Neural Metabolism In Vivo. In-Young Choi , Rolf Gruetter.
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Seite Bibliografische Informationen. On the choice of a sparse prior. Rev Neurosci 14 : 53— Diffusion of d-glucose measured in the cytosol of a single astrocyte. Cell Mol Life Sci 70 : — Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism.
Astroglial contribution to brain energy metabolism in humans revealed by 13C nuclear magnetic resonance spectroscopy: Elucidation of the dominant pathway for neurotransmitter glutamate repletion and measurement of astrocytic oxidative metabolism. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Immunorecognition, ultrastructure and phosphorylation status of astrocytic gap junctions and connexin43 in rat brain after cerebral focal ischaemia. Eur J Neurosci 10 : — Glutamate triggers rapid glucose transport stimulation in astrocytes as evidenced by real-time confocal microscopy.
J Neurosci 23 : — The transcriptome and metabolic gene signature of protoplasmic astrocytes in the adult murine cortex. Brain energy metabolism. In Fundamental neuroscience ed.
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Academic, New York. The perivascular astroglial sheath provides a complete covering of the brain microvessels: An electron microscopic 3D reconstruction. Brain glycogen supercompensation following exhaustive exercise. Application of subsecond spiral chemical shift imaging to real-time multislice metabolic imaging of the rat in vivo after injection of hyperpolarized 13C1-pyruvate. Intracellular acidification induced by passive and active transport of ammonium ions in astrocytes. Am J Physiol : C—C The inferential notion that myo-inositol levels detected by in vivo 1 H MRS reflect the extent of activation of astrocytes and microglia is less well supported.
Mice had ad libitum access to food and water. Female mice were used in all analyses. Samples were collected at the same time on each day over a period of 4 months before tissue extraction for 1 H NMR Spectroscopy. All procedures were authorised and approved by the University of Nottingham ethics committee and carried out in accordance with the UK Animals Scientific Procedures Act After the two liquid extract layers were separated, the solvents were removed using a concentrating evaporator system without heating Jouan RC The hydrophilic residues were reconstituted in phosphate-buffered pH 7.
All one-dimensional spectra were recorded at The TopSpin software v. To prepare the spectral data for pattern recognition analysis, the data points ranging from 9. To minimise any statistical contribution of tissue mass, all spectra were normalised to the total spectral area, i. Relative quantification of individual metabolites was performed by the sum of their data points in relation to the total spectral area, as calculated by the AMIX software.
Metabolite quantification was limited to a set of 30 specific metabolites. Peak annotations, some of which are denoted in Supplementary Fig. The bucketed dataset was pre-treated by mean-centring with and without scaling to unit variance in order to separately investigate the contribution of small and large signals to the statistical models. Principal component analysis PCA was performed to obtain information about major trends within datasets PCA is a method to reduce the complexity of multidimensional datasets, such as spectra, to a few latent variables termed principal components PCs.
Projection to latent structures by partial least squares PLS regression and discriminant analysis PLS-DA were deployed to define distinct group clusters relating to animal age and genotype, respectively. Similar to previous studies, Kolmogorov-Smirnov tests demonstrated that the endogenous metabolites in our study did not show Gaussian distribution Therefore, Mann-Whitney-U tests and the Z-statistic 51 were applied to compare individual metabolite concentrations between the two genotypes.
To minimise the risk of spurious positive results, Bonferroni-corrected p values were used. Protein concentration was determined using Bradford protein assay. Equal protein was subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by transfer to nitrocellulose membrane. Mice were perfusion-fixed with 0.
Counting was performed manually in ImageJ.
This was carried out as described previously Each image was inspected and corrected manually to avoid artifacts. Analysis provided the area occupied by microglia soma and isolated processes as a percentage of the ROI as well as the soma size. Details of statistical tests and number of biological replicates n are provided in the methods, figures and table legends. An elegant study describing species chronometry suggests that the final important steps in mouse brain development occur We note the limitation that the mice used in this study are juvenile in the biological context of sexual maturity, but we may consider the brain to be developed and analyses will have applicability to similar processes in human disease.
Multivariate statistical analysis of the whole dataset demonstrated clear metabolic differences between brain regions and age groups in line with previous reports in rodents Supplementary Fig. Therefore, genotypic comparisons were obtained separately for each brain region at each age. Metabolic changes were confirmed by univariate statistical analysis Fig. Early increases in lactate and choline-containing compounds were evident at 4 weeks-old to 1.
A late 1. B PCA loadings from 4. Reactive gliosis, involving astrocytes and microglia, is increasingly being recognised, not only as a pathological hallmark, but as a contributor to neurodegenerative disease and there is significant interest in identifying a metabolic signature that reflects gliosis in vivo 18 , Here we extend our data to show reactive astrogliosis is evident from 3 weeks-old by glial fibrillary acidic protein GFAP immunostaining and immunoblotting, well before evidence of neurodegeneration Fig.
