333 results on '"Magistretti PJ"'
Search Results
2. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa
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Watson HJ, Yilmaz Z, Thornton LM, Hübel C, Coleman JRI, Gaspar HA, Bryois J, Hinney A, Leppä VM, Mattheisen M, Medland SE, Ripke S, Yao S, Giusti-Rodríguez P, Anorexia Nervosa Genetics Initiative, Hanscombe KB, Purves KL, Eating Disorders Working Group of the Psychiatric Genomics Consortium, Adan RAH, Alfredsson L, Ando T, Andreassen OA, Baker JH, Berrettini WH, Boehm I, Boni C, Perica VB, Buehren K, Burghardt R, Cassina M, Cichon S, Clementi M, Cone RD, Courtet P, Crow S, Crowley JJ, Danner UN, Davis OSP, de Zwaan M, Dedoussis G, Degortes D, DeSocio JE, Dick DM, Dikeos D, Dina C, Dmitrzak-Weglarz M, Docampo E, Duncan LE, Egberts K, Ehrlich S, Escaramís G, Esko T, Estivill X, Farmer A, Favaro A, Fernández-Aranda F, Fichter MM, Fischer K, Föcker M, Foretova L, Forstner AJ, Forzan M, Franklin CS, Gallinger S, Giegling I, Giuranna J, Gonidakis F, Gorwood P, Mayora MG, Guillaume S, Guo Y, Hakonarson H, Hatzikotoulas K, Hauser J, Hebebrand J, Helder SG, Herms S, Herpertz-Dahlmann B, Herzog W, Huckins LM, Hudson JI, Imgart H, Inoko H, Janout V, Jiménez-Murcia S, Julià A, Kalsi G, Kaminská D, Kaprio J, Karhunen L, Karwautz A, Kas MJH, Kennedy JL, Keski-Rahkonen A, Kiezebrink K, Kim YR, Klareskog L, Klump KL, Knudsen GPS, La Via MC, Le Hellard S, Levitan RD, Li D, Lilenfeld L, Lin BD, Lissowska J, Luykx J, Magistretti PJ, Maj M, Mannik K, Marsal S, Marshall CR, Mattingsdal M, McDevitt S, McGuffin P, Metspalu A, Meulenbelt I, Micali N, Mitchell K, Monteleone AM, Monteleone P, Munn-Chernoff MA, Nacmias B, Navratilova M, Ntalla I, O'Toole JK, Ophoff RA, Padyukov L, Palotie A, Pantel J, Papezova H, Pinto D, Raquel Rabionet Janssen, Raevuori A, Ramoz N, Reichborn-Kjennerud T, Ricca V, Ripatti S, Ritschel F, Roberts M, Rotondo A, Rujescu D, Rybakowski F, Santonastaso P, Scherag A, Scherer SW, Schmidt U, Schork NJ, Schosser A, Seitz J, Slachtova L, Slagboom PE, Slof-Op 't Landt MCT, Slopien A, Sorbi S, Swiatkowska B, Szatkiewicz JP, Tachmazidou I, Tenconi E, Tortorella A, Tozzi F, Treasure J, Tsitsika A, Tyszkiewicz-Nwafor M, Tziouvas K, van Elburg AA, van Furth EF, Wagner G, Walton E, Widen E, Zeggini E, Zerwas S, Zipfel S, Bergen AW, Boden JM, Brandt H, Crawford S, Halmi KA, Horwood LJ, Johnson C, Kaplan AS, Kaye WH, Mitchell JE, Olsen CM, Pearson JF, Pedersen NL, Strober M, Werge T, Whiteman DC, Woodside DB, Stuber GD, Gordon S, Grove J, Henders AK, Juréus A, Kirk KM, Larsen JT, Parker R, Petersen L, Jordan J, Kennedy M, Montgomery GW, Wade TD, Birgegård A, Lichtenstein P, Norring C, Landén M, Martin NG, Mortensen PB, Sullivan PF, Breen G, and Bulik CM
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mental disorders - Abstract
Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness 1 , affecting 0.9-4% of women and 0.3% of men 2-4 , with twin-based heritability estimates of 50-60% 5 . Mortality rates are higher than those in other psychiatric disorders 6 , and outcomes are unacceptably poor 7 . Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI) 8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
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- 2019
3. Brain Lactate Metabolism in Humans With Subarachnoid Hemorrhage
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Oddo M, Levine JM, Frangos S, Maloney-Wilensky E, Carrera E, Daniel RT, Levivier M, Magistretti PJ, and LeRoux PD
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BACKGROUND AND PURPOSE: Lactate is central for the regulation of brain metabolism and is an alternative substrate to glucose after injury. Brain lactate metabolism in patients with subarachnoid hemorrhage has not been fully elucidated. METHODS: Thirty one subarachnoid hemorrhage patients monitored with cerebral microdialysis (CMD) and brain oxygen (PbtO(2)) were studied. Samples with elevated CMD lactate (>4 mmol/L) were matched to PbtO(2) and CMD pyruvate and categorized as hypoxic (PbtO(2) 119 µmol/L) versus nonhyperglycolytic. RESULTS: Median per patient samples with elevated CMD lactate was 54 (interquartile range 11 80). Lactate elevations were more often attributable to cerebral hyperglycolysis (78; interquartile range 5 98) than brain hypoxia (11; interquartile range 4 75). Mortality was associated with increased percentage of samples with elevated lactate and brain hypoxia (28 [interquartile range 9 95] in nonsurvivors versus 9 [interquartile range 3 17] in survivors; P=0.02) and lower percentage of elevated lactate and cerebral hyperglycolysis (13 [interquartile range 1 87] versus 88 [interquartile range 27 99]; P=0.07). Cerebral hyperglycolytic lactate production predicted good 6 month outcome (odds ratio for modified Rankin Scale score 0 3 1.49; CI 1.08 2.05; P=0.016) whereas increased lactate with brain hypoxia was associated with a reduced likelihood of good outcome (OR 0.78; CI 0.59 1.03; P=0.08). CONCLUSIONS: Brain lactate is frequently elevated in subarachnoid hemorrhage patients predominantly because of hyperglycolysis rather than hypoxia. A pattern of increased cerebral hyperglycolytic lactate was associated with good long term recovery. Our data suggest that lactate may be used as an aerobic substrate by the injured human brain.
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- 2012
4. A beta 42 Neurotoxicity Is Mediated by Ongoing Nucleated Polymerization Process Rather than by Discrete A beta 42 Species
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Jan A, Adolfsson O, Allaman I, Buccarello AL, Magistretti PJ, Pfeifer A, Muhs A, and Lashuel HA
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macromolecular substances - Abstract
The identification of toxic Aß species and/or the process of their formation is crucial for understanding the mechanism(s) of Aß neurotoxicity in Alzheimer disease and also for the development of effective diagnostic and therapeutic interventions. To elucidate the structural basis of Aß toxicity we developed different procedures to isolate Aß species of defined size and morphology distribution and we investigated their toxicity in different cell lines and primary neurons. We observed that crude Aß42 preparations containing a monomeric and heterogeneous mixture of Aß42 oligomers were more toxic than purified monomeric protofibrillar fractions or fibrils. The toxicity of protofibrils was directly linked to their interactions with monomeric Aß42 and strongly dependent on their ability to convert into amyloid fibrils. Subfractionation of protofibrils diminished their fibrillization and toxicity whereas reintroduction of monomeric Aß42 into purified protofibril fractions restored amyloid formation and enhanced their toxicity. Selective removal of monomeric Aß42 from these preparations using insulin degrading enzyme reversed the toxicity of Aß42 protofibrils. Together our findings demonstrate that Aß42 toxicity is not linked to specific prefibrillar aggregate(s) but rather to the ability of these species to grow and undergo fibril formation which depends on the presence of monomeric Aß42. These findings contribute significantly to the understanding of amyloid formation and toxicity in Alzheimer disease provide novel insight into mechanisms of Aß protofibril toxicity and important implications for designing anti amyloid therapies.
