Bulk Flow of Interstitial Fluid: a Watershed in the Brain Parenchyma

Abstract

Brain interstitial fluid (ISF) and cerebrospinal fluid are involved in the clearance of waste products from the brain. So far, different pathways of fluid drainage have been hypothesized. In particular, previous work pointed towards the perivascular space along cerebral vessels as a major drainage path. However, the pattern of fluid flow in the brain is still controversial. The aim of the current study was to visualize extravascular fluid transport in the normal mouse brain. Therefore, we injected FITC‐dextran (500 kD ) and Texas Red‐dextran (3 kD) in the striatum and in the cisterna magna and allowed the dyes to spread for 30 minutes. Horizontal and coronal brain sections were imaged using confocal microscopy and a 3D imaging cryomicrotome to reveal the pattern of distribution. We observed the tracers to distribute from the striatum towards the ventricular system, where they mixed with the cerebrospinal fluid and moved to the subarachnoid spaces. From there, tracers drained from the brain via olfactory nerves via the cribriform plate. Occasionally we observed that tracer close to the cortical surface found its way to the brain surface along blood vessels. This last observation suggests that there might be a point of highest interstitial pressure, close to the cortex, where ISF flows to either the ventricles or the cortex. After injection in the cisterna magna, tracers distributed over the subarachnoid space and followed the olfactory route out of the brain. Tracers were observed around blood vessels in the SAS and cisterns, but penetration into the brain parenchyma along perivascular spaces was limited. In conclusion, ISF, possibly originating from the capillaries, may generate a cumulating flow, small in regions far from the ventricles and much larger when approaching the ventricles. Disturbances in this transport pathway could influence the drainage of amyloid β and other waste products, which may be relevant for the pathophysiology of Alzheimer's disease.Support or Funding InformationThis work received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 606998.