Microfiberoptic fluorescence photobleaching reveals size‐dependent macromolecule diffusion in extracellular space deep in brain

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Abstract
Diffusion in brain extracellular space (ECS) is important for nonsynaptic intercellular communication, extracellular ionic buffering, and delivery of drugs and metabolites. We measured macromolecular diffusion in normally light-inaccessible regions of mouse brain by microfiberoptic epifluorescence photobleaching, in which a fiberoptic with a micron-size tip is introduced deep in brain tissue. In brain cortex, the diffusion of a noninteracting molecule [fluorescein isothiocyanate (FITC)-dextran, 70 kDa] was slowed 4.5 ± 0.5-fold compared with its diffusion in water (Do/D), and was depth-independent down to 800 μm from the brain surface. Diffusion was significantly accelerated (Do/D of 2.9±0.3) in mice lacking the glial water channel aquaporin-4. FITC-dextran diffusion varied greatly in different regions of brain, with Do/D of 3.5 ± 0.3 in hippocampus and 7.4 ± 0.3 in thalamus. Remarkably, Do/D in deep brain was strongly dependent on solute size, whereas diffusion in cortex changed little with solute size. ...
Funding Information
  • Cystic Fibrosis Foundation