiltration into an empty microglial niche. They noted an initial accumulation of GFP+ myeloid cells in a structure that runs beneath the hippocampal formation, rather than in the choroid plexus or blood vessels (the expected routes of infiltration), before spreading throughout the brain. Characterization of this tract in wild-type mice using immunohistochemical and anatomical approaches revealed that it is an extension of the meninges that runs between the hippocampus and thalamus, contains BAMs and peripheral myeloid cells, and aligns with the anatomical descriptions of the human VI.