The Alteration of Brain Interstitial Fluid Drainage with Myelination Development.

The integrity of myelination is crucial for maintaining brain interstitial fluid (ISF) drainage in adults; however, the mechanism of ISF drainage with immature myelin in the developing brain remains unknown. In the present study, the ISF drainage from the caudate nucleus (Cn) to the ipsilateral cortex was studied at different developmental stages of the rat brain (P 10, 20, 30, 40, 60, 80, 10-80). The results show that the traced ISF drained to the cortex from Cn and to the thalamus in an opposite direction before P30. From P40, we found impeded drainage to the thalamus due to myelin maturation. This altered drainage was accompanied by enhanced cognitive and social functions, which were consistent with those in the adult rats. A significant difference in diffusion parameters was also demonstrated between the extracellular space (ECS) before and after P30. The present study revealed the alteration of ISF drainage regulated by myelin at different stages during development, indicating that a regional ISF homeostasis may be essential for mature psychological and cognitive functions.

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

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.

Stimulation Modeling on Three-Dimensional Anisotropic Diffusion of MRI Tracer in the Brain Interstitial Space.

Purpose: To build a mathematical model based magnetic resonance (MR) method to simulate drug anisotropic distribution in vivo in the interstitial space (ISS) of the brain. Materials and Methods: An injection of signal intensity-related gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), which is an exogenous drug, was administered, and its diffusion was traced in the ISS of the brain using MRI. Dynamic MRI scans were performed to monitor and record the changes in signal intensity in each pixel of the region of interest. The transport parameters were calculated using the modified equation to simulate three-dimensional anisotropic diffusion, which was resolved using a Laplace transform and a linear regressive model. Results: After Gd-DTPA was introduced into the caudate nucleus, its distribution was demonstrated in real time. As the Gd-DTPA gradually cleared, the associated hyperintensity attenuated over time. The average diffusion coefficient (D) and the clearance rate constant (k) were (1.305 ± 0.364) × 10-4 mm2/s and (1.40 ± 0.206) × 10-5 s-1, respectively. Discussion: The combination of trace-based MRI and modified diffusion mathematical models can visualize and measure the three-dimensional anisotropic distribution of drugs in the ISS of the brain.

Bloodletting at Jing-well points decreases interstitial fluid flow in the thalamus of rats.

OBJECTIVE: To investigate the changes in the neuronal microenvironment of the middle cerebral artery (MCA) territory induced by Jing-well points bloodletting acupuncture (WPBA) and to explore the neuroprotective mechanism of WPBA in stroke. METHODS: Adult male Sprague Dawley (n = 32) rats were randomly divided into four groups of eight animals each: WPBA-thalamus group (WT), WPBA-caudate nucleus group (WC), sham-control thalamus group (ST) and sham-control caudate nucleus group (SC). Animals in the WT and WC groups received 2 µL of the extracellular tracer gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) injected into the thalamus or caudate nucleus, respectively, and 12 Jing-well points in the distal ends of the rats' digits were used for WPBA. Although 2 µL of Gd-DTPA was injected into the thalamus or caudate nucleus, respectively, for animals in the two sham groups (ST and SC), no acupuncture or bloodletting was performed. Brain extracellular space and interstitial fluid flow parameters were measured using Gd-DTPA-enhanced magnetic resonance imaging. RESULTS: The brain interstitial fluid flow speed was decreased in the thalamus after WPBA, with a significantly lower Gd-DTPA clearance rate and longer half-life of Gd-DTPA in the thalamus of treated rats than those in sham-control rats [WPBA-treated rats' clearance rate, (7.47 ± 3.15) x 10(-5)/s (P.= 0.009); half-life, (1.52 ± 0.13) h, P = 0.000]. By contrast, no significant changes in brain extracellular space and interstitial fluid flow parameters were detected in the caudate nucleus after WPBA (P = 0.649). In addition, no differences in the morphology of the brain extracellular space or the final distribution of the traced brain interstitial fluid were demonstrated between the WT and WC groups (P = 0.631, P = 0.970, respectively). CONCLUSION: The WPBA decreased the speed of the local thalamic ISF flow in rats, which is assumed to be a beneficial protection by down-modulated the metabolic rate of the attacked neurons under stroke.

Transportation in the Interstitial Space of the Brain Can Be Regulated by Neuronal Excitation.

The transportation of substances in the interstitial space (ISS) is crucial for the maintenance of brain homeostasis, however its link to neuronal activity remains unclear. Here, we report a marked reduction in substance transportation in the ISS after neuronal excitation. Using a tracer-based method, water molecules in the interstitial fluid (ISF) could be specifically visualized in magnetic resonance (MR) imaging. We first observed the flow of ISF in the thalamus and caudate nucleus of a rat. The ISF flow was then modulated using a painful stimulation model. We demonstrated that the flow of ISF slowed significantly following neuronal activity in the thalamus. This reduction in ISF flow continued for hours and was not accompanied by slow diffusion into the ISS. This observation suggests that the transportation of substances into the ISS can be regulated with a selective external stimulation.