UC San Diego

The blood vessels in the central nervous system (CNS) have a series of unique properties, termed the blood-brain barrier (BBB), which stringently regulate the entry of molecules into the brain, thus maintaining proper brain homeostasis. Despite the dynamic nature of the brain, the BBB has largely been studied in a static context. We sought to understand if the BBB exhibited plasticity and whether neural activity could regulate BBB properties. Using both chemogenetics and a volitional behavior paradigm, we identified a core set of brain endothelial genes whose expression is regulated by neural activity. In particular, neuronal activity regulates BBB efflux transporter expression and function, which is critical for excluding many small lipophilic molecules from the brain parenchyma. Furthermore, we found that neural activity regulates the expression of circadian clock genes within brain endothelial cells, which in turn mediate the activity-dependent control of BBB efflux transport. These results have important clinical implications for efficiency of CNS drug delivery in the day vs. night, the BBB’s role in clearance of CNS waste products including Aβ in health and Alzheimer’s Disease, and understanding how neural activity can control these and other diurnal processes.