| 1. |
- Garcia-Serrano, Alba M., et al.
(author)
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Brain Metabolism Alterations in Type 2 Diabetes : What Did We Learn From Diet-Induced Diabetes Models?
- 2020
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In: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 14
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Research review (peer-reviewed)abstract
- Type 2 diabetes (T2D) is a metabolic disease with impact on brain function through mechanisms that include glucose toxicity, vascular damage and blood–brain barrier (BBB) impairments, mitochondrial dysfunction, oxidative stress, brain insulin resistance, synaptic failure, neuroinflammation, and gliosis. Rodent models have been developed for investigating T2D, and have contributed to our understanding of mechanisms involved in T2D-induced brain dysfunction. Namely, mice or rats exposed to diabetogenic diets that are rich in fat and/or sugar have been widely used since they develop memory impairment, especially in tasks that depend on hippocampal processing. Here we summarize main findings on brain energy metabolism alterations underlying dysfunction of neuronal and glial cells promoted by diet-induced metabolic syndrome that progresses to a T2D phenotype.
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| 2. |
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| 3. |
- Le Page, Yannick, et al.
(author)
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Seasonality of vegetation fires as modified by human action : observing the deviation from eco-climatic fire regimes
- 2010
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In: Global Ecology and Biogeography. - : Blackwell Publishing Lt. - 1466-822X .- 1466-8238. ; 19:4, s. 575-588
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Journal article (peer-reviewed)abstract
- Aim In any region affected, fires exhibit a strong seasonal cycle driven by the dynamic of fuel moisture and ignition sources throughout the year. In this paper we investigate the global patterns of fire seasonality, which we relate to climatic, anthropogenic, land-cover and land-use variables. Location Global, with detailed analyses from single 1°× 1° grid cells. Methods We use a fire risk index, the Chandler burning index (CBI), as an indicator of the ‘natural’, eco-climatic fire seasonality, across all types of ecosystems. A simple metric, the middle of the fire season, is computed from both gridded CBI data and satellite-derived fire detections. We then interpret the difference between the eco-climatic and observed metrics as an indicator of the human footprint on fire seasonality. Results Deforestation, shifting cultivation, cropland production or tropical savanna fires are associated with specific timings due to land-use practices, sometimes largely decoupled from the CBI dynamics. Detailed time series from relevant locations provide comprehensive information about these practices and how they are adapted to eco-climatic conditions. Main conclusions We find a great influence of anthropogenic activities on global patterns of fire seasonality. The specificity of the main fire practices and their easy identification from global observation is a potential tool to support land-use monitoring efforts. Our results should also prove valuable in the development of a methodological approach for improving the representation of anthropogenic fire practices in dynamic global vegetation models.
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| 4. |
- Pedro, Joana Reis, et al.
(author)
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Transient gain of function of cannabinoid CB1 receptors in the control of frontocortical glucose consumption in a rat model of Type-1 diabetes
- 2020
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In: Brain Research Bulletin. - : Elsevier BV. - 0361-9230. ; 161, s. 106-115
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Journal article (peer-reviewed)abstract
- Here we aimed to unify some previous controversial reports on changes in both cannabinoid CB1 receptor (CB1R) expression and glucose metabolism in the forebrain of rodent models of diabetes. We determined how glucose metabolism and its modulation by CB1R ligands evolve in the frontal cortex of young adult male Wistar rats, in the first 8 weeks of streptozotocin-induced type-1 diabetes (T1D). We report that frontocortical CB1R protein density was biphasically altered in the first month of T1D, which was accompanied with a reduction of resting glucose uptake ex vivo in acute frontocortical slices that was normalized after eight weeks in T1D. This early reduction of glucose uptake in slices was also restored by ex vivo treatment with both the non-selective CB1R agonists, WIN55212−2 (500 nM) and the CB1R-selective agonist, ACEA (3 μM) while it was exacerbated by the CB1R-selective antagonist, O-2050 (500 nM). These results suggest a gain-of-function for the cerebrocortical CB1Rs in the control of glucose uptake in diabetes. Although insulin and IGF-1 receptor protein densities remained unaffected, phosphorylated GSKα and GSKβ levels showed different profiles 2 and 8 weeks after T1D induction in the frontal cortex. Altogether, the biphasic response in frontocortical CB1R density within a month after T1D induction resolves previous controversial reports on forebrain CB1R levels in T1D rodent models. Furthermore, this study also hints that cannabinoids may be useful to alleviate impaired glucoregulation in the diabetic cortex.