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- 2011
5. Brain Energy Metabolism: Focus on Astrocyte-Neuron Metabolic Cooperation
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Belanger M, Allaman I, and Magistretti PJ
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The energy requirements of the brain are very high and tight regulatory mechanisms operate to ensure adequate spatial and temporal delivery of energy substrates in register with neuronal activity. Astrocytes a type of glial cell have emerged as active players in brain energy delivery production utilization and storage. Our understanding of neuroenergetics is rapidly evolving from a "neurocentric" view to a more integrated picture involving an intense cooperativity between astrocytes and neurons. This review focuses on the cellular aspects of brain energy metabolism with a particular emphasis on the metabolic interactions between neurons and astrocytes. Copyright © 2011 Elsevier Inc. All rights reserved.
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- 2011
6. Differential effects of pro- and anti-inflammatory cytokines alone or in combinations on the metabolic profile of astrocytes
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Belanger M, Allaman I, and Magistretti PJ
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We have previously reported that the pro inflammatory cytokines tumor necrosis factor a (TNFa) and interleukin 1ß (IL 1ß) induce profound modifications of the metabolic profile of astrocytes. The present study was undertaken to further characterize the effects of cytokines in astrocytes and to determine whether similar effects could also be observed in neurons. To do so selected pro inflammatory (IL 6 and interferon ? in addition to the above mentioned TNFa and IL 1ß) and anti inflammatory cytokines (IL 4 IL 10 transforming growth factor ß1 and interferon ß) were applied to primary neuronal and astrocytic cultures and key metabolic parameters were assessed. As a general pattern we observed that pro inflammatory cytokines increased glucose utilization in astrocytes while the anti inflammatory cytokines IL 4 and IL 10 decreased astrocytic glucose utilization. In contrast no significant change could be observed in neurons. When pairs of pro inflammatory cytokines were co applied in astrocytes several additive or synergistic modifications could be observed. In contrast IL 10 partially attenuated the effects of pro inflammatory cytokines. Finally the modifications of the astrocytic metabolism induced by TNFa + IL 1ß and interferon ? modulated neuronal susceptibility to an excitotoxic insult in neuron astrocyte co cultures. Together these results suggest that pro and anti inflammatory cytokines differentially affect the metabolic profile of astrocytes and that these changes have functional consequences for surrounding neurons. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.
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- 2011
7. Astrocyte-neuron metabolic relationships: for better and for worse
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Allaman I, Belanger M, and Magistretti PJ
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In recent years previously unsuspected roles of astrocytes have been revealed largely owing to the development of new tools enabling their selective study in situ. These exciting findings add to the large body of evidence demonstrating that astrocytes play a central role in brain homeostasis in particular via the numerous cooperative metabolic processes they establish with neurons such as the supply of energy metabolites and neurotransmitter recycling functions. Furthermore impairments in astrocytic function are increasingly being recognized as an important contributor to neuronal dysfunction and in particular neurodegenerative processes. In this review we discuss recent evidence supporting important roles for astrocytes in neuropathological conditions such as neuroinflammation amyotrophic lateral sclerosis and Alzheimer's disease. We also explore the potential for neuroprotective therapeutics based on the modulation of astrocytic functions. Copyright © 2010 Elsevier Ltd. All rights reserved.
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- 2011
8. Neuron-glia metabolic coupling and plasticity
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Magistretti PJ
- Abstract
The focus of the current research projects in my laboratory revolves around the question of metabolic plasticity of neuron glia coupling. Our hypothesis is that behavioural conditions such as for example learning or the sleep wake cycle in which synaptic plasticity is well documented or during specific pathological conditions are accompanied by changes in the regulation of energy metabolism of astrocytes. We have indeed observed that the 'metabolic profile' of astrocytes is modified during the sleep wake cycle and during conditions mimicking neuroinflammation in the presence or absence of amyloid ß. The effect of amyloid ß on energy metabolism is dependent on its state of aggregation and on internalization of the peptide by astrocytes. Distinct patterns of metabolic activity could be observed during the learning and recall phases in a spatial learning task. Gene expression analysis in activated areas notably hippocampous and retrosplenial cortex demonstrated that the expression levels of several genes implicated in astrocyte neuron metabolic coupling are enhanced by learning. Regarding metabolic plasticity during the sleep wake cycle we have observed that the level of expression of a panel of selected genes which we know are key for neuron glia metabolic coupling is modulated by sleep deprivation.
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- 2011
9. Deletion of the CREB Coactivator CRTC1 Induces Pathological Aggression, Depression-Related Behaviors, and Neuroplasticity Genes Dysregulation in Mice
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Breuillaud L, Merinat C, Rossetti C, Halfon O, Magistretti PJ, and Cardinaux JR
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BACKGROUND: Mood disorders are polygenic disorders in which the alteration of several susceptibility genes results in dysfunctional mood regulation. However the molecular mechanisms underlying their transcriptional dysregulation are still unclear. The transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the neurotrophin brain derived neurotrophic factor (BDNF) have been implicated in rodent models of depression. We previously provided evidence that Bdnf expression critically rely on a potent CREB coactivator called CREB regulated transcription coactivator 1 (CRTC1). METHODS: To further evaluate the role of CRTC1 in the brain we generated a knockout mouse line and analyzed its behavioral and molecular phenotype. RESULTS: We found that mice lacking CRTC1 associate neurobehavioral endophenotypes related to mood disorders. Crtc1( / ) mice exhibit impulsive aggressiveness social withdrawal and decreased sexual motivation together with increased behavioral despair anhedonia and anxiety related behavior in the novelty induced hypophagia test. They also present psychomotor retardation as well as increased emotional response to stressful events. Crtc1( / ) mice have a blunted response to the antidepressant fluoxetine in behavioral despair paradigms whereas fluoxetine normalizes their aggressiveness and their behavioral response in the novelty induced hypophagia test. Crtc1( / ) mice strikingly show in addition to a reduced dopamine and serotonin turnover in the prefrontal cortex a concomitant decreased expression of several susceptibility genes involved in neuroplasticity including Bdnf its receptor TrkB the nuclear receptors Nr4a1 3 and several other CREB regulated genes. CONCLUSIONS: Collectively these findings support a role for the CRTC1 CREB pathway in mood disorders etiology and behavioral response to antidepressants and identify CRTC1 as an essential coactivator of genes involved in mood regulation.
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- 2011
10. Altered glycogen metabolism in cultured astrocytes from mice with chronic glutathione deficit; relevance for neuroenergetics in schizophrenia
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Lavoie S, Allaman I, Petit JM, Do KQ, and Magistretti PJ
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- 2011
11. Glycogen Metabolism as a Marker of Astrocyte Differentiation
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Brunet, JF, primary, Allaman, I, additional, Magistretti, PJ, additional, and Pellerin, L, additional
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- 2009
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12. Mécanismes cellulaires du métabolisme énergétique cérébral : implications pour l'imagerie fonctionnelle.
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Magistretti, PJ, primary and Pellerin, L, additional
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- 1999
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13. Vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, and noradrenaline induce the transcription factors CCAAT/enhancer binding protein (C/EBP)-beta and C/EBP delta in mouse cortical astrocytes: involvement in cAMP-regulated glycogen metabolism
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Cardinaux, JR, primary and Magistretti, PJ, additional
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- 1996
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14. Metabolic coupling between glia and neurons
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Tsacopoulos, M, primary and Magistretti, PJ, additional
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- 1996
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15. Modulation of the glutamate-evoked release of arachidonic acid from mouse cortical neurons: involvement of a pH-sensitive membrane phospholipase A2
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Stella, N, primary, Pellerin, L, additional, and Magistretti, PJ, additional
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- 1995
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16. Vasoactive intestinal peptide and noradrenaline exert long-term control on glycogen levels in astrocytes: blockade by protein synthesis inhibition
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Sorg, O, primary and Magistretti, PJ, additional
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- 1992
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17. Metabolic response of the cerebral cortex following gentle sleep deprivation and modafinil administration.
