Aquaporin-4-dependent glymphatic solute transport in the rodent brain.
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ABSTRACT:
SUBMITTER: Mestre H
PROVIDER: S-EPMC6307855 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
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Project description:Transport of solutes through brain involves diffusion and convection. The importance of convective flow in the subarachnoid and paravascular spaces has long been recognized; a recently proposed 'glymphatic' clearance mechanism additionally suggests that aquaporin-4 (AQP4) water channels facilitate convective transport through brain parenchyma. Here, the major experimental underpinnings of the glymphatic mechanism were re-examined by measurements of solute movement in mouse brain following intracisternal or intraparenchymal solute injection. We found that: (i) transport of fluorescent dextrans in brain parenchyma depended on dextran size in a manner consistent with diffusive rather than convective transport; (ii) transport of dextrans in the parenchymal extracellular space, measured by 2-photon fluorescence recovery after photobleaching, was not affected just after cardiorespiratory arrest; and (iii) Aqp4 gene deletion did not impair transport of fluorescent solutes from sub-arachnoid space to brain in mice or rats. Our results do not support the proposed glymphatic mechanism of convective solute transport in brain parenchyma.
| S-EPMC5578736 | biostudies-literature
Project description:Whether you are reading, running or sleeping, your brain and its fluid environment continuously interacts to distribute nutrients and clear metabolic waste. Yet, the precise mechanisms for solute transport within the human brain have remained hard to quantify using imaging techniques alone. From multi-modal human brain MRI data sets in sleeping and sleep-deprived subjects, we identify and quantify CSF tracer transport parameters using forward and inverse subject-specific computational modelling. Our findings support the notion that extracellular diffusion alone is not sufficient as a brain-wide tracer transport mechanism. Instead, we show that human MRI observations align well with transport by either by an effective diffusion coefficent 3.5[Formula: see text] that of extracellular diffusion in combination with local clearance rates corresponding to a tracer half-life of up to 5 h, or by extracellular diffusion augmented by advection with brain-wide average flow speeds on the order of 1-9 [Formula: see text]m/min. Reduced advection fully explains reduced tracer clearance after sleep-deprivation, supporting the role of sleep and sleep deprivation on human brain clearance.
| S-EPMC10439559 | biostudies-literature
Project description:A "glymphatic system," which involves convective fluid transport from para-arterial to paravenous cerebrospinal fluid through brain extracellular space (ECS), has been proposed to account for solute clearance in brain, and aquaporin-4 water channels in astrocyte endfeet may have a role in this process. Here, we investigate the major predictions of the glymphatic mechanism by modeling diffusive and convective transport in brain ECS and by solving the Navier-Stokes and convection-diffusion equations, using realistic ECS geometry for short-range transport between para-arterial and paravenous spaces. Major model parameters include para-arterial and paravenous pressures, ECS volume fraction, solute diffusion coefficient, and astrocyte foot-process water permeability. The model predicts solute accumulation and clearance from the ECS after a step change in solute concentration in para-arterial fluid. The principal and robust conclusions of the model are as follows: (a) significant convective transport requires a sustained pressure difference of several mmHg between the para-arterial and paravenous fluid and is not affected by pulsatile pressure fluctuations; (b) astrocyte endfoot water permeability does not substantially alter the rate of convective transport in ECS as the resistance to flow across endfeet is far greater than in the gaps surrounding them; and (c) diffusion (without convection) in the ECS is adequate to account for experimental transport studies in brain parenchyma. Therefore, our modeling results do not support a physiologically important role for local parenchymal convective flow in solute transport through brain ECS.
| S-EPMC5129742 | biostudies-literature
Project description:The glymphatic system (GS) hypothesis states that advective driven cerebrospinal fluid (CSF) influx from the perivascular spaces into the interstitial fluid space rapidly transport solutes and clear waste from brain. However, the presence of advection in neuropil is contested and solutes are claimed to be transported by diffusion only. To address this controversy, we implemented a regularized version of the optimal mass transport (rOMT) problem, wherein the advection/diffusion equation is the only a priori assumption required. rOMT analysis with a Lagrangian perspective of GS transport revealed that solute speed was faster in CSF compared to grey and white matter. Further, rOMT analysis also demonstrated 2-fold differences in regional solute speed within the brain. Collectively, these results imply that advective transport dominates in CSF while diffusion and advection both contribute to GS transport in parenchyma. In a rat model of cerebral small vessel disease (cSVD), solute transport in the perivascular spaces (PVS) and PVS-to-tissue transfer was slower compared to normal rats. Thus, the analytical framework of rOMT provides novel insights in the local dynamics of GS transport that may have implications for neurodegenerative diseases. Future studies should apply the rOMT analysis approach to confirm GS transport reductions in humans with cSVD.
