The Drainage of Interstitial Fluid in the Deep Brain is Controlled by the Integrity of Myelination

Abstract

In searching for the drainage route of the interstitial fluid (ISF) in the deep brain, we discovered a regionalized ISF drainage system as well as a new function of myelin in regulating the drainage. The traced ISF from the caudate nucleus drained to the ipsilateral cortex along myelin fiber tracts, while in the opposite direction, its movement to the adjacent thalamus was completely impeded by a barrier structure, which was identified as the converged, compact myelin fascicle. The regulating and the barrier effects of myelin were unchanged in AQP4-knockout rats but were impaired as the integrity of boundary structure of drainage system was destroyed in a demyelinated rat model. We thus proposed that the brain homeostasis was maintained within each ISF drainage division locally, rather than across the brain as a whole. A new brain division system and a new pathogenic mechanism of demyelination are therefore proposed.

The Interstitial System of the Brain in Health and Disease

“…However, the magnitude, locus, and proportions of the brain ISS are not static. Significant transformations ensue in ISS during the development of the brain due to events such as neurogenesis, neuronal migration and differentiation, expansion of dendritic tree, synaptogenesis, gliogenesis, synaptic stripping by microglia, and myelination [1,[5][6][7][8][9][10]. The geometry of the brain ISS also undergoes modification in aging due to the loss of synapses, neurons, dendritic regression, changes in morphology and numbers of glia, senoinflammation, and deposition of amyloid plaques [11][12][13][14][15].…”

“…Three potential conduits have been suggested for the drainage of ISF from the ISS. One path is via the wall of ventricles through ependymal cells, which allows the passage of macromolecules [10,46,86] (Fig. 2).…”

“…Ependymal cells, covered in a layer of cilia, line the ventricles, and play an essential role in the regulation of CSF production. The second passageway is at the surface of the brain and spinal cord via pia-glial membranes [10,23,46,87] (Fig. 2).…”

“…The ISF pathway is mostly active during sleep when the clearance of harmful metabolites such as beta-amyloid increases two-fold relative to the waking state [74]. By using a newly developed in vivo tracer-based MRI technique, Han and his group demonstrated the drainage of ISF from deep brain regions into the surface of the cerebral cortex [10,46,93]. In addition, they showed that the traced ISF from the caudate nucleus drained into the ipsilateral cerebral cortex along the myelin fiber tracts and then into the subarachnoid space [10].…”

“…By using a newly developed in vivo tracer-based MRI technique, Han and his group demonstrated the drainage of ISF from deep brain regions into the surface of the cerebral cortex [10,46,93]. In addition, they showed that the traced ISF from the caudate nucleus drained into the ipsilateral cerebral cortex along the myelin fiber tracts and then into the subarachnoid space [10]. A study using an in vivo two-photon imaging also verified the ISF-CSF exchange between the ISS of the cerebral cortex and the CSF in the subarachnoid space [23].…”