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Petit JM, Tobler I, Kopp C, Morgenthaler F, Borbély AA, and Magistretti PJ
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- 2010
18. Release of vasoactive intestinal peptide in mouse cerebral cortex: evidence for a role of arachidonic acid metabolites
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Martin, JL, primary and Magistretti, PJ, additional
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- 1989
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19. Adenosine stimulates glycogenolysis in mouse cerebral cortex: a possible coupling mechanism between neuronal activity and energy metabolism
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Magistretti, PJ, primary, Hof, PR, additional, and Martin, JL, additional
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- 1986
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20. K+ at concentrations reached in the extracellular space during neuronal activity promotes a Ca2+-dependent glycogen hydrolysis in mouse cerebral cortex
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Hof, PR, primary, Pascale, E, additional, and Magistretti, PJ, additional
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- 1988
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21. Norepinephrine and histamine potentiate the increases in cyclic adenosine 3':5'-monophosphate elicited by vasoactive intestinal polypeptide in mouse cerebral cortical slices: mediation by alpha 1- adrenergic and H1-histaminergic receptors
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Magistretti, PJ, primary and Schorderet, M, additional
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- 1985
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22. Quantitative Phase Contrast Microscopy of Living Astrocytes By Numerical Reconstruction of Digital Holograms.
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Bailey, GW, Jerome, WG, McKernan, S, Mansfield, JF, Price, RL, Marquet, P, Cuche, E, Chatton, J-Y, Depeursinge, Ch, and Magistretti, PJ
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- 1999
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23. Increase In Intracellular Sodium Evoked by Glutamate Transporter Activation In Cortical Astrocytes: A Fluorescence Microscopy Analysis.
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Bailey, GW, Jerome, WG, McKernan, S, Mansfield, JF, Price, RL, Chatton, J-Y, Marquet, P, and Magistretti, PJ
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- 1999
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24. Increase In Intracellular Sodium Evoked by Glutamate Transporter Activation In Cortical Astrocytes: A Fluorescence Microscopy Analysis
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Chatton, J-Y, Marquet, P, and Magistretti, PJ
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Primary cultures of mouse cortical astrocytes were used to investigate the changes in intracellular Na+concentration ([Na+]i) following exposure to the excitatory neurotransmitter glutamate. The fluorescent probe sodium-binding benzofuran isophthalate (SBFI) was used to measure [Na+]iby epifluorescence microscopy imaging. Detection of the low light level fluorescent signal was accomplished using a Gen III+ intensified CCD camera. Fluorescence excitation ratio images of dye-loaded cells were obtained after sequential illumination at 340nnm and 380nm, with an emission observed at >520nm. Ratio images were proportional in intensity to [Na+]i. In situcalibration of the fluorescent signals was obtained for each experiment and each cell under study by equilibrating [Na+]iwith external Na+after treatment with the cation ionophores monensin and gramicidin, and with ouabain, a specific inhibitor of the Na+/K+ ATPase. Cells on glass coverslips were perfused at 35°C in a closed microscope chamber using solutions buffered with 25 mM bicarbonate/5%CO2.
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- 1999
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25. Quantitative Phase Contrast Microscopy of Living Astrocytes By Numerical Reconstruction of Digital Holograms
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Marquet, P, Cuche, E, Chatton, J-Y, Depeursinge, Ch, and Magistretti, PJ
- Abstract
We have developed a method of numerical holography which allows simultaneous intensity and quantitative phase contrast imaging. Measurement of optical path length provides precise information about the cell morphology. As presented in Fig. 1, the experimental set-up for the recording of digital holograms is basically a Mach-Zender interferometer. At the exit of the interferometer, a CCD camera records a hologram which is made by the interference between a reference wave R and the object wave O that is transmitted by the biological sample. In order to obtain a plane wave as reference, a beam expander (B.E.) including a pinhole is introduced in the reference arm and enlarges the beam diameter to about 2cm. A similar system which produces a smaller beam diameter (≈5mm) is inserted in the objet arm. To perform holography in the off-axis geometry, the mirror in the reference arm is oriented in such a way that the reference wave reaches the CCD camera with a small incidence angle.
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- 1999
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26. Astrocyte-derived lactate in stress disorders.
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Chamaa F, Magistretti PJ, and Fiumelli H
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- Humans, Glucose metabolism, Energy Metabolism physiology, Antidepressive Agents, Lactic Acid metabolism, Astrocytes metabolism
- Abstract
Stress disorders are psychiatric disorders arising following stressful or traumatic events. They could deleteriously affect an individual's health because they often co-occur with mental illnesses. Considerable attention has been focused on neurons when considering the neurobiology of stress disorders. However, like other mental health conditions, recent studies have highlighted the importance of astrocytes in the pathophysiology of stress-related disorders. In addition to their structural and homeostatic support role, astrocytes actively serve several functions in regulating synaptic transmission and plasticity, protecting neurons from toxic compounds, and providing metabolic support for neurons. The astrocyte-neuron lactate shuttle model sets forth the importance of astrocytes in providing lactate for the metabolic supply of neurons under intense activity. Lactate also plays a role as a signaling molecule and has been recently studied regarding its antidepressant activity. This review discusses the involvement of astrocytes and brain energy metabolism in stress and further reflects on the importance of lactate as an energy supply in the brain and its emerging antidepressant role in stress-related disorders., Competing Interests: Declaration of competing interest The authors have no relevant financial or nonfinancial interests to disclose., (Copyright © 2023. Published by Elsevier Inc.)
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- 2024
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27. Photo-Chemical Stimulation of Neurons with Organic Semiconductors.
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Savva A, Hama A, Herrera-López G, Schmidt T, Migliaccio L, Steiner N, Kawan M, Fiumelli H, Magistretti PJ, McCulloch I, Baran D, Gasparini N, Schindl R, Głowacki ED, and Inal S
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- Stimulation, Chemical, Cell Culture Techniques, Polymers chemistry, Semiconductors, Neurons
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Recent advances in light-responsive materials enabled the development of devices that can wirelessly activate tissue with light. Here it is shown that solution-processed organic heterojunctions can stimulate the activity of primary neurons at low intensities of light via photochemical reactions. The p-type semiconducting polymer PDCBT and the n-type semiconducting small molecule ITIC (a non-fullerene acceptor) are coated on glass supports, forming a p-n junction with high photosensitivity. Patch clamp measurements show that low-intensity white light is converted into a cue that triggers action potentials in primary cortical neurons. The study shows that neat organic semiconducting p-n bilayers can exchange photogenerated charges with oxygen and other chemical compounds in cell culture conditions. Through several controlled experimental conditions, photo-capacitive, photo-thermal, and direct hydrogen peroxide effects on neural function are excluded, with photochemical delivery being the possible mechanism. The profound advantages of low-intensity photo-chemical intervention with neuron electrophysiology pave the way for developing wireless light-based therapy based on emerging organic semiconductors., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)
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- 2023
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28. Beyond the symptom: the biology of fatigue.
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Raizen DM, Mullington J, Anaclet C, Clarke G, Critchley H, Dantzer R, Davis R, Drew KL, Fessel J, Fuller PM, Gibson EM, Harrington M, Ian Lipkin W, Klerman EB, Klimas N, Komaroff AL, Koroshetz W, Krupp L, Kuppuswamy A, Lasselin J, Lewis LD, Magistretti PJ, Matos HY, Miaskowski C, Miller AH, Nath A, Nedergaard M, Opp MR, Ritchie MD, Rogulja D, Rolls A, Salamone JD, Saper C, Whittemore V, Wylie G, Younger J, Zee PC, and Craig Heller H
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- Humans, Biology, Fatigue, Motivation
- Abstract
A workshop titled "Beyond the Symptom: The Biology of Fatigue" was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them., (Published by Oxford University Press on behalf of Sleep Research Society (SRS) 2023.)
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- 2023
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29. Ultraliser: a framework for creating multiscale, high-fidelity and geometrically realistic 3D models for in silico neuroscience.