| S-EPMC7004986 | biostudies-literature
Project description:BackgroundThe glymphatic pathway transports cerebrospinal fluid through the brain, thereby facilitating waste removal. A unique aspect of this pathway is that its function depends on the state of consciousness of the brain and is associated with norepinephrine activity. A current view is that all anesthetics will increase glymphatic transport by inducing unconsciousness. This view implies that the effect of anesthetics on glymphatic transport should be independent of their mechanism of action, as long as they induce unconsciousness. We tested this hypothesis by comparing the supplementary effect of dexmedetomidine, which lowers norepinephrine, with isoflurane only, which does not.MethodsFemale rats were anesthetized with either isoflurane (N = 8) or dexmedetomidine plus low-dose isoflurane (N = 8). Physiologic parameters were recorded continuously. Glymphatic transport was quantified by contrast-enhanced magnetic resonance imaging. Cerebrospinal fluid and gray and white matter volumes were quantified from T1 maps, and blood vessel diameters were extracted from time-of-flight magnetic resonance angiograms. Electroencephalograms were recorded in separate groups of rats.ResultsGlymphatic transport was enhanced by 32% in rats anesthetized with dexmedetomidine plus low-dose isoflurane when compared with isoflurane. In the hippocampus, glymphatic clearance was sixfold more efficient during dexmedetomidine plus low-dose isoflurane anesthesia when compared with isoflurane. The respiratory and blood gas status was comparable in rats anesthetized with the two different anesthesia regimens. In the dexmedetomidine plus low-dose isoflurane rats, spindle oscillations (9 to 15 Hz) could be observed but not in isoflurane anesthetized rats.ConclusionsWe propose that anesthetics affect the glymphatic pathway transport not simply by inducing unconsciousness but also by additional mechanisms, one of which is the repression of norepinephrine release.
| S-EPMC5685871 | biostudies-literature
Project description:Potassium (K(+)) ions released into brain extracellular space (ECS) during neuroexcitation are efficiently taken up by astrocytes. Deletion of astrocyte water channel aquaporin-4 (AQP4) in mice alters neuroexcitation by reducing ECS [K(+)] accumulation and slowing K(+) reuptake. These effects could involve AQP4-dependent: (a) K(+) permeability, (b) resting ECS volume, (c) ECS contraction during K(+) reuptake, and (d) diffusion-limited water/K(+) transport coupling. To investigate the role of these mechanisms, we compared experimental data to predictions of a model of K(+) and water uptake into astrocytes after neuronal release of K(+) into the ECS. The model computed the kinetics of ECS [K(+)] and volume, with input parameters including initial ECS volume, astrocyte K(+) conductance and water permeability, and diffusion in astrocyte cytoplasm. Numerical methods were developed to compute transport and diffusion for a nonstationary astrocyte-ECS interface. The modeling showed that mechanisms b-d, together, can predict experimentally observed impairment in K(+) reuptake from the ECS in AQP4 deficiency, as well as altered K(+) accumulation in the ECS after neuroexcitation, provided that astrocyte water permeability is sufficiently reduced in AQP4 deficiency and that solute diffusion in astrocyte cytoplasm is sufficiently low. The modeling thus provides a potential explanation for AQP4-dependent K(+)/water coupling in the ECS without requiring AQP4-dependent astrocyte K(+) permeability. Our model links the physical and ion/water transport properties of brain cells with the dynamics of neuroexcitation, and supports the conclusion that reduced AQP4-dependent water transport is responsible for defective neuroexcitation in AQP4 deficiency.