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| 5. |
- Rafiee, Zeinab, et al.
(author)
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Taurine Supplementation as a Neuroprotective Strategy upon Brain Dysfunction in Metabolic Syndrome and Diabetes
- 2022
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In: Nutrients. - : MDPI AG. - 2072-6643. ; 14:6
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Research review (peer-reviewed)abstract
- Obesity, type 2 diabetes, and their associated comorbidities impact brain metabolism and function and constitute risk factors for cognitive impairment. Alterations to taurine homeostasis can impact a number of biological processes, such as osmolarity control, calcium homeostasis, and inhibitory neurotransmission, and have been reported in both metabolic and neurodegenerative disorders. Models of neurodegenerative disorders show reduced brain taurine concentrations. On the other hand, models of insulin-dependent diabetes, insulin resistance, and diet-induced obesity display taurine accumulation in the hippocampus. Given the possible cytoprotective actions of taurine, such cerebral accumulation of taurine might constitute a compensatory mechanism that attempts to prevent neurodegeneration. The present article provides an overview of brain taurine homeostasis and reviews the mechanisms by which taurine can afford neuroprotection in individuals with obesity and diabetes. We conclude that further research is needed for understanding taurine homeostasis in metabolic disorders with an impact on brain function.
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| 6. |
- Skoug, Cecilia, et al.
(author)
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Density of Sphingosine-1-Phosphate Receptors Is Altered in Cortical Nerve-Terminals of Insulin-Resistant Goto-Kakizaki Rats and Diet-Induced Obese Mice
- 2023
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In: Neurochemical Research. - 0364-3190.
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Journal article (peer-reviewed)abstract
- Sphingosine-1-phosphate (S1P) is a phosphosphingolipid with pleiotropic biological functions. S1P acts as an intracellular second messenger, as well as extracellular ligand to five G-protein coupled receptors (S1PR1-5). In the brain, S1P regulates neuronal proliferation, apoptosis, synaptic activity and neuroglia activation. Moreover, S1P metabolism alterations have been reported in neurodegenerative disorders. We have previously reported that S1PRs are present in nerve terminals, exhibiting distinct sub-synaptic localization and neuromodulation actions. Since type 2 diabetes (T2D) causes synaptic dysfunction, we hypothesized that S1P signaling is modified in nerve terminals. In this study, we determined the density of S1PRs in cortical synaptosomes from insulin-resistant Goto-Kakizaki (GK) rats and Wistar controls, and from mice fed a high-fat diet (HFD) and low-fat-fed controls. Relative to their controls, GK rats showed similar cortical S1P concentration despite higher S1P levels in plasma, yet lower density of S1PR1, S1PR2 and S1PR4 in nerve-terminal-enriched membranes. HFD-fed mice exhibited increased plasma and cortical concentrations of S1P, and decreased density of S1PR1 and S1PR4. These findings point towards altered S1P signaling in synapses of insulin resistance and diet-induced obesity models, suggesting a role of S1P signaling in T2D-associated synaptic dysfunction.
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| 7. |
- Soares, Ana Francisca, et al.