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Abdellah M, Cantero JJG, Guerrero NR, Foni A, Coggan JS, Calì C, Agus M, Zisis E, Keller D, Hadwiger M, Magistretti PJ, Markram H, and Schürmann F
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- Computer Simulation, Software, Neurons
- Abstract
Ultraliser is a neuroscience-specific software framework capable of creating accurate and biologically realistic 3D models of complex neuroscientific structures at intracellular (e.g. mitochondria and endoplasmic reticula), cellular (e.g. neurons and glia) and even multicellular scales of resolution (e.g. cerebral vasculature and minicolumns). Resulting models are exported as triangulated surface meshes and annotated volumes for multiple applications in in silico neuroscience, allowing scalable supercomputer simulations that can unravel intricate cellular structure-function relationships. Ultraliser implements a high-performance and unconditionally robust voxelization engine adapted to create optimized watertight surface meshes and annotated voxel grids from arbitrary non-watertight triangular soups, digitized morphological skeletons or binary volumetric masks. The framework represents a major leap forward in simulation-based neuroscience, making it possible to employ high-resolution 3D structural models for quantification of surface areas and volumes, which are of the utmost importance for cellular and system simulations. The power of Ultraliser is demonstrated with several use cases in which hundreds of models are created for potential application in diverse types of simulations. Ultraliser is publicly released under the GNU GPL3 license on GitHub (BlueBrain/Ultraliser)., Significance: There is crystal clear evidence on the impact of cell shape on its signaling mechanisms. Structural models can therefore be insightful to realize the function; the more realistic the structure can be, the further we get insights into the function. Creating realistic structural models from existing ones is challenging, particularly when needed for detailed subcellular simulations. We present Ultraliser, a neuroscience-dedicated framework capable of building these structural models with realistic and detailed cellular geometries that can be used for simulations., (© The Author(s) 2022. Published by Oxford University Press.)
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- 2023
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30. The critical periods of cerebral plasticity: A key aspect in a dialog between psychoanalysis and neuroscience centered on the psychopathology of schizophrenia.
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Tran The J, Magistretti PJ, and Ansermet F
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Through research into the molecular and cellular mechanisms that occur during critical periods, recent experimental neurobiological data have brought to light the importance of early childhood. These have demonstrated that childhood and early environmental stimuli play a part not only in our subjective construction, but also in brain development; thus, confirming Freud's intuition regarding the central role of childhood and early experiences of the environment in our psychological development and our subjective outcomes. "Critical periods" of cerebral development represent temporal windows that mark favorable, but also circumscribed, moments in developmental cerebral plasticity. They also vary between different cortical areas. There are, therefore, strictly defined temporal periods for learning language, music, etc., after which this learning becomes more difficult, or even impossible, to acquire. Now, research into these critical periods can be seen as having a significant part to play in the interdisciplinary dialog between psychoanalysis and neurosciences with regard to the role of early experiences in the etiology of some psychopathological conditions. Research into the cellular and molecular mechanisms controlling the onset and end of these critical periods, notably controlled by the maturation of parvalbumin-expressing basket cells, have brought to light the presence of anomalies in the maturation of these neurons in patients with schizophrenia. Starting from these findings we propose revisiting the psychoanalytic theories on the etiology of psychosis from an interdisciplinary perspective. Our study works from the observation, common to both psychoanalysis and neurosciences, that experience leaves a trace; be it a "psychic" or a "synaptic" trace. Thus, we develop a hypothesis for an "absence of trace" in psychosis; reexamining psychosis through the prism of the biological theory of critical periods in plasticity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tran The, Magistretti and Ansermet.)
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- 2022
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31. Hyperactivity of the default mode network in schizophrenia and free energy: A dialogue between Freudian theory of psychosis and neuroscience.
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Tran The J, Ansermet JP, Magistretti PJ, and Ansermet F
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The economic conceptualization of Freudian metapsychology, based on an energetics model of the psyche's workings, offers remarkable commonalities with some recent discoveries in neuroscience, notably in the field of neuroenergetics. The pattern of cerebral activity at resting state and the identification of a default mode network (DMN), a network of areas whose activity is detectable at baseline conditions by neuroimaging techniques, offers a promising field of research in the dialogue between psychoanalysis and neuroscience. In this article we study one significant clinical application of this interdisciplinary dialogue by looking at the role of the DMN in the psychopathology of schizophrenia. Anomalies in the functioning of the DMN have been observed in schizophrenia. Studies have evidenced the existence of hyperactivity in this network in schizophrenia patients, particularly among those for whom a positive symptomatology is dominant. These data are particularly interesting when considered from the perspective of the psychoanalytic understanding of the positive symptoms of psychosis, most notably the Freudian hypothesis of delusions as an "attempt at recovery." Combining the data from research in neuroimaging of schizophrenia patients with the Freudian hypothesis, we propose considering the hyperactivity of the DMN as a consequence of a process of massive reassociation of traces occurring in schizophrenia. This is a process that may constitute an attempt at minimizing the excess of free energy present in psychosis. Modern models of active inference and the free energy principle (FEP) may shed some light on these processes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tran The, Ansermet, Magistretti and Ansermet.)
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- 2022
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32. Lactate supply overtakes glucose when neural computational and cognitive loads scale up.
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Dembitskaya Y, Piette C, Perez S, Berry H, Magistretti PJ, and Venance L
- Subjects
- Long-Term Potentiation physiology, Neuronal Plasticity physiology, Cognition, Glucose, Lactic Acid
- Abstract
Neural computational power is determined by neuroenergetics, but how and which energy substrates are allocated to various forms of memory engram is unclear. To solve this question, we asked whether neuronal fueling by glucose or lactate scales differently upon increasing neural computation and cognitive loads. Here, using electrophysiology, two-photon imaging, cognitive tasks, and mathematical modeling, we show that both glucose and lactate are involved in engram formation, with lactate supporting long-term synaptic plasticity evoked by high-stimulation load activity patterns and high attentional load in cognitive tasks and glucose being sufficient for less demanding neural computation and learning tasks. Indeed, we show that lactate is mandatory for demanding neural computation, such as theta-burst stimulation, while glucose is sufficient for lighter forms of activity-dependent long-term potentiation (LTP), such as spike timing-dependent plasticity (STDP). We find that subtle variations of spike number or frequency in STDP are sufficient to shift the on-demand fueling from glucose to lactate. Finally, we demonstrate that lactate is necessary for a cognitive task requiring high attentional load, such as the object-in-place task, and for the corresponding in vivo hippocampal LTP expression but is not needed for a less demanding task, such as a simple novel object recognition. Overall, these results demonstrate that glucose and lactate metabolism are differentially engaged in neuronal fueling depending on the complexity of the activity-dependent plasticity and behavior.
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- 2022
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33. Nonlinear Reconstruction of Images from Patterns Generated by Deterministic or Random Optical Masks-Concepts and Review of Research.
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Smith D, Gopinath S, Arockiaraj FG, Reddy ANK, Balasubramani V, Kumar R, Dubey N, Ng SH, Katkus T, Selva SJ, Renganathan D, Kamalam MBR, John Francis Rajeswary AS, Navaneethakrishnan S, Inbanathan SR, Valdma SM, Praveen PA, Amudhavel J, Kumar M, Ganeev RA, Magistretti PJ, Depeursinge C, Juodkazis S, Rosen J, and Anand V
- Abstract
Indirect-imaging methods involve at least two steps, namely optical recording and computational reconstruction. The optical-recording process uses an optical modulator that transforms the light from the object into a typical intensity distribution. This distribution is numerically processed to reconstruct the object's image corresponding to different spatial and spectral dimensions. There have been numerous optical-modulation functions and reconstruction methods developed in the past few years for different applications. In most cases, a compatible pair of the optical-modulation function and reconstruction method gives optimal performance. A new reconstruction method, termed nonlinear reconstruction (NLR), was developed in 2017 to reconstruct the object image in the case of optical-scattering modulators. Over the years, it has been revealed that the NLR can reconstruct an object's image modulated by an axicons, bifocal lenses and even exotic spiral diffractive elements, which generate deterministic optical fields. Apparently, NLR seems to be a universal reconstruction method for indirect imaging. In this review, the performance of NLR isinvestigated for many deterministic and stochastic optical fields. Simulation and experimental results for different cases are presented and discussed.