| S-EPMC3536523 | biostudies-literature
Project description: Not available
| S-EPMC9531841 | biostudies-literature
Project description:Adeno-associated viruses (AAV) are currently being evaluated in clinical trials for gene therapy of CNS disorders. However, host factors that influence the spread, clearance, and transduction efficiency of AAV vectors in the brain are not well understood. Recent studies have demonstrated that fluid flow mediated by aquaporin-4 (AQP4) channels located on astroglial end feet is essential for exchange of solutes between interstitial and cerebrospinal fluid. This phenomenon, which is essential for interstitial clearance of solutes from the CNS, has been termed glial-associated lymphatic transport or glymphatic transport. In the current study, we demonstrate that glymphatic transport profoundly affects various aspects of AAV gene transfer in the CNS. Altered localization of AQP4 in aged mouse brains correlated with significantly increased retention of AAV vectors in the parenchyma and reduced systemic leakage following ventricular administration. We observed a similar increase in AAV retention and transgene expression upon i.c.v. administration in AQP4-/- mice. Consistent with this observation, fluorophore-labeled AAV vectors showed markedly reduced flux from the ventricles of AQP4-/- mice compared with WT mice. These results were further corroborated by reduced AAV clearance from the AQP4-null brain, as demonstrated by reduced transgene expression and vector genome accumulation in systemic organs. We postulate that deregulation of glymphatic transport in aged and diseased brains could markedly affect the parenchymal spread, clearance, and gene transfer efficiency of AAV vectors. Assessment of biomarkers that report the kinetics of CSF flux in prospective gene therapy patients might inform variable treatment outcomes and guide future clinical trial design.
| S-EPMC5033923 | biostudies-literature
Project description:The blood-brain barrier remains a major roadblock to the delivery of drugs to the brain. While in vitro and in vivo measurements of permeability are widely used to predict brain penetration, very little is known about the mechanisms of passive transport. Detailed insight into interactions between solutes and cell membranes could provide new insight into drug design and screening. Here, we perform unbiased atomistic MD simulations to visualize translocation of a library of 24 solutes across a lipid bilayer representative of brain microvascular endothelial cells. A temperature bias is used to achieve steady state of all solutes, including those with low permeability. Based on free-energy surface profiles, we show that the solutes can be classified into three groups that describe distinct mechanisms of transport across the bilayer. Simulations down to 310 K for solutes with fast permeability were used to justify the extrapolation of values at 310 K from higher temperatures. Comparison of permeabilities at 310 K to experimental values obtained from in vitro transwell measurements and in situ brain perfusion revealed that permeabilities obtained from simulations vary from close to the experimental values to more than 3 orders of magnitude faster. The magnitude of the difference was dependent on the group defined by free-energy surface profiles. Overall, these results show that MD simulations can provide new insight into the mechanistic details of brain penetration and provide a new approach for drug discovery.
| S-EPMC8757349 | biostudies-literature
Project description:BackgroundUnderstanding molecular transport in the brain is critical to care and prevention of neurological disease and injury. A key question is whether transport occurs primarily by diffusion, or also by convection or dispersion. Dynamic contrast-enhanced (DCE-MRI) experiments have long reported solute transport in the brain that appears to be faster than diffusion alone, but this transport rate has not been quantified to a physically relevant value that can be compared to known diffusive rates of tracers.MethodsIn this work, DCE-MRI experimental data is analyzed using subject-specific finite-element models to quantify transport in different anatomical regions across the whole mouse brain. The set of regional effective diffusivities ([Formula: see text]), a transport parameter combining all mechanisms of transport, that best represent the experimental data are determined and compared to apparent diffusivity ([Formula: see text]), the known rate of diffusion through brain tissue, to draw conclusions about dominant transport mechanisms in each region.ResultsIn the perivascular regions of major arteries, [Formula: see text] for gadoteridol (550 Da) was over 10,000 times greater than [Formula: see text]. In the brain tissue, constituting interstitial space and the perivascular space of smaller blood vessels, [Formula: see text] was 10-25 times greater than [Formula: see text].ConclusionsThe analysis concludes that convection is present throughout the brain. Convection is dominant in the perivascular space of major surface and branching arteries (Pe > 1000) and significant to large molecules (> 1 kDa) in the combined interstitial space and perivascular space of smaller vessels (not resolved by DCE-MRI). Importantly, this work supports perivascular convection along penetrating blood vessels.
| S-EPMC8650464 | biostudies-literature