Astrocyte activation was less dramatic in the hippocampus, increasing from 1. No significant differences were evident in control cortices; therefore the control image is representative of all ages. Insets show the region of cortex shown LHS; oval and a higher magnification image of the neuropathological finding RHS; white box. Images were cropped from those shown in Supplementary Figure 7. Control microglia displayed a resting morphology, with smaller compact perikarya and many long thin ramified processes Fig.
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A Representative horizontal brain sections immunostained with Iba1. Interestingly, we support this by showing significantly increased levels of glutamate dehydrogenase 1. Images were cropped from those shown in Supplementary Figure 6. Asterisks and arrows indicate astrocytes and Lewy-like inclusions respectively. These metabolic changes were followed by decreased glutamine and increased glutamate from 5 weeks-old. Metabolic differences were corroborated in the hippocampus, but not observed in the cerebellum up to 6 weeks-old.
We also reveal an early significant glial response to targeted neuronal dysfunction and by comparing significant metabolic changes with pathological and molecular alterations provide novel insights into the neuronal and glial responses to neuronal 26S proteasome dysfunction. NAA is highly concentrated in neurons and as one of the most abundant metabolites in 1 H MRS of the brain is employed as a non-invasive marker for neuronal health, providing a tool for diagnosis and evaluation of various neuropathologies in the clinical setting as well as the effects of potential neuroprotective therapies 29 , 30 , Numerous correlative clinical MRS studies and animal models have shown NAA reduction in neurodegenerative disease 32 , 33 , 34 , The physiological functions of NAA, however, remain controversial.
Substantial evidence couples NAA synthesis to energy production in neuronal mitochondria and decreased NAA may reflect primarily an impaired mitochondrial metabolism rather than neuronal loss, suggesting that reduced NAA could simultaneously represent both neuronal dysfunction as well as death 27 , 28 , These observations were associated with morphologically abnormal, fragmented mitochondria and furthermore, with decreased mitochondrial membrane potential and complex I activity We show that the number of paranuclear mitochondrial aggregates increases between 3 and 5 weeks-old, and then decreases at 6 weeks-old coinciding with increasing loss of neurons.
The early significant decrease in NAA, therefore, may also be associated with changes in brain neuroenergetics, supporting the use of this metabolite to track neuronal health as well as death, underpinning clinical MRS studies in neurodegenerative disease Supplementary Fig. Most 1 H MRS -based metabolomic studies report a decrease in the levels of glutamate, along with NAA, in experimental and clinical neurodegeneration This cycle is open, actively interfacing with other pathways, i. Interestingly, GDH was also associated with neuronal Lewy-like inclusions. However, GDH was recently shown to be important for oxidative metabolism of glutamine in neurons during elevated energy demand We cannot exclude that glutamine is also exported out of the brain into the circulation to maintain nitrogen levels during amino acid oxidation.
Intercellular metabolic coupling by the lactate shuttle may serve a protective function by ensuring a supply of substrates for activity in neurons, which convert lactate to pyruvate for oxidative metabolism. Lactate may be transferred to neurons or used to support astrogliosis in this context. Activation of glia has been associated with several metabolites using 1 H MRS in patients and models, but changes in myo-inositol, which is mostly located in glial cells, are expected to represent the extent of gliosis 36 , 37 , 38 , However, more recent studies have not found an association between neuropathologic measures reflecting astrocyte or microglia activation and myo-inositol levels, suggesting that myo-inositol may not be sensitive to glial activation and mainly reflects glial cell density in line with its elevation in gliomas 39 , 41 , Furthermore, low baseline cortical myo-inositol levels and potential interspecies differences may contribute to the apparent lower sensitivity of myo-insoitol in mouse models compared to humans.
Glycine and myo-inositol can easily be differentiated by in vitro 1 H NMR , allowing quantitation of both metabolites here However, these metabolites cannot be reliably separated using standard clinical 1 H MRS making it possible that glycine changes contribute to the myo-inositol-attributed gliosis signal at 3. Taken together, the use of myo-inositol as a gliosis marker may have limited sensitivity.
Specificity and interspecies differences still require clarification, highlighting the need for identification of additional metabolic neuroinflammation markers. Amino acids cannot be provided by autophagy in this context because continued 26S proteasome dysfunction impairs autophagic degradation An interesting study showed that amino acid supplementation could rescue cell death following proteasome inhibition in yeast, mammalian cells and flies Changes in choline have been inconsistently reported in experimental and clinical research, but several studies suggest elevated choline may be associated with the breakdown of neurons during the progression of neurodegenerative disease or membrane turnover associated with fibrillary gliosis, supporting our observations 38 , 41 , 74 , 75 , Future studies using pharmacological or genetic approaches to target astroglia and microglia with comparable metabolomics will be of great interest to enlighten further which metabolites best represent neuroinflammation.
Taken together, our study contributes to limited knowledge of metabolite changes during significant neuroinflammation triggered as a consequence of neuronal dysfunction. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Patti, G.
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