GNPS - Brain energy metabolism adenosine mediated cAMP signaling in astrocytes.
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Xevo TQ-S
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Virag Sagi-Kiss
PROVIDER: MSV000094445 | GNPS | Mon Apr 01 08:51:00 BST 2024
REPOSITORIES: GNPS
Publications
Adenosine signalling to astrocytes coordinates brain metabolism and function.
Theparambil Shefeeq M SM Kopach Olga O Braga Alice A Nizari Shereen S Hosford Patrick S PS Sagi-Kiss Virag V Hadjihambi Anna A Konstantinou Christos C Esteras Noemi N Gutierrez Del Arroyo Ana A Ackland Gareth L GL Teschemacher Anja G AG Dale Nicholas N Eckle Tobias T Andrikopoulos Petros P Rusakov Dmitri A DA Kasparov Sergey S Gourine Alexander V AV
Nature 20240703 8023
Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply<sup>1,2</sup>. Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism<sup>3,4</sup>, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood<sup>5,6</sup>. Here we show, using experimental in vitro and in vivo animal models, that n ...[more]
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Project description:Whole brain mouse central carbon targeted LCMS metabolomics.
2024-04-01 | MSV000094445 | MassIVE
Project description: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.
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Project description:Cloutier2009 - Brain Energy Metabolism
This model was taken from the
CellML
repository
and
automatically converted to SBML. Following the
submission the parameters are manually encoded and annotated as
spices and global quantities by BioModels curators.
The
original model was:
Cloutier M, Bolger FB, Lowry JP, Wellstead P. (2009) -
version=1.0
The
original CellML model was created by:
Catherine
Lloyd
c.lloyd@auckland.ac.nz
The
University of Auckland
This model is described in the article:
An integrative dynamic model
of brain energy metabolism using in vivo neurochemical
measurements.
Cloutier M, Bolger FB, Lowry JP,
Wellstead P.
J Comput Neurosci 2009 Dec; 27(3):
391-414
Abstract:
An integrative, systems approach to the modelling of brain
energy metabolism is presented. Mechanisms such as glutamate
cycling between neurons and astrocytes and glycogen storage in
astrocytes have been implemented. A unique feature of the model
is its calibration using in vivo data of brain glucose and
lactate from freely moving rats under various stimuli. The
model has been used to perform simulated perturbation
experiments that show that glycogen breakdown in astrocytes is
significantly activated during sensory (tail pinch)
stimulation. This mechanism provides an additional input of
energy substrate during high consumption phases. By way of
validation, data from the perfusion of 50 microM propranolol in
the rat brain was compared with the model outputs. Propranolol
affects the glucose dynamics during stimulation, and this was
accurately reproduced in the model by a reduction in the
glycogen breakdown in astrocytes. The model's predictive
capacity was verified by using data from a sensory stimulation
(restraint) that was not used for model calibration. Finally, a
sensitivity analysis was conducted on the model parameters,
this showed that the control of energy metabolism and transport
processes are critical in the metabolic behaviour of cerebral
tissue.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000554.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000554 | BioModels
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2018-10-12 | GSE121041 | GEO
Project description:Winter2017 - Brain Energy Metabolism with PPP
This model is described in the article:
Mathematical analysis of the
influence of brain metabolism on the BOLD signal in Alzheimer's
disease
Felix Winter1,2, Catrin
Bludszuweit-Philipp1 and Olaf Wolkenhauer2,3
Journal of Cerebral Blood Flow &
Metabolism
Abstract:
Blood oxygen level-dependent functional magnetic resonance
imaging (BOLD-fMRI) is a standard clinical tool for the
detection of brain activation. In Alzheimer’s disease
(AD), task-related and resting state fMRI have been used to
detect brain dysfunction. It has been shown that the shape of
the BOLD response is affected in early AD. To correctly
interpret these changes, the mechanisms responsible for the
observed behaviour need to be known. The parameters of the
canonical hemodynamic response function (HRF) commonly used in
the analysis of fMRI data have no direct biological
interpretation and cannot be used to answer this question. We
here present a model that allows relating AD-specific changes
in the BOLD shape to changes in the underlying energy
metabolism. According to our findings, the classic view that
differences in the BOLD shape are only attributed to changes in
strength and duration of the stimulus does not hold. Instead,
peak height, peak timing and full width at half maximum are
sensitive to changes in the reaction rate of several metabolic
reactions. Our systems-theoretic approach allows the use of
patient-specific clinical data to predict dementia- driven
changes in the HRF, which can be used to improve the results of
fMRI analyses in AD patients.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000627.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000627 | BioModels
Project description:Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply1,2. Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism3,4, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood5,6. Here we show, using experimental in vitro and in vivo animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by neuromodulator adenosine acting on astrocytic A2B receptors. Stimulation of A2B receptors recruits the canonical cyclic adenosine 3',5'-monophosphate-protein kinase A signalling pathway, leading to rapid activation of astrocyte glucose metabolism and the release of lactate, which supplements the extracellular pool of readily available energy substrates. Experimental mouse models involving conditional deletion of the gene encoding A2B receptors in astrocytes showed that adenosine-mediated metabolic signalling is essential for maintaining synaptic function, especially under conditions of high energy demand or reduced energy supply. Knockdown of A2B receptor expression in astrocytes led to a major reprogramming of brain energy metabolism, prevented synaptic plasticity in the hippocampus, severely impaired recognition memory and disrupted sleep. These data identify the adenosine A2B receptor as an astrocytic sensor of neuronal activity and show that cAMP signalling in astrocytes tunes brain energy metabolism to support its fundamental functions such as sleep and memory.
