A volumetric census of the Barents Sea in a changing climate

The Barents Sea, located between the Norwegian Sea and the Arctic Ocean, is one of the main pathways of the Atlantic Meridional Overturning Circulation. Changes in the water mass transformations in the Barents Sea potentially affect the thermohaline circulation through the alteration of the dense water formation process. In order to investigate such changes, we present here a seasonal atlas of the Barents Sea including both temperature and salinity for the period 1965–2016. The atlas is built as a compilation of datasets from the World Ocean Database, the Polar Branch of the Russian Federal Research Institute of Fisheries and Oceanography and the Norwegian Polar Institute using the Data-Interpolating Variational Analysis (DIVA) tool. DIVA allows for a minimization of the expected error with respect to the true field. The atlas is used to provide a volumetric analysis of water mass characteristics and an estimation of the ocean heat and freshwater contents. The results show a recent “Atlantification” of the Barents Sea, that is a general increase in both temperature and salinity, while its density remains stable. The atlas is made freely accessible as user-friendly NetCDF files to encourage further research in the Barents Sea physics (https://doi.org/10.21335/NMDC-2058021735, Watelet et al., 2020).publishedVersio

Response to Notter and Meyer's Letter to the Editor Regarding Increased Expression of Translocator Protein (TSPO) Marks Pro-inflammatory Microglia but Does Not Predict Neurodegeneration

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Neuronal Dysfunction and Behavioral Abnormalities Are Evoked by Neural Cells and Aggravated by Inflammatory Microglia in Peroxisomal β-Oxidation Deficiency

It is becoming evident that microglia, the resident immune cells of the central nervous system (CNS), are active contributors in neurological disorders. Nevertheless, the impact of microgliosis on neuropathology, behavior and clinical decline in neuropathological conditions remains elusive. A mouse model lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develops a fatal disorder characterized by motor problems similar to the milder form of human disease. The molecular mechanisms underlying neurological decline in men and mice remain unknown. The hallmark of disease in the mouse model is chronic proliferation of microglia in the brain without provoking neuronal loss or demyelination. In order to define the contribution of Mfp2−/− neural cells to development of microgliosis and clinical neuropathology, the constitutive Mfp2−/− mouse model was compared to a neural selective Nestin-Mfp2−/− mouse model. We demonstrate in this study that, in contrast to early-onset and severe microgliosis in constitutive Mfp2−/− mice, Mfp2+/+ microglia in Nestin-Mfp2−/− mice only become mildly inflammatory at end stage of disease. Mfp2−/− microglia are primed and acquire a chronic and strong inflammatory state in Mfp2−/− mice whereas Mfp2+/+ microglia in Nestin-Mfp2−/− mice are not primed and adopt a minimal activation state. The inflammatory microglial phenotype in Mfp2−/− mice is correlated with more severe neuronal dysfunction, faster clinical deterioration and reduced life span compared to Nestin-Mfp2−/− mice. Taken together, our study shows that deletion of MFP2 impairs behavior and locomotion. Clinical decline and neural pathology is aggravated by an early-onset and excessive microglial response in Mfp2−/− mice and strongly indicates a cell-autonomous role of MFP2 in microglia

Identification of a chronic non-neurodegenerative microglia activation state in a mouse model of peroxisomal β-oxidation deficiency

