Abstract
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.
Highlights
The adult human brain comprises only about 2 % of the body’s weight, yet, it consumes nearly 20 % of its resting metabolic resources [14]
We stained adult brain sections with an antibody directed against glial fibrillary acidic protein (GFAP) [8]
We developed a system for targeting this cellular machinery, and in particular, the brain’s astrocytes that serve as an intermediary in this unit
Summary
The adult human brain comprises only about 2 % of the body’s weight, yet, it consumes nearly 20 % of its resting metabolic resources [14]. Studies employing in vivo functional neuroimaging have consistently demonstrated that the central nervous system exhibits a high metabolic demand [15, 54]. There is a complex interplay between neurons and the vasculature in the behaving animal [38, 64]. The mechanisms underlying this functional coupling remain poorly understood. This is due in part to a shortage of effective methods to target the neurovascular coupling machinery. The blood brain barrier, the interface between neurons and vessels, is formed by tight junctions of brain endothelial cells [22]. The barrier is further wrapped by pericytes and astrocytes, which work together throughout life to ensure structural stability
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