(author)
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Glycogen metabolism is impaired in the brain of male type 2 diabetic Goto-Kakizaki rats
- 2019
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In: Journal of Neuroscience Research. - : Wiley. - 1097-4547 .- 0360-4012. ; 97:8, s. 1004-1017
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Journal article (peer-reviewed)abstract
- Diabetes impacts the central nervous system predisposing to cognitive decline. While glucose is the main source of energy fueling the adult brain, brain glycogen is necessary for adequate neuronal function, synaptic plasticity and memory. In this study, we tested the hypothesis that brain glycogen metabolism is impaired in type 2 diabetes (T2D). 13 C magnetic resonance spectroscopy (MRS) during [1-13 C]glucose i.v. infusion was employed to detect 13 C incorporation into whole-brain glycogen in male Goto-Kakizaki (GK) rats, a lean model of T2D, and control Wistar rats. Labeling from [1-13 C]glucose into brain glycogen occurred at a rate of 0.25 ± 0.12 and 0.48 ± 0.22 µmol/g/h in GK and Wistar rats, respectively (p = 0.028), despite similar brain glycogen concentrations. In addition, the appearance of [1-13 C]glucose in the brain was used to evaluate glucose transport and consumption. T2D caused a 31% reduction (p = 0.031) of the apparent maximum transport rate (Tmax ) and a tendency for reduced cerebral metabolic rate of glucose (CMRglc ; -29%, p = 0.062), indicating impaired glucose utilization in T2D. After MRS in vivo, gas chromatography-mass spectrometry was employed to measure regional 13 C fractional enrichment of glucose and glycogen in the cortex, hippocampus, striatum, and hypothalamus. The diabetes-induced reduction in glycogen labeling was most prominent in the hippocampus and hypothalamus, which are crucial for memory and energy homeostasis, respectively. These findings were further supported by changes in the phosphorylation rate of glycogen synthase, as analyzed by Western blotting. Altogether, the present results indicate that T2D is associated with impaired brain glycogen metabolism.
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| 8. |
- Belenguer, Pascale, et al.
(author)
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Mitochondria and the Brain : Bioenergetics and Beyond
- 2019
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In: Neurotoxicity Research. - : Springer Science and Business Media LLC. - 1029-8428 .- 1476-3524. ; 36:2, s. 219-238
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Journal article (peer-reviewed)abstract
- The view of mitochondria acting solely as a powerhouse of the cell is no longer accurate. Besides cell bioenergetics, primary targets of mitochondrial studies include their interplay with essential processes within the cell, including redox and calcium homeostasis, and apoptosis. Recent studies evidence the dynamic behavior of mitochondria, continuously moving, fusing, and dividing, and the interaction of these events with cellular degeneration and plasticity in neural cells. Our review summarizes novel data and technologies that are developed and applied to the identification and clarification of the mitochondrial role in neural plasticity using both cultured cells and in vivo approaches. The complete understanding and modulation of such mechanisms may represent a novel and promising therapeutic approach for treatment of diseases affecting central and peripheral nervous system.
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| 9. |
- Duarte, João M N, et al.
(author)
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Impact of Caffeine Consumption on Type 2 Diabetes-Induced Spatial Memory Impairment and Neurochemical Alterations in the Hippocampus
- 2019
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In: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 12, s. 1-15
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Journal article (peer-reviewed)abstract
- Diabetes affects the morphology and plasticity of the hippocampus, and leads to learning and memory deficits. Caffeine has been proposed to prevent memory impairment upon multiple chronic disorders with neurological involvement. We tested whether long-term caffeine consumption prevents type 2 diabetes (T2D)-induced spatial memory impairment and hippocampal alterations, including synaptic degeneration, astrogliosis, and metabolic modifications. Control Wistar rats and Goto-Kakizaki (GK) rats that develop T2D were treated with caffeine (1 g/L in drinking water) for 4 months. Spatial memory was evaluated in a Y-maze. Hippocampal metabolic profile and glucose homeostasis were investigated by 1H magnetic resonance spectroscopy. The density of neuronal, synaptic, and glial-specific markers was evaluated by Western blot analysis. GK rats displayed reduced Y-maze spontaneous alternation and a lower amplitude of hippocampal long-term potentiation when compared to controls, suggesting impaired hippocampal-dependent spatial memory. Diabetes did not impact the relation of hippocampal to plasma glucose concentrations, but altered the neurochemical profile of the hippocampus, such as increased in levels of the osmolites taurine (P < 0.001) and myo-inositol (P < 0.05). The diabetic hippocampus showed decreased density of the presynaptic proteins synaptophysin (P < 0.05) and SNAP25 (P < 0.05), suggesting synaptic degeneration, and increased GFAP (P < 0.001) and vimentin (P < 0.05) immunoreactivities that are indicative of astrogliosis. The effects of caffeine intake on hippocampal metabolism added to those of T2D, namely reducing myo-inositol levels (P < 0.001) and further increasing taurine levels (P < 0.05). Caffeine prevented T2D-induced alterations of GFAP, vimentin and SNAP25, and improved memory deficits. We conclude that caffeine consumption has beneficial effects counteracting alterations in the hippocampus of GK rats, leading to the improvement of T2D-associated memory impairment.
