Blood-Brain Barrier Gene Expression and Function Changes with Neuronal Activity

Post by D. Chloe Chung

What's the science?

The blood-brain barrier (BBB) is a semi-permeable structure that tightly controls the movement of molecules between the brain and neighboring blood vessels. Several studies have described the dynamic communication between the brain vasculature and neuronal activity. For example, blood volume and flow increase following neuronal activity (likely for oxygen and nutrient provision). However, it is not yet well understood whether changes in neuronal activity can directly influence the properties of BBB. This week in Neuron, Pulido and colleagues report that neuronal activity in the mouse brain, either chemically or behaviorally stimulated, can regulate efflux via BBB transporters (i.e. for waste removal) by altering its gene expression profile.

How did they do it?

The authors used transgenic mouse models in which glutamatergic neurons can be either activated or silenced using specific drugs. Three hours after drug injection, the authors collected endothelial cells, which form blood vessel walls, from the mice and performed RNA sequencing to examine gene expression changes in the BBB. These mice were also injected with fluorescent-labeled substrates of one of the BBB transporters to test whether functional properties of BBB, such as molecule transport, changed with neuronal activity. As an additional approach to stimulate neuronal activity, the authors capitalized on the knowledge that whisker movement typically leads to neuronal firing in a specific brain area. They designated two groups: mice with intact whiskers were made to explore their cage with many things to interact with using their whiskers, while mice with their whiskers trimmed off were left in an empty cage. Similar to the transgenic mouse models, these mice were analyzed for the gene expression changes in their endothelial cells. To evaluate the relationship between BBB efflux and neuronal activity-regulated circadian rhythm, the authors made an additional mouse model in which circadian genes can be deleted specifically in endothelial cells.

What did they find?

The authors found that changes in glutamatergic neuronal activity can dramatically regulate the expression level of hundreds of genes in endothelial cells, including multiple transporters and efflux pumps that can control the transfer of molecules across the BBB. In particular, several BBB efflux transporters were upregulated when neuronal activity was silenced, and downregulated when neuronal activity was higher. These gene expression changes led to transporter substrates (but not the non-substrates) entering the mouse brain more readily when neurons were activated. 

In addition to transporters, several genes involved in circadian rhythm were also differentially regulated upon neuronal activity. They showed a similar pattern to transporters: gene expression was upregulated with neuronal silencing and downregulated with neuronal activation. In the context of circadian rhythm, the authors observed that the gene expression level of a BBB efflux transporter and its permeability rhythmically fluctuated throughout the light-dark cycle and generally correlated with net neuronal activity throughout the day. Interestingly, this rhythmic fluctuation and acute neuronal regulation were completely abolished when one of the circadian genes was deleted in the endothelial cells, indicating that circadian genes, regulated by neuronal activity, can impact the expression and function of the BBB efflux transporter. Of note, the same transporters and circadian genes were also downregulated in mice in which neurons were activated via whisker stimulation, further demonstrating that neuronal activity can modulate these genes in the BBB.

What’s the impact?

This work revealed that the gene expression profile and functional properties of the BBB can be regulated by neuronal activity, in contrast to the previous belief that the BBB remains largely static. As the authors suggest, future studies examining activity-dependent gene expression changes in the endothelial cells across different time points will expand our understanding of the dynamic nature of the BBB. From a clinical standpoint, this study can be useful in optimizing drugs to cross the BBB with higher efficiency, as these BBB efflux transporters pose a major obstacle for drug delivery into the brain. Finally, findings from this work may be applied to investigate the relationship between dysregulated BBB efflux and neurological disorders.

Pulido et al. Neuronal Activity Regulates Blood-Brain Barrier Efflux Transport through Endothelial Circadian Genes. Neuron (2020). Access the original scientific publication here.