UC San Diego

The blood-brain barrier (BBB) is a set of properties belonging to endothelial cells that make up blood vessels in the central nervous system (CNS). The BBB’s function is to reduce the transport of nonspecific ions and molecules between the blood and brain and import specific molecules to maintain brain homeostasis. The cerebral vasculature is also known to be tightly coupled to neural activity and dynamically changes blood flow to satisfy the energy demand of active brain regions. Although the cerebral vascular blood flow is tightly coupled to neural activity, the question remains whether BBB properties can dynamically respond to neural activity, as well. Through manipulating glutamatergic neurons in mice, we have shown that neural activity can dynamically regulate both the expression and function of BBB genes in the cerebral vasculature, namely, ATP- binding cassette (ABC) efflux transporters. Additionally, we found that neural activity dynamically regulates circadian clock-related genes in endothelial cells. This led us to ask the question of what is the functional role of the circadian clock in endothelial cells of the cerebral vasculature? Through knocking out a core clock gene, Bmal1, specifically in endothelial cells, we found that the vascular clock regulates ABC efflux transport and animal behavior. We propose the idea that neural activity entrains the vascular-specific circadian clock, which regulates ABC transporter activity in a circadian manner, and deletion of the clock in endothelial cells causes dysregulation of ABC transport, thus disrupting the chemical microenvironment of the brain, resulting in complex behavioral phenotypes.