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- 2022
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34. Representing stimulus information in an energy metabolism pathway.
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Coggan JS, Keller D, Markram H, Schürmann F, and Magistretti PJ
- Subjects
- Action Potentials, Brain metabolism, Glycolysis, Astrocytes metabolism, Energy Metabolism physiology
- Abstract
We explored a computational model of astrocytic energy metabolism and demonstrated the theoretical plausibility that this type of pathway might be capable of coding information about stimuli in addition to its known functions in cellular energy and carbon budgets. Simulation results indicate that glycogenolytic glycolysis triggered by activation of adrenergic receptors can capture the intensity and duration features of a neuromodulator waveform and can respond in a dose-dependent manner, including non-linear state changes that are analogous to action potentials. We show how this metabolic pathway can translate information about external stimuli to production profiles of energy-carrying molecules such as lactate with a precision beyond simple signal transduction or non-linear amplification. The results suggest the operation of a metabolic state-machine from the spatially discontiguous yet interdependent metabolite elements. Such metabolic pathways might be well-positioned to code an additional level of salient information about a cell's environmental demands to impact its function. Our hypothesis has implications for the computational power and energy efficiency of the brain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2022
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35. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.
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Mullins N, Kang J, Campos AI, Coleman JRI, Edwards AC, Galfalvy H, Levey DF, Lori A, Shabalin A, Starnawska A, Su MH, Watson HJ, Adams M, Awasthi S, Gandal M, Hafferty JD, Hishimoto A, Kim M, Okazaki S, Otsuka I, Ripke S, Ware EB, Bergen AW, Berrettini WH, Bohus M, Brandt H, Chang X, Chen WJ, Chen HC, Crawford S, Crow S, DiBlasi E, Duriez P, Fernández-Aranda F, Fichter MM, Gallinger S, Glatt SJ, Gorwood P, Guo Y, Hakonarson H, Halmi KA, Hwu HG, Jain S, Jamain S, Jiménez-Murcia S, Johnson C, Kaplan AS, Kaye WH, Keel PK, Kennedy JL, Klump KL, Li D, Liao SC, Lieb K, Lilenfeld L, Liu CM, Magistretti PJ, Marshall CR, Mitchell JE, Monson ET, Myers RM, Pinto D, Powers A, Ramoz N, Roepke S, Rozanov V, Scherer SW, Schmahl C, Sokolowski M, Strober M, Thornton LM, Treasure J, Tsuang MT, Witt SH, Woodside DB, Yilmaz Z, Zillich L, Adolfsson R, Agartz I, Air TM, Alda M, Alfredsson L, Andreassen OA, Anjorin A, Appadurai V, Soler Artigas M, Van der Auwera S, Azevedo MH, Bass N, Bau CHD, Baune BT, Bellivier F, Berger K, Biernacka JM, Bigdeli TB, Binder EB, Boehnke M, Boks MP, Bosch R, Braff DL, Bryant R, Budde M, Byrne EM, Cahn W, Casas M, Castelao E, Cervilla JA, Chaumette B, Cichon S, Corvin A, Craddock N, Craig D, Degenhardt F, Djurovic S, Edenberg HJ, Fanous AH, Foo JC, Forstner AJ, Frye M, Fullerton JM, Gatt JM, Gejman PV, Giegling I, Grabe HJ, Green MJ, Grevet EH, Grigoroiu-Serbanescu M, Gutierrez B, Guzman-Parra J, Hamilton SP, Hamshere ML, Hartmann A, Hauser J, Heilmann-Heimbach S, Hoffmann P, Ising M, Jones I, Jones LA, Jonsson L, Kahn RS, Kelsoe JR, Kendler KS, Kloiber S, Koenen KC, Kogevinas M, Konte B, Krebs MO, Landén M, Lawrence J, Leboyer M, Lee PH, Levinson DF, Liao C, Lissowska J, Lucae S, Mayoral F, McElroy SL, McGrath P, McGuffin P, McQuillin A, Medland SE, Mehta D, Melle I, Milaneschi Y, Mitchell PB, Molina E, Morken G, Mortensen PB, Müller-Myhsok B, Nievergelt C, Nimgaonkar V, Nöthen MM, O'Donovan MC, Ophoff RA, Owen MJ, Pato C, Pato MT, Penninx BWJH, Pimm J, Pistis G, Potash JB, Power RA, Preisig M, Quested D, Ramos-Quiroga JA, Reif A, Ribasés M, Richarte V, Rietschel M, Rivera M, Roberts A, Roberts G, Rouleau GA, Rovaris DL, Rujescu D, Sánchez-Mora C, Sanders AR, Schofield PR, Schulze TG, Scott LJ, Serretti A, Shi J, Shyn SI, Sirignano L, Sklar P, Smeland OB, Smoller JW, Sonuga-Barke EJS, Spalletta G, Strauss JS, Świątkowska B, Trzaskowski M, Turecki G, Vilar-Ribó L, Vincent JB, Völzke H, Walters JTR, Shannon Weickert C, Weickert TW, Weissman MM, Williams LM, Wray NR, Zai CC, Ashley-Koch AE, Beckham JC, Hauser ER, Hauser MA, Kimbrel NA, Lindquist JH, McMahon B, Oslin DW, Qin X, Agerbo E, Børglum AD, Breen G, Erlangsen A, Esko T, Gelernter J, Hougaard DM, Kessler RC, Kranzler HR, Li QS, Martin NG, McIntosh AM, Mors O, Nordentoft M, Olsen CM, Porteous D, Ursano RJ, Wasserman D, Werge T, Whiteman DC, Bulik CM, Coon H, Demontis D, Docherty AR, Kuo PH, Lewis CM, Mann JJ, Rentería ME, Smith DJ, Stahl EA, Stein MB, Streit F, Willour V, and Ruderfer DM
- Subjects
- Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk Factors, Suicide, Attempted, Depressive Disorder, Major genetics, Mental Disorders genetics
- Abstract
Background: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders., Methods: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors., Results: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged., Conclusions: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)
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- 2022
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36. Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives.
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Beard E, Lengacher S, Dias S, Magistretti PJ, and Finsterwald C
- Abstract
Astrocytes play key roles in the regulation of brain energy metabolism, which has a major impact on brain functions, including memory, neuroprotection, resistance to oxidative stress and homeostatic tone. Energy demands of the brain are very large, as they continuously account for 20-25% of the whole body's energy consumption. Energy supply of the brain is tightly linked to neuronal activity, providing the origin of the signals detected by the widely used functional brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography. In particular, neuroenergetic coupling is regulated by astrocytes through glutamate uptake that triggers astrocytic aerobic glycolysis and leads to glucose uptake and lactate release, a mechanism known as the Astrocyte Neuron Lactate Shuttle. Other neurotransmitters such as noradrenaline and Vasoactive Intestinal Peptide mobilize glycogen, the reserve for glucose exclusively localized in astrocytes, also resulting in lactate release. Lactate is then transferred to neurons where it is used, after conversion to pyruvate, as a rapid energy substrate, and also as a signal that modulates neuronal excitability, homeostasis, and the expression of survival and plasticity genes. Importantly, glycolysis in astrocytes and more generally cerebral glucose metabolism progressively deteriorate in aging and age-associated neurodegenerative diseases such as Alzheimer's disease. This decreased glycolysis actually represents a common feature of several neurological pathologies. Here, we review the critical role of astrocytes in the regulation of brain energy metabolism, and how dysregulation of astrocyte-mediated metabolic pathways is involved in brain hypometabolism. Further, we summarize recent efforts at preclinical and clinical stages to target brain hypometabolism for the development of new therapeutic interventions in age-related neurodegenerative diseases., Competing Interests: EB, SL, SD, PM, and CF were employed by company GliaPharm SA., (Copyright © 2022 Beard, Lengacher, Dias, Magistretti and Finsterwald.)
- Published
- 2022
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37. Roadmap on Digital Holography-Based Quantitative Phase Imaging.
