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      Diffusion MRI reveals in vivo and non-invasively changes in astrocyte function induced by an aquaporin-4 inhibitor

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          Abstract

          The Glymphatic System (GS) has been proposed as a mechanism to clear brain tissue from waste. Its dysfunction might lead to several brain pathologies, including the Alzheimer’s disease. A key component of the GS and brain tissue water circulation is the astrocyte which is regulated by acquaporin-4 (AQP4), a membrane-bound water channel on the astrocytic end-feet. Here we investigated the potential of diffusion MRI to monitor astrocyte activity in a mouse brain model through the inhibition of AQP4 channels with TGN-020. Upon TGN-020 injection, we observed a significant decrease in the Sindex, a diffusion marker of tissue microstructure, and a significant increase of the water diffusion coefficient (sADC) in cerebral cortex and hippocampus compared to saline injection. These results indicate the suitability of diffusion MRI to monitor astrocytic activity in vivo and non-invasively.

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          Most cited references38

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          A mesoscale connectome of the mouse brain.

          Comprehensive knowledge of the brain's wiring diagram is fundamental for understanding how the nervous system processes information at both local and global scales. However, with the singular exception of the C. elegans microscale connectome, there are no complete connectivity data sets in other species. Here we report a brain-wide, cellular-level, mesoscale connectome for the mouse. The Allen Mouse Brain Connectivity Atlas uses enhanced green fluorescent protein (EGFP)-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain. This systematic and standardized approach allows spatial registration of individual experiments into a common three dimensional (3D) reference space, resulting in a whole-brain connectivity matrix. A computational model yields insights into connectional strength distribution, symmetry and other network properties. Virtual tractography illustrates 3D topography among interconnected regions. Cortico-thalamic pathway analysis demonstrates segregation and integration of parallel pathways. The Allen Mouse Brain Connectivity Atlas is a freely available, foundational resource for structural and functional investigations into the neural circuits that support behavioural and cognitive processes in health and disease.
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            Brain-wide pathway for waste clearance captured by contrast-enhanced MRI.

            The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer's disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer's disease susceptibility and progression in the live human brain.
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              Genetic compensation: A phenomenon in search of mechanisms

              Several recent studies in a number of model systems including zebrafish, Arabidopsis, and mouse have revealed phenotypic differences between knockouts (i.e., mutants) and knockdowns (e.g., antisense-treated animals). These differences have been attributed to a number of reasons including off-target effects of the antisense reagents. An alternative explanation was recently proposed based on a zebrafish study reporting that genetic compensation was observed in egfl7 mutant but not knockdown animals. Dosage compensation was first reported in Drosophila in 1932, and genetic compensation in response to a gene knockout was first reported in yeast in 1969. Since then, genetic compensation has been documented many times in a number of model organisms; however, our understanding of the underlying molecular mechanisms remains limited. In this review, we revisit studies reporting genetic compensation in higher eukaryotes and outline possible molecular mechanisms, which may include both transcriptional and posttranscriptional processes.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SoftwareRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                15 May 2020
                2020
                : 15
                : 5
                : e0229702
                Affiliations
                [001]NeuroSpin, Gif-sur-Yvette, France
                Henry Ford Health System, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-4887-7920
                http://orcid.org/0000-0002-4454-729X
                Article
                PONE-D-20-03675
                10.1371/journal.pone.0229702
                7228049
                32413082
                602aa6d3-3248-4bc7-8d89-15f00c172de1
                © 2020 Debaker et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 11 February 2020
                : 28 April 2020
                Page count
                Figures: 5, Tables: 0, Pages: 14
                Funding
                Funded by: ANR
                Award ID: ANR-17-CE37-0010
                Award Recipient :
                This research was supported by a public grant of the French National Research Agency (project “MrGLY”, reference: ANR-17-CE37-0010, DLB=PI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Glial Cells
                Macroglial Cells
                Astrocytes
                Biology and Life Sciences
                Neuroscience
                Brain Mapping
                Brain Morphometry
                Diffusion Magnetic Resonance Imaging
                Medicine and Health Sciences
                Diagnostic Medicine
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Brain Morphometry
                Diffusion Magnetic Resonance Imaging
                Research and Analysis Methods
                Imaging Techniques
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Brain Morphometry
                Diffusion Magnetic Resonance Imaging
                Medicine and Health Sciences
                Radiology and Imaging
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Brain Morphometry
                Diffusion Magnetic Resonance Imaging
                Research and Analysis Methods
                Imaging Techniques
                Neuroimaging
                Brain Morphometry
                Diffusion Magnetic Resonance Imaging
                Biology and Life Sciences
                Neuroscience
                Neuroimaging
                Brain Morphometry
                Diffusion Magnetic Resonance Imaging
                Biology and Life Sciences
                Anatomy
                Brain
                Hippocampus
                Medicine and Health Sciences
                Anatomy
                Brain
                Hippocampus
                Biology and Life Sciences
                Anatomy
                Brain
                Neostriatum
                Medicine and Health Sciences
                Anatomy
                Brain
                Neostriatum
                Medicine and Health Sciences
                Diagnostic Medicine
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Research and Analysis Methods
                Imaging Techniques
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Medicine and Health Sciences
                Radiology and Imaging
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Physical Sciences
                Materials Science
                Materials Physics
                Microstructure
                Physical Sciences
                Physics
                Materials Physics
                Microstructure
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Cerebrospinal Fluid
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Cerebrospinal Fluid
                Biology and Life Sciences
                Physiology
                Body Fluids
                Cerebrospinal Fluid
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Cerebrospinal Fluid
                Biology and Life Sciences
                Anatomy
                Nervous System
                Cerebrospinal Fluid
                Medicine and Health Sciences
                Anatomy
                Nervous System
                Cerebrospinal Fluid
                Medicine and Health Sciences
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