Glymphatic influx and clearance are accelerated by neurovascular coupling

• Published in: Nature neuroscience 2023-06, Vol.26 (6), p.1042-1053
• Main Authors: Holstein-Rønsbo, Stephanie, Gan, Yiming, Giannetto, Michael J., Rasmussen, Martin Kaag, Sigurdsson, Björn, Beinlich, Felix Ralf Michael, Rose, Laura, Untiet, Verena, Hablitz, Lauren M., Kelley, Douglas H., Nedergaard, Maiken
• Format: Article
• Language: English
• Subjects: 14/34; 14/63; 14/69; 631/378/2607; 631/378/2620; 64/60; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological activity; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Blood flow; Brain - metabolism; Cerebral blood flow; Cerebrospinal fluid; Cortex (somatosensory); Coupling; Flow velocity; Glymphatic System - metabolism; Hemodynamics; Hyperemia; Hyperemia - metabolism; Metabolic wastes; Metabolism; Metabolites; Mice; Muscles; Neurobiology; Neurosciences; Neurovascular Coupling; Particle tracking; Particle tracking velocimetry; Smooth muscle; Stimulation; Velocity
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-023-01327-2

Functional hyperemia, also known as neurovascular coupling, is a phenomenon that occurs when neural activity increases local cerebral blood flow. Because all biological activity produces metabolic waste, we here sought to investigate the relationship between functional hyperemia and waste clearance via the glymphatic system. The analysis showed that whisker stimulation increased both glymphatic influx and clearance in the mouse somatosensory cortex with a 1.6-fold increase in periarterial cerebrospinal fluid (CSF) influx velocity in the activated hemisphere. Particle tracking velocimetry revealed a direct coupling between arterial dilation/constriction and periarterial CSF flow velocity. Optogenetic manipulation of vascular smooth muscle cells enhanced glymphatic influx in the absence of neural activation. We propose that impedance pumping allows arterial pulsatility to drive CSF in the same direction as blood flow, and we present a simulation that supports this idea. Thus, functional hyperemia boosts not only the supply of metabolites but also the removal of metabolic waste. Holstein-Rønsbo et al. show that functional hyperemia increases glymphatic CSF inflow and clearance. Direct stimulation of vascular smooth muscle cells, in the absence of neuronal activation, similarly enhances glymphatic flow.