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| 10. |
- Duarte, João M.N.
(author)
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Loss of brain energy metabolism control as a driver for memory impairment upon insulin resistance
- 2023
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In: Biochemical Society Transactions. - 0300-5127. ; 51:1, s. 287-301
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Research review (peer-reviewed)abstract
- The pathophysiological mechanisms intersecting metabolic and neurodegenerative disorders include insulin resistance, which has a strong involvement of environmental factors. Besides central regulation of whole-body homeostasis, insulin in the central nervous system controls molecular signalling that is critical for cognitive performance, namely signalling through pathways that modulate synaptic transmission and plasticity, and metabolism in neurons and astrocytes. This review provides an overview on how insulin signalling in the brain might regulate brain energy metabolism, and further identified molecular mechanisms by which brain insulin resistance might impair synaptic fuelling, and lead to cognitive deterioration.
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| 11. |
- Duarte, João M.N., et al.
(author)
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Magnetic Resonance Spectroscopy in Schizophrenia : Evidence for Glutamatergic Dysfunction and Impaired Energy Metabolism
- 2019
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In: Neurochemical Research. - : Springer Science and Business Media LLC. - 0364-3190 .- 1573-6903. ; 44:1, s. 102-116
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Journal article (peer-reviewed)abstract
- In the past couple of decades, major efforts were made to increase reliability of metabolic assessments by magnetic resonance methods. Magnetic resonance spectroscopy (MRS) has been valuable for providing in vivo evidence and investigating biomarkers in neuropsychiatric disorders, namely schizophrenia. Alterations of glutamate and glutamine levels in brains of schizophrenia patients relative to healthy subjects are generally interpreted as markers of glutamatergic dysfunction. However, only a small fraction of MRS-detectable glutamate is involved in neurotransmission. Here we review and discuss brain metabolic processes that involve glutamate and that are likely to be implicated in neuropsychiatric disorders.
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| 12. |
- Duarte, João M.N.
(author)
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Serine racemase modulation for improving brain insulin resistance : An Editorial Highlight for “Deletion of serine racemase reverses neuronal insulin signaling inhibition by amyloid-β oligomers”
- 2022
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In: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 163:1, s. 6-7
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Journal article (peer-reviewed)abstract
- This Editorial highlights an interesting study in the current issue of the Journal of Neurochemistry in which Zhou et al. report new data showing that the ablation of serine racemase increases local insulin production in neurons of the hippocampus. The authors explored some of the possible mechanisms mediating the interaction between dampening production of D-serine and the local synthesis of insulin, and they further propose that stimulating insulin production could counteract hippocampal insulin resistance in Alzheimer's disease (AD). Most importantly, they leave open a number of questions that need to be experimentally addressed to ascertain whether D-serine modulation of neuronal insulin expression can effectively improve insulin sensitivity in AD, as well as in metabolic disease with neurological impact.
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| 13. |
- Kubota, Manabu, et al.
(author)
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Dynamic alterations in the central glutamatergic status following food and glucose intake : in vivo multimodal assessments in humans and animal models
- 2021
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In: Journal of Cerebral Blood Flow and Metabolism. - 0271-678X. ; 41:11, s. 2928-2943
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Journal article (peer-reviewed)abstract
- Fluctuations of neuronal activities in the brain may underlie relatively slow components of neurofunctional alterations, which can be modulated by food intake and related systemic metabolic statuses. Glutamatergic neurotransmission plays a major role in the regulation of excitatory tones in the central nervous system, although just how dietary elements contribute to the tuning of this system remains elusive. Here, we provide the first demonstration by bimodal positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) that metabotropic glutamate receptor subtype 5 (mGluR5) ligand binding and glutamate levels in human brains are dynamically altered in a manner dependent on food intake and consequent changes in plasma glucose levels. The brain-wide modulations of central mGluR5 ligand binding and glutamate levels and profound neuronal activations following systemic glucose administration were further proven by PET, MRS, and intravital two-photon microscopy, respectively, in living rodents. The present findings consistently support the notion that food-associated glucose intake is mechanistically linked to glutamatergic tones in the brain, which are translationally accessible in vivo by bimodal PET and MRS measurements in both clinical and non-clinical settings.
