Classic and novel features of the dentate gyrus vascular niche quantified through 3D vessel reconstruction

Abstract

Adult neurogenesis, the continued generation of new neurons throughout life, supports a variety of emotional and cognitive functions in mammals. Lifelong neurogenesis occurs in the dentate gyrus (DG) of the hippocampus, where a neurogenic niche supports the survival and growth of neural stem cells (NSCs), which divide to generate new neurons. A key component of this niche is the surrounding vasculature, thought to give NSCs access to circulating support molecules, oxygen, and nutrient metabolites. The DG vasculature is strikingly variable across layers. Vascular density and linearity, for example, have been noted to differ substantially in the different cell layers that make up the DG. Most of these prior descriptions of the DG vasculature have been qualitative, and other important aspects of vessel morphology, like vessel diameter, have not been previously reported to our knowledge. To provide a more complete and quantitative description of the adult DG vasculature, we used a 3D imaging technique to fully characterize the vasculature of each DG cellular layer. Our 3D reconstructions of DG blood vessels provide a quantitative method for measuring several known, qualitative features of the neurogenic niche, such as blood vessel density and tortuosity. In some cases, we reproduce qualitative observations, such as affirming that vessel density is high in the subgranular zone (SGZ) where NSCs reside and low in the granule cell layer. In other cases, our findings go counter to what qualitative observations suggest. For example, the SGZ is often described as having uniquely linear blood vessels, but we found that linearity was similar between the SGZ and hilus layer. We also report new measures of features of DG layer vascular architecture: vessel diameter and branching. Together, these findings offer a global, quantitative characterization of the DG vascular niche in adult mice. Beyond providing more detailed characterization of DG vasculature, we also anticipate our methods and estimates of variance in mice will be useful for investigators wishing to plan their own quantitative studies of changes in the vascular structure of the DG.