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Balasubramani V, Kujawińska M, Allier C, Anand V, Cheng CJ, Depeursinge C, Hai N, Juodkazis S, Kalkman J, Kuś A, Lee M, Magistretti PJ, Marquet P, Ng SH, Rosen J, Park YK, and Ziemczonok M
- Abstract
Quantitative Phase Imaging (QPI) provides unique means for the imaging of biological or technical microstructures, merging beneficial features identified with microscopy, interferometry, holography, and numerical computations. This roadmap article reviews several digital holography-based QPI approaches developed by prominent research groups. It also briefly discusses the present and future perspectives of 2D and 3D QPI research based on digital holographic microscopy, holographic tomography, and their applications.
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- 2021
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38. Role of adult hippocampal neurogenesis in the antidepressant actions of lactate.
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Carrard A, Cassé F, Carron C, Burlet-Godinot S, Toni N, Magistretti PJ, and Martin JL
- Subjects
- Animals, Depression drug therapy, Hippocampus, Neurogenesis physiology, Neuronal Plasticity physiology, Antidepressive Agents pharmacology, Lactic Acid pharmacology
- Abstract
In addition to its role as a neuronal energy substrate and signaling molecule involved in synaptic plasticity and memory consolidation, recent evidence shows that lactate produces antidepressant effects in animal models. However, the mechanisms underpinning lactate's antidepressant actions remain largely unknown. In this study, we report that lactate reverses the effects of corticosterone on depressive-like behavior, as well as on the inhibition of both the survival and proliferation of new neurons in the adult hippocampus. Furthermore, the inhibition of adult hippocampal neurogenesis prevents the antidepressant-like effects of lactate. Pyruvate, the oxidized form of lactate, did not mimic the effects of lactate on adult hippocampal neurogenesis and depression-like behavior. Finally, our data suggest that conversion of lactate to pyruvate with the concomitant production of NADH is necessary for the neurogenic and antidepressant effects of lactate., (© 2021. The Author(s).)
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- 2021
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39. Digital Reconstruction of the Neuro-Glia-Vascular Architecture.
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Zisis E, Keller D, Kanari L, Arnaudon A, Gevaert M, Delemontex T, Coste B, Foni A, Abdellah M, Calì C, Hess K, Magistretti PJ, Schürmann F, and Markram H
- Subjects
- Animals, Neurons physiology, Rats, Signal Transduction, Somatosensory Cortex, Astrocytes physiology, Neuroglia
- Abstract
Astrocytes connect the vasculature to neurons mediating the supply of nutrients and biochemicals. They are involved in a growing number of physiological and pathophysiological processes that result from biophysical, physiological, and molecular interactions in this neuro-glia-vascular ensemble (NGV). The lack of a detailed cytoarchitecture severely restricts the understanding of how they support brain function. To address this problem, we used data from multiple sources to create a data-driven digital reconstruction of the NGV at micrometer anatomical resolution. We reconstructed 0.2 mm3 of the rat somatosensory cortex with 16 000 morphologically detailed neurons, 2500 protoplasmic astrocytes, and its microvasculature. The consistency of the reconstruction with a wide array of experimental measurements allows novel predictions of the NGV organization, allowing the anatomical reconstruction of overlapping astrocytic microdomains and the quantification of endfeet connecting each astrocyte to the vasculature, as well as the extent to which they cover the latter. Structural analysis showed that astrocytes optimize their positions to provide uniform vascular coverage for trophic support and signaling. However, this optimal organization rapidly declines as their density increases. The NGV digital reconstruction is a resource that will enable a better understanding of the anatomical principles and geometric constraints, which govern how astrocytes support brain function., (© The Author(s) 2021. Published by Oxford University Press.)
- Published
- 2021
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40. l-Lactate: Food for Thoughts, Memory and Behavior.
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Veloz Castillo MF, Magistretti PJ, and Calì C
- Abstract
More and more evidence shows how brain energy metabolism is the linkage between physiological and morphological synaptic plasticity and memory consolidation. Different types of memory are associated with differential inputs, each with specific inputs that are upstream diverse molecular cascades depending on the receptor activity. No matter how heterogeneous the response is, energy availability represents the lowest common denominator since all these mechanisms are energy consuming and the brain networks adapt their performance accordingly. Astrocytes exert a primary role in this sense by acting as an energy buffer; glycogen granules, a mechanism to store glucose, are redistributed at glance and conveyed to neurons via the Astrocyte-Neuron Lactate Shuttle (ANLS). Here, we review how different types of memory relate to the mechanisms of energy delivery in the brain.
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- 2021
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41. Interoception Disorder and Insular Cortex Abnormalities in Schizophrenia: A New Perspective Between Psychoanalysis and Neuroscience.
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Tran The J, Magistretti PJ, and Ansermet F
- Abstract
The existence of disturbances in the perception of somatic states and in the representation of the body with the presence of cœnesthetic hallucinations, of delusional hypochondriac ideas or of dysmorphophobias is a recognized fact in the psychopathology of schizophrenia. Freudian psychoanalytic theory had accorded a privileged place to the alteration of the perception of the body in schizophrenia. Freud had attributed to these phenomena a primary and prodromal role in the psychopathology of psychosis. We propose to look at this theory in a new way, starting from the perspective of recent studies about the role of the insula in the perception and representation of somatic states, since this structure has been identified as underpinning the sense of interoception. The data in the neurobiological literature about abnormalities in the insular cortex in schizophrenia has shown that insula dysfunction could constitute one of the biological substrates of disorders of body perception in schizophrenia, and could be a source of the alteration of the sense of self that is characteristic of this psychiatric pathology. Moreover, this alteration could thus be involved in the positive symptomatology of schizophrenia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tran The, Magistretti and Ansermet.)
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- 2021
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42. Hydroxycarboxylic Acid Receptor 1 and Neuroprotection in a Mouse Model of Cerebral Ischemia-Reperfusion.
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Buscemi L, Blochet C, Magistretti PJ, and Hirt L
- Abstract
Lactate is an intriguing molecule with emerging physiological roles in the brain. It has beneficial effects in animal models of acute brain injuries and traumatic brain injury or subarachnoid hemorrhage patients. However, the mechanism by which lactate provides protection is unclear. While there is evidence of a metabolic effect of lactate providing energy to deprived neurons, it can also activate the hydroxycarboxylic acid receptor 1 (HCAR1), a Gi-coupled protein receptor that modulates neuronal firing rates. After cerebral hypoxia-ischemia, endogenously produced brain lactate is largely increased, and the exogenous administration of more lactate can decrease lesion size and ameliorate the neurological outcome. To test whether HCAR1 plays a role in lactate-induced neuroprotection, we injected the agonists 3-chloro-5-hydroxybenzoic acid and 3,5-dihydroxybenzoic acid into mice subjected to 30-min middle cerebral artery occlusion. The in vivo administration of HCAR1 agonists at reperfusion did not appear to exert any relevant protective effect as seen with lactate administration. Our results suggest that the protective effects of lactate after hypoxia-ischemia come rather from the metabolic effects of lactate than its signaling through HCAR1., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Buscemi, Blochet, Magistretti and Hirt.)
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- 2021
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43. Ganglioside GM1 Targets Astrocytes to Stimulate Cerebral Energy Metabolism.
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Finsterwald C, Dias S, Magistretti PJ, and Lengacher S
- Abstract
Gangliosides are major constituents of the plasma membrane and are known to promote a number of physiological actions in the brain, including synaptic plasticity and neuroprotection. In particular, the ganglioside GM1 was found to have a wide range of preclinical and clinical benefits in brain diseases such as spinal cord injury, Huntington's disease and Parkinson's disease. However, little is known about the underlying cellular and molecular mechanisms of GM1 in the brain. In the present study, we show that GM1 exerts its actions through the promotion of glycolysis in astrocytes, which leads to glucose uptake and lactate release by these cells. In astrocytes, GM1 stimulates the expression of several genes involved in the regulation of glucose metabolism. GM1 also enhances neuronal mitochondrial activity and triggers the expression of neuroprotection genes when neurons are cultured in the presence of astrocytes. Finally, GM1 leads to a neuroprotective effect in astrocyte-neuron co-culture. Together, these data identify a previously unrecognized mechanism mediated by astrocytes by which GM1 exerts its metabolic and neuroprotective effects., Competing Interests: CF, SD and SL are employees of GliaPharm SA. CF, PM and SL are co-founders of GliaPharm SA., (Copyright © 2021 Finsterwald, Dias, Magistretti and Lengacher.)
