Impact of neurovascular coupling on receptor-mediated transport of proteins into the brain

PROJECT SUMMARY Transport of blood-borne signals into the brain must be tightly controlled to maintain neuronal health. Selective transport across endothelial cells is achieved by receptor-mediated transcytosis, yet little is known about what physiological signals stimulate this transport. Transcytosis is affected by alterations in membrane tension, such as those caused by changes in blood vessel diameter. Hemodynamics are coupled to neural activity via neurovascular coupling (NVC). While disruption of NVC is associated with neurodegeneration, the normal physiological purpose of NVC is unknown. This proposal will test the hypothesis that NVC stimulates receptor- mediated transport of proteins into the brain. To visualize movement of blood-borne proteins out of endothelial cells, plasma proteins will be fluorescently labelled, and injected into mice with fluorescently-labelled endothelial cells and visualized using two-photon microscopy. To understand how vascular dynamics can drive transport, vasoconstriction and vasodilation will be pharmacologically induced. The contributions of neural activity to protein uptake will be tested by sensory stimulation and by chemogenetically modulating the activity of genetically defined neuronal populations. If neurovascular coupling gates protein uptake into the brain, this would provide a novel form of temporally and spatially controllable body-brain communication. These experiments will contribute to our fundamental knowledge of the signaling mechanisms controlling movement of blood-borne protein signals from the body into the brain, which could inform the targeting of therapeutics for neurodegenerative diseases.