Genetic dissection of the neuro-glio-vascular machinery in the adult brain

The adult brain actively controls its metabolic homeostasis via the circulatory system at the blood brain barrier interface. The mechanisms underlying the functional coupling from neuron to vessel remain poorly understood. Here, we established a novel method to genetically isolate the individual components of this coupling machinery using a combination of viral vectors. We first discovered a surprising non-uniformity of the glio-vascular structure in different brain regions. We carried out a viral injection screen and found that intravenous Canine Adenovirus 2 (CAV2) preferentially targeted perivascular astrocytes throughout the adult brain, with sparing of the hippocampal hilus from infection. Using this new intravenous method to target astrocytes, we selectively ablated these cells and observed severe defects in hippocampus-dependent contextual memory and the metabolically regulated process of hippocampal neurogenesis. Combined with AAV9 targeting of neurons and endothelial cells, all components of the neuro-glio-vascular machinery can be simultaneously labeled for genetic manipulation. Together, we demonstrate a novel method, which we term CATNAP (CAV/AAV Targeting of Neurons and Astrocytes Perivascularly), to target and manipulate the neuro-glio-vascular machinery in the adult brain.