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| 14. |
- Lizarbe, Blanca, et al.
(author)
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High-fat diet consumption alters energy metabolism in the mouse hypothalamus
- 2019
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In: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 43:6, s. 1295-1304
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Journal article (peer-reviewed)abstract
- Background/Objectives: High-fat diet consumption is known to trigger an inflammatory response in the hypothalamus, which has been characterized by an initial expression of pro-inflammatory genes followed by hypothalamic astrocytosis, microgliosis, and the appearance of neuronal injury markers. The specific effects of high-fat diet on hypothalamic energy metabolism and neurotransmission are however not yet known and have not been investigated before. Subjects/Methods: We used 1H and 13C magnetic resonance spectroscopy (MRS) and immunofluorescence techniques to evaluate in vivo the consequences of high-saturated fat diet administration to mice, and explored the effects on hypothalamic metabolism in three mouse cohorts at different time points for up to 4 months. Results: We found that high-fat diet increases significantly the hypothalamic levels of glucose (P < 0.001), osmolytes (P < 0.001), and neurotransmitters (P < 0.05) from 2 months of diet, and alters the rates of metabolic (P < 0.05) and neurotransmission fluxes (P < 0.001), and the contribution of non-glycolytic substrates to hypothalamic metabolism (P < 0.05) after 10 weeks of high-fat feeding. Conclusions/interpretation: We report changes that reveal a high-fat diet-induced alteration of hypothalamic metabolism and neurotransmission that is quantifiable by 1H and 13C MRS in vivo, and present the first evidence of the extension of the inflammation pathology to a localized metabolic imbalance.
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| 15. |
- Lizarbe, Blanca, et al.
(author)
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Neurochemical Modifications in the Hippocampus, Cortex and Hypothalamus of Mice Exposed to Long-Term High-Fat Diet
- 2018
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In: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 12
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Journal article (peer-reviewed)abstract
- Metabolic syndrome and diabetes impact brain function and metabolism. While it is well established that rodents exposed to diets rich in saturated fat develop brain dysfunction, contrasting results abound in the literature, likely as result of exposure to different high-fat diet (HFD) compositions and for varied periods of time. In the present study, we investigated alterations of hippocampal-dependent spatial memory by measuring Y-maze spontaneous alternation, metabolic profiles of the hippocampus, cortex and hypothalamus by 1H magnetic resonance spectroscopy (MRS), and levels of proteins specific to synaptic and glial compartments in mice exposed for 6 months to different amounts of fat (10, 45, or 60% of total energy intake). Increasing the dietary amount of fat from 10 to 45% or 60% resulted in obesity accompanied by increased leptin, fasting blood glucose and insulin, and reduced glucose tolerance. In comparison to controls (10%-fat), only mice fed the 60%-fat diet showed increased fed glycemia, as well as plasma corticosterone that has a major impact on brain function. HFD-induced metabolic profile modifications measured by 1H MRS were observed across the three brain areas in mice exposed to 60%- but not 45%-fat diet, while both HFD groups displayed impaired hippocampal-dependent memory. HFD also affected systems involved in neuro- or gliotransmission in the hippocampus. Namely, relative to controls, 60%-fat-fed mice showed reduced SNAP-25, PSD-95 and syntaxin-4 immunoreactivity, while 45%-fat-fed mice showed reduced gephyrin and syntaxin-4 immunoreactivity. For both HFD levels, reductions of the vesicular glutamate transporter vGlut1 and levels of the vesicular GABA transporter were observed in the hippocampus and hypothalamus, relative to controls. Immunoreactivity against GFAP and/or Iba-1 in the hypothalamus was higher in mice exposed to HFD than controls, suggesting occurrence of gliosis. We conclude that different levels of dietary fat result in distinct neurochemical alterations in the brain.