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Checkpoint blockade therapy, in particular PD-1 and PD-L1 inhibition, has recently shown clinical efficacy in multiple types of solid tumors. The investigators propose to study the efficacy of checkpoint blockade therapy in patients with solid tumors and refractory/recurrent brain metastases. The investigators will assess the efficacy of MEDI4736, a novel PD-L1 inhibitory monoclonal antibody, in this study.
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2021-06-11 | PXD026622 | Pride
Project description:UNLABELLED:Astrocytes are well established modulators of extracellular glutamate, but their direct influence on energy balance-relevant behaviors is largely understudied. As the anorectic effects of glucagon-like peptide-1 receptor (GLP-1R) agonists are partly mediated by central modulation of glutamatergic signaling, we tested the hypothesis that astrocytic GLP-1R signaling regulates energy balance in rats. Central or peripheral administration of a fluorophore-labeled GLP-1R agonist, exendin-4, localizes within astrocytes and neurons in the nucleus tractus solitarius (NTS), a hindbrain nucleus critical for energy balance control. This effect is mediated by GLP-1R, as the uptake of systemically administered fluorophore-tagged exendin-4 was blocked by central pretreatment with the competitive GLP-1R antagonist exendin-(9-39). Ex vivo analyses show prolonged exendin-4-induced activation (live cell calcium signaling) of NTS astrocytes and neurons; these effects are also attenuated by exendin-(9-39), indicating mediation by the GLP-1R. In vitro analyses show that the application of GLP-1R agonists increases cAMP levels in astrocytes. Immunohistochemical analyses reveal that endogenous GLP-1 axons form close synaptic apposition with NTS astrocytes. Finally, pharmacological inhibition of NTS astrocytes attenuates the anorectic and body weight-suppressive effects of intra-NTS GLP-1R activation. Collectively, data demonstrate a role for NTS astrocytic GLP-1R signaling in energy balance control. SIGNIFICANCE STATEMENT:Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce food intake and are approved by the Food and Drug Administration for the treatment of obesity, but the cellular mechanisms underlying the anorectic effects of GLP-1 require further investigation. Astrocytes represent a major cellular population in the CNS that regulates neurotransmission, yet the role of astrocytes in mediating energy balance is largely unstudied. The current data provide novel evidence that astrocytes within the NTS are relevant for energy balance control by GLP-1 signaling. Here, we report that GLP-1R agonists activate and internalize within NTS astrocytes, while behavioral data suggest the pharmacological relevance of NTS astrocytic GLP-1R activation for food intake and body weight. These findings support a previously unknown role for CNS astrocytes in energy balance control by GLP-1 signaling.
| S-EPMC4804010 | biostudies-literature
Project description:Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder. Several studies have attempted to characterize molecular alterations associated with PTSD, but most findings were limited to the investigation of specific cellular markers in the periphery or defined brain regions. In the current study, we aimed to unravel affected molecular pathways/mechanisms in the fear circuitry associated with PTSD. We interrogated a foot shock induced-PTSD mouse model by integrating proteomics and metabolomics profiling data. Alterations at the proteome level were analyzed using in vivo 15N metabolic labeling combined with mass spectrometry in prelimbic cortex (PrL), anterior cingulate cortex (ACC), basolateral amygdala (BLA), central nucleus of amygdala (CeA) and CA1 of hippocampus between shocked and non-shocked (control) mice, with and without fluoxetine treatment.
2018-10-17 | PXD002231 | Pride