The functional diversity and molecular adaptations of reactive microglia in the chronically inflamed central nervous system (CNS) are poorly understood. We previously showed that mice lacking multifunctional protein 2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, persistently accumulate reactive myeloid cells in the gray matter of the CNS. Here, we show that the increased numbers of myeloid cells solely derive from the proliferation of resident microglia and not from infiltrating monocytes. We defined the signature of Mfp2(-/-) microglia by gene expression profiling after acute isolation, which was validated by quantitative polymerase reaction (qPCR), immunohistochemical, and flow cytometric analysis. The features of Mfp2(-/-) microglia were compared with those from SOD1(G93A) mice, an amyotrophic lateral sclerosis model. In contrast to the neurodegenerative milieu of SOD1(G93A) spinal cord, neurons were intact in Mfp2(-/-) brain and Mfp2(-/-) microglia lacked signs of phagocytic and neurotoxic activity. The chronically reactive state of Mfp2(-/-) microglia was accompanied by the downregulation of markers that specify the unique microglial signature in homeostatic conditions. In contrast, mammalian target of rapamycin (mTOR) and downstream glycolytic and protein translation pathways were induced, indicative of metabolic adaptations. Mfp2(-/-) microglia were immunologically activated but not polarized to a pro- or anti-inflammatory phenotype. A peripheral lipopolysaccharide challenge provoked an exaggerated inflammatory response in Mfp2(-/-) brain, consistent with a primed state. Taken together, we demonstrate that chronic activation of resident microglia does not necessarily lead to phagocytosis nor overt neurotoxicity. GLIA 2015.status: publishe

Image_2_Neuronal Dysfunction and Behavioral Abnormalities Are Evoked by Neural Cells and Aggravated by Inflammatory Microglia in Peroxisomal β-Oxidation Deficiency.TIF

<p>It is becoming evident that microglia, the resident immune cells of the central nervous system (CNS), are active contributors in neurological disorders. Nevertheless, the impact of microgliosis on neuropathology, behavior and clinical decline in neuropathological conditions remains elusive. A mouse model lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develops a fatal disorder characterized by motor problems similar to the milder form of human disease. The molecular mechanisms underlying neurological decline in men and mice remain unknown. The hallmark of disease in the mouse model is chronic proliferation of microglia in the brain without provoking neuronal loss or demyelination. In order to define the contribution of Mfp2^−/− neural cells to development of microgliosis and clinical neuropathology, the constitutive Mfp2^−/− mouse model was compared to a neural selective Nestin-Mfp2^−/− mouse model. We demonstrate in this study that, in contrast to early-onset and severe microgliosis in constitutive Mfp2^−/− mice, Mfp2^+/+ microglia in Nestin-Mfp2^−/− mice only become mildly inflammatory at end stage of disease. Mfp2^−/− microglia are primed and acquire a chronic and strong inflammatory state in Mfp2^−/− mice whereas Mfp2^+/+ microglia in Nestin-Mfp2^−/− mice are not primed and adopt a minimal activation state. The inflammatory microglial phenotype in Mfp2^−/− mice is correlated with more severe neuronal dysfunction, faster clinical deterioration and reduced life span compared to Nestin-Mfp2^−/− mice. Taken together, our study shows that deletion of MFP2 impairs behavior and locomotion. Clinical decline and neural pathology is aggravated by an early-onset and excessive microglial response in Mfp2^−/− mice and strongly indicates a cell-autonomous role of MFP2 in microglia.</p

Image_1_Neuronal Dysfunction and Behavioral Abnormalities Are Evoked by Neural Cells and Aggravated by Inflammatory Microglia in Peroxisomal β-Oxidation Deficiency.TIF

<p>It is becoming evident that microglia, the resident immune cells of the central nervous system (CNS), are active contributors in neurological disorders. Nevertheless, the impact of microgliosis on neuropathology, behavior and clinical decline in neuropathological conditions remains elusive. A mouse model lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develops a fatal disorder characterized by motor problems similar to the milder form of human disease. The molecular mechanisms underlying neurological decline in men and mice remain unknown. The hallmark of disease in the mouse model is chronic proliferation of microglia in the brain without provoking neuronal loss or demyelination. In order to define the contribution of Mfp2^−/− neural cells to development of microgliosis and clinical neuropathology, the constitutive Mfp2^−/− mouse model was compared to a neural selective Nestin-Mfp2^−/− mouse model. We demonstrate in this study that, in contrast to early-onset and severe microgliosis in constitutive Mfp2^−/− mice, Mfp2^+/+ microglia in Nestin-Mfp2^−/− mice only become mildly inflammatory at end stage of disease. Mfp2^−/− microglia are primed and acquire a chronic and strong inflammatory state in Mfp2^−/− mice whereas Mfp2^+/+ microglia in Nestin-Mfp2^−/− mice are not primed and adopt a minimal activation state. The inflammatory microglial phenotype in Mfp2^−/− mice is correlated with more severe neuronal dysfunction, faster clinical deterioration and reduced life span compared to Nestin-Mfp2^−/− mice. Taken together, our study shows that deletion of MFP2 impairs behavior and locomotion. Clinical decline and neural pathology is aggravated by an early-onset and excessive microglial response in Mfp2^−/− mice and strongly indicates a cell-autonomous role of MFP2 in microglia.</p

