Aquaporin-4-dependent glymphatic solute transport in the rodent brain
- University of Rochester Medical Center, United States
- University of Copenhagen, Denmark
- Nanjing Medical University, China
- RIKEN, Japan
- The University of North Carolina at Chapel Hill, United States
- Oregon Health and Science University, United States
- Haukeland University Hospital, Norway
- Lund University, Sweden
- Keio University, Japan
- University of Rochester, United States
Abstract
The glymphatic system is a brain-wide clearance pathway; its impairment contributes to the accumulation of amyloid-β. Influx of cerebrospinal fluid(CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4(AQP4). Prompted by a recent failure to find an effect of Aqp4 knock-out(KO) on CSF and interstitial fluid(ISF) tracer transport, five groups re-examined the importance of AQP4 in glymphatic transport. We concur that CSF influx is higher in wildtype mice than in four different Aqp4 KO lines and in one line that lacks perivascular AQP4(Snta1 KO). Meta-analysis of all studies demonstrated a significant decrease in tracer transport in KO mice and rats compared to controls. Meta-regression indicated that anesthesia, age, and tracer delivery explain the opposing results. We also report that intrastriatal injections suppress glymphatic function. This validates the role of AQP4 in accordance with the glymphatic system and shows that invasive procedures should not be utilized.
Data availability
All data generated or analysed during this study are included in the manuscript.
Article and author information
Author details
Funding
National Institutes of Health (NS100366)
- Maiken Nedergaard
Japan Society for the Promotion of Science (18H02606)
- Masato Yasui
Human Frontier Science Program (RGP0036/2014)
- Hajime Hirase
Japan Society for the Promotion of Science (Core-to-Core Program)
- Hajime Hirase
Lundbeckfonden (Visiting Professorship)
- Hajime Hirase
Knut och Alice Wallenbergs Stiftelse (Helse Vet)
- Alexander S Thrane
National Institutes of Health (NS061800)
- Aravind Asokan
National Institutes of Health (AG048769)
- Maiken Nedergaard
National Institutes of Health (AG054456)
- Jeffrey J Iliff
National Institutes of Health (NS099371)
- Aravind Asokan
National Institutes of Health (HL089221)
- Aravind Asokan
National Institutes of Health (NS089709)
- Jeffrey J Iliff
National Institutes of Health (NS078394)
- Maiken Nedergaard
National Institutes of Health (AG048769)
- Maiken Nedergaard
Japan Society for the Promotion of Science (18K14859)
- Hiromu Monai
Japan Society for the Promotion of Science (16H01888)
- Hajime Hirase
Japan Society for the Promotion of Science (18H05150)
- Hajime Hirase
Japan Society for the Promotion of Science (17K19637)
- Yoichiro Abe
Japan Society for the Promotion of Science (16H05134)
- Yoichiro Abe
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were approved by the Institutional Animal Care and Use Committee of Nanjing Medical University (IACUC-1601106), Wako Animal Experiment Committee, RIKEN (Recombinant DNA experimentation protocol: 2016-038; Animal experimentation protocol: H29-2-227), The University of North Carolina at Chapel Hill Institutional Animal Care and Use Committee (protocol 15-109), the University Committee on Animal Resources of the University of Rochester (protocol 2011-023), and the IACUC of Oregon Health and Science University (protocol IP00000394). All experiments were performed in accordance with the approved guidelines and regulations. All efforts were made to minimize animal suffering and to reduce the number of animals used for the experiments.
Copyright
© 2018, Mestre et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Aquaporin-4-dependent glymphatic solute transport in the rodent brain
eLife 7:e40070.
https://doi.org/10.7554/eLife.40070
Further reading
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Pain is heavily modulated by expectations. Whereas the integration of expectations with sensory information has been examined in some detail, little is known about how positive and negative expectations are generated and their neural dynamics from generation over anticipation to the integration with sensory information. The present preregistered study employed a novel paradigm to induce positive and negative expectations on a trial-by-trial basis and examined the neural mechanisms using combined EEG-fMRI measurements (n=50). We observed substantially different neural representations between the anticipatory and the actual pain period. In the anticipation phase i.e., before the nociceptive input, the insular cortex, dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC) showed increased activity for directed expectations regardless of their valence. Interestingly, a differentiation between positive and negative expectations within the majority of areas only occurred after the arrival of nociceptive information. FMRI-informed EEG analyses could reliably track the temporal sequence of processing showing an early effect in the DLPFC, followed by the anterior insula and late effects in the ACC. The observed effects indicate the involvement of different expectation-related subprocesses, including the transformation of visual information into a value signal that is maintained and differentiated according to its valence only during stimulus processing.
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Background:
Alcohol use disorder (AUD) is a global health problem with limited therapeutic options. The biochemical mechanisms that lead to this disorder are not yet fully understood, and in this respect, metabolomics represents a promising approach to decipher metabolic events related to AUD. The plasma metabolome contains a plethora of bioactive molecules that reflects the functional changes in host metabolism but also the impact of the gut microbiome and nutritional habits.
Methods:
In this study, we investigated the impact of severe AUD (sAUD), and of a 3-week period of alcohol abstinence, on the blood metabolome (non-targeted LC-MS metabolomics analysis) in 96 sAUD patients hospitalized for alcohol withdrawal.
Results:
We found that the plasma levels of different lipids ((lyso)phosphatidylcholines, long-chain fatty acids), short-chain fatty acids (i.e. 3-hydroxyvaleric acid) and bile acids were altered in sAUD patients. In addition, several microbial metabolites, including indole-3-propionic acid, p-cresol sulfate, hippuric acid, pyrocatechol sulfate, and metabolites belonging to xanthine class (paraxanthine, theobromine and theophylline) were sensitive to alcohol exposure and alcohol withdrawal. 3-Hydroxyvaleric acid, caffeine metabolites (theobromine, paraxanthine, and theophylline) and microbial metabolites (hippuric acid and pyrocatechol sulfate) were correlated with anxiety, depression and alcohol craving. Metabolomics analysis in postmortem samples of frontal cortex and cerebrospinal fluid of those consuming a high level of alcohol revealed that those metabolites can be found also in brain tissue.
Conclusions:
Our data allow the identification of neuroactive metabolites, from interactions between food components and microbiota, which may represent new targets arising in the management of neuropsychiatric diseases such as sAUD.
Funding:
Gut2Behave project was initiated from ERA-NET NEURON network (Joint Transnational Call 2019) and was financed by Academy of Finland, French National Research Agency (ANR-19-NEUR-0003-03) and the Fonds de la Recherche Scientifique (FRS-FNRS; PINT-MULTI R.8013.19, Belgium). Metabolomics analysis of the TSDS samples was supported by grant from the Finnish Foundation for Alcohol Studies.