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| 16. |
- Rae, Caroline D., et al.
(author)
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Brain energy metabolism : A roadmap for future research
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In: Journal of Neurochemistry. - 0022-3042.
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Journal article (peer-reviewed)abstract
- Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+, as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research.
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| 17. |
- Skoug, Cecilia, et al.
(author)
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Genetic deletion of hormone-sensitive lipase in mice reduces cerebral blood flow but does not aggravate the impact of diet-induced obesity on memory
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In: Journal of Neurochemistry. - 0022-3042.
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Journal article (peer-reviewed)abstract
- Hormone-sensitive lipase (HSL) is active throughout the brain and its genetic ablation impacts brain function. Its activity in the brain was proposed to regulate bioactive lipid availability, namely eicosanoids that are inflammatory mediators and regulate cerebral blood flow (CBF). We aimed at testing whether HSL deletion increases susceptibility to neuroinflammation and impaired brain perfusion upon diet-induced obesity. HSL−/−, HSL+/−, and HSL+/+ mice of either sex were fed high-fat diet (HFD) or control diet for 8 weeks, and then assessed in behavior tests (object recognition, open field, and elevated plus maze), metabolic tests (insulin and glucose tolerance tests and indirect calorimetry in metabolic cages), and CBF determination by arterial spin labeling (ASL) magnetic resonance imaging (MRI). Immunofluorescence microscopy was used to determine coverage of blood vessels, and morphology of astrocytes and microglia in brain slices. HSL deletion reduced CBF, most prominently in cortex and hippocampus, while HFD feeding only lowered CBF in the hippocampus of wild-type mice. CBF was positively correlated with lectin-stained vessel density. HSL deletion did not exacerbate HFD-induced microgliosis in the hippocampus and hypothalamus. HSL−/− mice showed preserved memory performance when compared to wild-type mice, and HSL deletion did not significantly aggravate HFD-induced memory impairment in object recognition tests. In contrast, HSL deletion conferred protection against HFD-induced obesity, glucose intolerance, and insulin resistance. Altogether, this study points to distinct roles of HSL in periphery and brain during diet-induced obesity. While HSL−/− mice were protected against metabolic syndrome development, HSL deletion reduced brain perfusion without leading to aggravated HFD-induced neuroinflammation and memory dysfunction.
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| 18. |
- Skoug, Cecilia, et al.
(author)
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Sphingosine 1-Phoshpate Receptors are Located in Synapses and Control Spontaneous Activity of Mouse Neurons in Culture
- 2022
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In: Neurochemical Research. - : Springer Science and Business Media LLC. - 1573-6903 .- 0364-3190. ; 47:10, s. 3114-3125
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Journal article (peer-reviewed)abstract
- Sphingosine-1-phosphate (S1P) is best known for its roles as vascular and immune regulator. Besides, it is also present in the central nervous system (CNS) where it can act as neuromodulator via five S1P receptors (S1PRs), and thus control neurotransmitter release. The distribution of S1PRs in the active zone and postsynaptic density of CNS synapses remains unknown. In the current study, we investigated the localization of S1PR1-5 in synapses of the mouse cortex. Cortical nerve terminals purified in a sucrose gradient were endowed with all five S1PRs. Further subcellular fractionation of cortical nerve terminals revealed S1PR2 and S1PR4 immunoreactivity in the active zone of presynaptic nerve terminals. Interestingly, only S1PR2 and S1PR3 immunoreactivity was found in the postsynaptic density. All receptors were present outside the active zone of nerve terminals. Neurons in the mouse cortex and primary neurons in culture showed immunoreactivity against all five S1PRs, and Ca 2+ imaging revealed that S1P inhibits spontaneous neuronal activity in a dose-dependent fashion. When testing selective agonists for each of the receptors, we found that only S1PR1, S1PR2 and S1PR4 control spontaneous neuronal activity. We conclude that S1PR2 and S1PR4 are located in the active zone of nerve terminals and inhibit neuronal activity. Future studies need to test whether these receptors modulate stimulation-induced neurotransmitter release.