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- 2021
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44. Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.
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Munn-Chernoff MA, Johnson EC, Chou YL, Coleman JRI, Thornton LM, Walters RK, Yilmaz Z, Baker JH, Hübel C, Gordon S, Medland SE, Watson HJ, Gaspar HA, Bryois J, Hinney A, Leppä VM, Mattheisen M, Ripke S, Yao S, Giusti-Rodríguez P, Hanscombe KB, Adan RAH, Alfredsson L, Ando T, Andreassen OA, Berrettini WH, Boehm I, Boni C, Boraska Perica V, Buehren K, Burghardt R, Cassina M, Cichon S, Clementi M, Cone RD, Courtet P, Crow S, Crowley JJ, Danner UN, Davis OSP, de Zwaan M, Dedoussis G, Degortes D, DeSocio JE, Dick DM, Dikeos D, Dina C, Dmitrzak-Weglarz M, Docampo E, Duncan LE, Egberts K, Ehrlich S, Escaramís G, Esko T, Estivill X, Farmer A, Favaro A, Fernández-Aranda F, Fichter MM, Fischer K, Föcker M, Foretova L, Forstner AJ, Forzan M, Franklin CS, Gallinger S, Giegling I, Giuranna J, Gonidakis F, Gorwood P, Gratacos Mayora M, Guillaume S, Guo Y, Hakonarson H, Hatzikotoulas K, Hauser J, Hebebrand J, Helder SG, Herms S, Herpertz-Dahlmann B, Herzog W, Huckins LM, Hudson JI, Imgart H, Inoko H, Janout V, Jiménez-Murcia S, Julià A, Kalsi G, Kaminská D, Karhunen L, Karwautz A, Kas MJH, Kennedy JL, Keski-Rahkonen A, Kiezebrink K, Kim YR, Klump KL, Knudsen GPS, La Via MC, Le Hellard S, Levitan RD, Li D, Lilenfeld L, Lin BD, Lissowska J, Luykx J, Magistretti PJ, Maj M, Mannik K, Marsal S, Marshall CR, Mattingsdal M, McDevitt S, McGuffin P, Metspalu A, Meulenbelt I, Micali N, Mitchell K, Monteleone AM, Monteleone P, Nacmias B, Navratilova M, Ntalla I, O'Toole JK, Ophoff RA, Padyukov L, Palotie A, Pantel J, Papezova H, Pinto D, Rabionet R, Raevuori A, Ramoz N, Reichborn-Kjennerud T, Ricca V, Ripatti S, Ritschel F, Roberts M, Rotondo A, Rujescu D, Rybakowski F, Santonastaso P, Scherag A, Scherer SW, Schmidt U, Schork NJ, Schosser A, Seitz J, Slachtova L, Slagboom PE, Slof-Op't Landt MCT, Slopien A, Sorbi S, Świątkowska B, Szatkiewicz JP, Tachmazidou I, Tenconi E, Tortorella A, Tozzi F, Treasure J, Tsitsika A, Tyszkiewicz-Nwafor M, Tziouvas K, van Elburg AA, van Furth EF, Wagner G, Walton E, Widen E, Zeggini E, Zerwas S, Zipfel S, Bergen AW, Boden JM, Brandt H, Crawford S, Halmi KA, Horwood LJ, Johnson C, Kaplan AS, Kaye WH, Mitchell J, Olsen CM, Pearson JF, Pedersen NL, Strober M, Werge T, Whiteman DC, Woodside DB, Grove J, Henders AK, Larsen JT, Parker R, Petersen LV, Jordan J, Kennedy MA, Birgegård A, Lichtenstein P, Norring C, Landén M, Mortensen PB, Polimanti R, McClintick JN, Adkins AE, Aliev F, Bacanu SA, Batzler A, Bertelsen S, Biernacka JM, Bigdeli TB, Chen LS, Clarke TK, Degenhardt F, Docherty AR, Edwards AC, Foo JC, Fox L, Frank J, Hack LM, Hartmann AM, Hartz SM, Heilmann-Heimbach S, Hodgkinson C, Hoffmann P, Hottenga JJ, Konte B, Lahti J, Lahti-Pulkkinen M, Lai D, Ligthart L, Loukola A, Maher BS, Mbarek H, McIntosh AM, McQueen MB, Meyers JL, Milaneschi Y, Palviainen T, Peterson RE, Ryu E, Saccone NL, Salvatore JE, Sanchez-Roige S, Schwandt M, Sherva R, Streit F, Strohmaier J, Thomas N, Wang JC, Webb BT, Wedow R, Wetherill L, Wills AG, Zhou H, Boardman JD, Chen D, Choi DS, Copeland WE, Culverhouse RC, Dahmen N, Degenhardt L, Domingue BW, Frye MA, Gäebel W, Hayward C, Ising M, Keyes M, Kiefer F, Koller G, Kramer J, Kuperman S, Lucae S, Lynskey MT, Maier W, Mann K, Männistö S, Müller-Myhsok B, Murray AD, Nurnberger JI, Preuss U, Räikkönen K, Reynolds MD, Ridinger M, Scherbaum N, Schuckit MA, Soyka M, Treutlein J, Witt SH, Wodarz N, Zill P, Adkins DE, Boomsma DI, Bierut LJ, Brown SA, Bucholz KK, Costello EJ, de Wit H, Diazgranados N, Eriksson JG, Farrer LA, Foroud TM, Gillespie NA, Goate AM, Goldman D, Grucza RA, Hancock DB, Harris KM, Hesselbrock V, Hewitt JK, Hopfer CJ, Iacono WG, Johnson EO, Karpyak VM, Kendler KS, Kranzler HR, Krauter K, Lind PA, McGue M, MacKillop J, Madden PAF, Maes HH, Magnusson PKE, Nelson EC, Nöthen MM, Palmer AA, Penninx BWJH, Porjesz B, Rice JP, Rietschel M, Riley BP, Rose RJ, Shen PH, Silberg J, Stallings MC, Tarter RE, Vanyukov MM, Vrieze S, Wall TL, Whitfield JB, Zhao H, Neale BM, Wade TD, Heath AC, Montgomery GW, Martin NG, Sullivan PF, Kaprio J, Breen G, Gelernter J, Edenberg HJ, Bulik CM, and Agrawal A
- Subjects
- Alcoholism genetics, Depressive Disorder, Major genetics, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Schizophrenia genetics, Tobacco Use Disorder genetics, Feeding and Eating Disorders genetics, Substance-Related Disorders genetics
- Abstract
Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r
g ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors., (© 2020 Society for the Study of Addiction.)- Published
- 2021
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45. Reactive Oxygen Species: Beyond Their Reactive Behavior.
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Tauffenberger A and Magistretti PJ
- Subjects
- Aging metabolism, Animals, Astrocytes metabolism, Brain metabolism, Humans, Neurons metabolism, Reactive Oxygen Species metabolism, Signal Transduction physiology
- Abstract
Cellular homeostasis plays a critical role in how an organism will develop and age. Disruption of this fragile equilibrium is often associated with health degradation and ultimately, death. Reactive oxygen species (ROS) have been closely associated with health decline and neurological disorders, such as Alzheimer's disease or Parkinson's disease. ROS were first identified as by-products of the cellular activity, mainly mitochondrial respiration, and their high reactivity is linked to a disruption of macromolecules such as proteins, lipids and DNA. More recent research suggests more complex function of ROS, reaching far beyond the cellular dysfunction. ROS are active actors in most of the signaling cascades involved in cell development, proliferation and survival, constituting important second messengers. In the brain, their impact on neurons and astrocytes has been associated with synaptic plasticity and neuron survival. This review provides an overview of ROS function in cell signaling in the context of aging and degeneration in the brain and guarding the fragile balance between health and disease.