Microglia lacking a peroxisomal β-oxidation enzyme chronically alter their inflammatory profile without evoking neuronal and behavioral deficits

Abstract Background Microglia play a central role in most neurological disorders, but the impact of microgliosis on brain environment and clinical functions is not fully understood. Mice lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develop a fatal disorder characterized by motor problems similar to the milder form of MFP2 deficiency in humans. The hallmark of disease in mice is the chronic proliferation of microglia in the brain, but molecular pathomechanisms that drive rapid clinical deterioration in human and mice remain unknown. In the present study, we identified the effects of specific deletion of MFP2 from microglia in the brain on immune responses, neuronal functioning, and behavior. Methods We created a novel Cx3cr1-Mfp2 −/− mouse model and studied the impact of MFP2 deficiency on microglial behavior at different ages using immunohistochemistry and real-time PCR. Pro- and anti-inflammatory responses of Mfp2 −/− microglia were assessed in vitro and in vivo after stimulation with IL-1β/INFγ and IL-4 (in vitro) and LPS and IL-4 (in vivo). Facial nerve axotomy was unilaterally performed in Cx3cr1-Mfp2 −/− and control mice, and microglial functioning in response to neuronal injury was subsequently analyzed by histology and real-time PCR. Finally, neuronal function, motor function, behavior, and cognition were assessed using brainstem auditory evoked potentials, grip strength and inverted grid test, open field exploration, and passive avoidance learning, respectively. Results We found that Mfp2 −/− microglia in a genetically intact brain environment adopt an inflammatory activated and proliferative state. In addition, we found that acute inflammatory and neuronal injury provoked normal responses of Mfp2 −/− microglia in Cx3cr1-Mfp2 −/− mice during the post-injury period. Despite chronic pro-inflammatory microglial reactivity, Cx3cr1-Mfp2 −/− mice exhibited normal neuronal transmission, clinical performance, and cognition. Conclusion Our data demonstrate that MFP2 deficiency in microglia causes intrinsic dysregulation of their inflammatory profile, which is not harmful to neuronal function, motor function, and cognition in mice during their first year of life

The oxysterol and cholestenoic acid profile of mouse cerebrospinal fluid

Oxysterols and cholestenoic acids are oxidised forms of cholesterol with a host of biological functions. The possible roles of oxysterols in various neurological diseases makes the analysis of these metabolites in the central nervous system of particular interest. Here, we report the identification and quantification of a panel of twelve sterols in mouse cerebrospinal fluid (CSF) using liquid chromatography-mass spectrometry exploiting enzyme assisted derivatisation for sterol analysis technology. We found low levels of oxysterols and cholestenoic acids in CSF the range of 5pg/mL-2.6ng/mL. As found in man, these concentrations are one to two orders of magnitude lower than in plasma.publisher: Elsevier articletitle: The oxysterol and cholestenoic acid profile of mouse cerebrospinal fluid journaltitle: Steroids articlelink: http://dx.doi.org/10.1016/j.steroids.2015.02.021 content_type: article copyright: Copyright © 2015 The Authors. Published by Elsevier Inc.status: publishe