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| 19. |
- Sonnay, Sarah, et al.
(author)
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Astrocytic and neuronal oxidative metabolism are coupled to the rate of glutamate–glutamine cycle in the tree shrew visual cortex
- 2018
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In: GLIA. - : Wiley. - 0894-1491. ; 66:3, s. 477-491
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Journal article (peer-reviewed)abstract
- Astrocytes play an important role in glutamatergic neurotransmission, namely by clearing synaptic glutamate and converting it into glutamine that is transferred back to neurons. The rate of this glutamate–glutamine cycle (VNT) has been proposed to couple to that of glucose utilization and of neuronal tricarboxylic acid (TCA) cycle. In this study, we tested the hypothesis that glutamatergic neurotransmission is also coupled to the TCA cycle rate in astrocytes. For that we investigated energy metabolism by means of magnetic resonance spectroscopy (MRS) in the primary visual cortex of tree shrews (Tupaia belangeri) under light isoflurane anesthesia at rest and during continuous visual stimulation. After identifying the activated cortical volume by blood oxygenation level-dependent functional magnetic resonance imaging, 1H MRS was performed to measure stimulation-induced variations in metabolite concentrations. Relative to baseline, stimulation of cortical activity for 20 min caused a reduction of glucose concentration by −0.34 ± 0.09 µmol/g (p < 0.001), as well as a −9% ± 1% decrease of the ratio of phosphocreatine-to-creatine (p < 0.05). Then 13C MRS during [1,6-13C]glucose infusion was employed to measure fluxes of energy metabolism. Stimulation of glutamatergic activity, as indicated by a 20% increase of VNT, resulted in increased TCA cycle rates in neurons by 12% ((VTCA n, p < 0.001), p < 0.001) and in astrocytes by 24% ((VTCA g, p = 0.007). We further observed linear relationships between VNT and both VTCA n and VTCA g. Altogether, these results suggest that in the tree shrew primary visual cortex glutamatergic neurotransmission is linked to overall glucose oxidation and to mitochondrial metabolism in both neurons and astrocytes.
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| 20. |
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| 21. |
- Vanherle, Lotte, et al.
(author)
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Restoring myocardial infarction-induced long-term memory impairment by targeting the cystic fibrosis transmembrane regulator
- 2022
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In: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 86
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Journal article (peer-reviewed)abstract
- BACKGROUND: Cognitive impairment is a serious comorbidity in heart failure patients, but effective therapies are lacking. We investigated the mechanisms that alter hippocampal neurons following myocardial infarction (MI).METHODS: MI was induced in male C57Bl/6 mice by left anterior descending coronary artery ligation. We utilised standard procedures to measure cystic fibrosis transmembrane regulator (CFTR) protein levels, inflammatory mediator expression, neuronal structure, and hippocampal memory. Using in vitro and in vivo approaches, we assessed the role of neuroinflammation in hippocampal neuron degradation and the therapeutic potential of CFTR correction as an intervention.FINDINGS: Hippocampal dendrite length and spine density are reduced after MI, effects that associate with decreased neuronal CFTR expression and concomitant microglia activation and inflammatory cytokine expression. Conditioned medium from lipopolysaccharide-stimulated microglia (LCM) reduces neuronal cell CFTR protein expression and the mRNA expression of the synaptic regulator post-synaptic density protein 95 (PSD-95) in vitro. Blocking CFTR activity also down-regulates PSD-95 in neurons, indicating a relationship between CFTR expression and neuronal health. Pharmacologically correcting CFTR expression in vitro rescues the LCM-mediated down-regulation of PSD-95. In vivo, pharmacologically increasing hippocampal neuron CFTR expression improves MI-associated alterations in neuronal arborisation, spine density, and memory function, with a wide therapeutic time window.INTERPRETATION: Our results indicate that CFTR therapeutics improve inflammation-induced alterations in hippocampal neuronal structure and attenuate memory dysfunction following MI.
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