- Published
- 2021
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46. Gut microbiota modulates expression of genes involved in the astrocyte-neuron lactate shuttle in the hippocampus.
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Margineanu MB, Sherwin E, Golubeva A, Peterson V, Hoban A, Fiumelli H, Rea K, Cryan JF, and Magistretti PJ
- Subjects
- Animals, Energy Metabolism physiology, Gene Expression, Male, Mice, Mice, Inbred C57BL, Prebiotics administration & dosage, Astrocytes metabolism, Gastrointestinal Microbiome physiology, Germ-Free Life physiology, Hippocampus metabolism, Lactic Acid metabolism, Neurons metabolism
- Abstract
The gut microbiota modulates brain physiology, development, and behavior and has been implicated as a key regulator in several central nervous system disorders. Its effect on the metabolic coupling between neurons and astrocytes has not been studied to date, even though this is an important component of brain energy metabolism and physiology and it is perturbed in neurodegenerative and cognitive disorders. In this study, we have investigated the mRNA expression of 6 genes encoding proteins implicated in the astrocyte-neuron lactate shuttle (Atp1a2, Ldha, Ldhb, Mct1, Gys1, Pfkfb3), in relation to different gut microbiota manipulations, in the mouse brain hippocampus, a region with critical functions in cognition and behavior. We have discovered that Atp1a2 and Pfkfb3, encoding the ATPase, Na+/K+ transporting, alpha 2 sub-unit, respectively and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, two genes predominantly expressed in astrocytes, were upregulated in the hippocampus after microbial colonization of germ-free mice for 24 h, compared with conventionally raised mice. Pfkfb3 was also upregulated in germ-free mice compared with conventionally raised mice, while an increase in Atp1a2 expression in germ-free mice was confirmed only at the protein level by Western blot. In a separate cohort of mice, Atp1a2 and Pfkfb3 mRNA expression was upregulated in the hippocampus following 6-week dietary supplementation with prebiotics (fructo- and galacto-oligosaccharides) in an animal model of chronic psychosocial stress. To our knowledge, these findings are the first to report an influence of the gut microbiota and prebiotics on mRNA expression of genes implicated in the metabolic coupling between neurons and astrocytes., (Copyright © 2020. Published by Elsevier B.V.)
- Published
- 2020
- Full Text
- View/download PDF
47. How lactate links cannabis to social behaviour.
- Author
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Magistretti PJ
- Subjects
- Glucose, Lactic Acid, Mitochondria, Social Behavior, Cannabinoids, Cannabis
- Published
- 2020
- Full Text
- View/download PDF
48. Ultrastructural Evidence for a Role of Astrocytes and Glycogen-Derived Lactate in Learning-Dependent Synaptic Stabilization.
- Author
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Vezzoli E, Calì C, De Roo M, Ponzoni L, Sogne E, Gagnon N, Francolini M, Braida D, Sala M, Muller D, Falqui A, and Magistretti PJ
- Subjects
- Animals, Astrocytes drug effects, Astrocytes metabolism, Hippocampus drug effects, Hippocampus metabolism, Hippocampus ultrastructure, Learning drug effects, Male, Mice, Mice, Inbred C57BL, Organ Culture Techniques, Synapses drug effects, Astrocytes ultrastructure, Glycogen metabolism, Lactic Acid administration & dosage, Learning physiology, Synapses metabolism, Synapses ultrastructure
- Abstract
Long-term memory formation (LTM) is a process accompanied by energy-demanding structural changes at synapses and increased spine density. Concomitant increases in both spine volume and postsynaptic density (PSD) surface area have been suggested but never quantified in vivo by clear-cut experimental evidence. Using novel object recognition in mice as a learning task followed by 3D electron microscopy analysis, we demonstrate that LTM induced all aforementioned synaptic changes, together with an increase in the size of astrocytic glycogen granules, which are a source of lactate for neurons. The selective inhibition of glycogen metabolism in astrocytes impaired learning, affecting all the related synaptic changes. Intrahippocampal administration of l-lactate rescued the behavioral phenotype, along with spine density within 24 hours. Spine dynamics in hippocampal organotypic slices undergoing theta burst-induced long-term potentiation was similarly affected by inhibition of glycogen metabolism and rescued by l-lactate. These results suggest that learning primes astrocytic energy stores and signaling to sustain synaptic plasticity via l-lactate., (© The Author(s) 2019. Published by Oxford University Press.)
- Published
- 2020
- Full Text
- View/download PDF
49. Excitation states of metabolic networks predict dose-response fingerprinting and ligand pulse phase signalling.
- Author
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Coggan JS, Keller D, Markram H, Schürmann F, and Magistretti PJ
- Subjects
- Action Potentials, Astrocytes, Ligands, Metabolic Networks and Pathways, Signal Transduction
- Abstract
With a computational model of energy metabolism in an astrocyte, we show how a system of enzymes in a cascade can act as a functional unit of interdependent reactions, rather than merely a series of independent reactions. These systems may exist in multiple states, depending on the level of stimulation, and the effects of substrates at any point will depend on those states. Response trajectories of metabolites downstream from cAMP-stimulated glycogenolysis exhibit a host of non-linear dynamical response characteristics including hysteresis and response envelopes. Dose-dependent phase transitions predict a novel intracellular signalling mechanism and suggest a theoretical framework that could be relevant to single cell information processing, drug discovery or synthetic biology. Ligands may produce unique dose-response fingerprints depending on the state of the system, allowing selective output tuning. We conclude with the observation that state- and dose-dependent phase transitions, what we dub "ligand pulses" (LPs), may carry information and resemble action potentials (APs) generated from excitatory postsynaptic potentials. In our model, the relevant information from a cAMP-dependent glycolytic cascade in astrocytes could reflect the level of neuromodulatory input that signals an energy demand threshold. We propose that both APs and LPs represent specialized cases of molecular phase signalling with a common evolutionary root., (Copyright © 2019. Published by Elsevier Ltd.)
- Published
- 2020
- Full Text
- View/download PDF
50. 3D cellular reconstruction of cortical glia and parenchymal morphometric analysis from Serial Block-Face Electron Microscopy of juvenile rat.
- Author
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Calì C, Agus M, Kare K, Boges DJ, Lehväslaiho H, Hadwiger M, and Magistretti PJ
- Subjects
- Animals, Microscopy, Electron, Rats, Somatosensory Cortex cytology, Somatosensory Cortex diagnostic imaging, Astrocytes ultrastructure, Brain cytology, Brain diagnostic imaging, Imaging, Three-Dimensional, Microglia ultrastructure, Microscopy, Electron, Scanning, Neurons ultrastructure, Pericytes ultrastructure
- Abstract
With the rapid evolution in the automation of serial electron microscopy in life sciences, the acquisition of terabyte-sized datasets is becoming increasingly common. High resolution serial block-face imaging (SBEM) of biological tissues offers the opportunity to segment and reconstruct nanoscale structures to reveal spatial features previously inaccessible with simple, single section, two-dimensional images. In particular, we focussed here on glial cells, whose reconstruction efforts in literature are still limited, compared to neurons. We imaged a 750,000 cubic micron volume of the somatosensory cortex from a juvenile P14 rat, with 20 nm accuracy. We recognized a total of 186 cells using their nuclei, and classified them as neuronal or glial based on features of the soma and the processes. We reconstructed for the first time 4 almost complete astrocytes and neurons, 4 complete microglia and 4 complete pericytes, including their intracellular mitochondria, 186 nuclei and 213 myelinated axons. We then performed quantitative analysis on the three-dimensional models. Out of the data that we generated, we observed that neurons have larger nuclei, which correlated with their lesser density, and that astrocytes and pericytes have a higher surface to volume ratio, compared to other cell types. All reconstructed morphologies represent an important resource for computational neuroscientists, as morphological quantitative information can be inferred, to tune simulations that take into account the spatial compartmentalization of the different cell types., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
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