The astrocyte biochemistry Souza, Débora G.; Almeida, Roberto F.; Souza, Diogo O. ...
Seminars in cell & developmental biology,
November 2019, 2019-11-00, 20191101, Letnik:
95
Journal Article
Recenzirano
•Astrocytes, a subset of glial cells, are essential for regulating metabolic fuel availability in the brain.•Astrocytes have at least two sources of glucose: the bloodstream or glycogen, which they ...convert to lactate for export.•Astrocytes may oxidize fatty acids and produce ATP and ketone bodies with it, depending on the metabolic status.•Astrocytes, trough energy-demanding processes, take up glutamate and GABA.•Glutamate and GABA can also be ATP sources.
Astrocytes are a unique and dynamic subtype of glial cells in the central nervous system (CNS). Understanding their biochemical reactions and their influence in the surrounding cells is extremely important in the neuroscience field. They exert important influence in the neurotransmission, ionic homeostasis and also release neuroactive molecules termed gliotransmitters. Additionally, they metabolize, store and release metabolic substrates to meet high brain energy requirements. In this review, we highlight the main biochemical reactions regarding energy metabolism that take place in astrocytes. Special attention is given to synthesis, storage and catabolism of glucose, release of lactate, oxidation of fatty acids, production of ketone bodies, and metabolism of the main neurotransmitters, glutamate and GABA. The recent findings allow proposing these cells as key players controlling the energetic homeostasis in the CNS.
The open tank paradigm, also known as novel tank diving test, is a protocol used to evaluate the zebrafish behavior. Several characteristics have been described for this species, including ...scototaxis, which is the natural preference for dark environments in detriment of bright ones. However, there is no evidence regarding the influence of "natural stimuli" in zebrafish subjected to novelty-based paradigms. In this report, we evaluated the spatio-temporal exploratory activity of the short-fin zebrafish phenotype in the open tank after a short-period confinement into dark/bright environments. A total of 44 animals were individually confined during a 10-min single session into one of three environments: black-painted, white-painted, and transparent cylinders (dark, bright, and transparent groups). Fish were further subjected to the novel tank test and their exploratory profile was recorded during a 15-min trial. The results demonstrated that zebrafish increased their vertical exploratory activity during the first 6-min, where the bright group spent more time and travelled a higher distance in the top area. Interestingly, all behavioral parameters measured for the dark group were similar to the transparent one. These data were confirmed by automated analysis of track and occupancy plots and also demonstrated that zebrafish display a classical homebase formation in the bottom area of the tank. A detailed spatio-temporal study of zebrafish exploratory behavior and the construction of representative ethograms showed that the experimental groups presented significant differences in the first 3-min vs. last 3-min of test. Although the main factors involved in these behavioral responses still remain ambiguous and require further investigation, the current report describes an alternative methodological approach for assessing the zebrafish behavior after a forced exposure to different environments. Additionally, the analysis of ethologically-relevant patterns across time could be a potential phenotyping tool to evaluate the zebrafish exploratory profile in the open tank task.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The ability to live in coherent superpositions is a signature trait of quantum systems and constitutes an irreplaceable resource for quantum-enhanced technologies. However, decoherence effects ...usually destroy quantum superpositions. It was recently predicted that, in a composite quantum system exposed to dephasing noise, quantum coherence in a transversal reference basis can stay protected for an indefinite time. This can occur for a class of quantum states independently of the measure used to quantify coherence, and it requires no control on the system during the dynamics. Here, such an invariant coherence phenomenon is observed experimentally in two different setups based on nuclear magnetic resonance at room temperature, realizing an effective quantum simulator of two- and four-qubit spin systems. Our study further reveals a novel interplay between coherence and various forms of correlations, and it highlights the natural resilience of quantum effects in complex systems.
The excitatory amino acid transporter 2 (EAAT2) plays a key role in the clearance and recycling of glutamate - the major excitatory neurotransmitter in the mammalian brain. EAAT2 loss/dysfunction ...triggers a cascade of neurodegenerative events, comprising glutamatergic excitotoxicity and neuronal death. Nevertheless, our current knowledge regarding EAAT2 in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD), is restricted to post-mortem analysis of brain tissue and experimental models. Thus, detecting EAAT2 in the living human brain might be crucial to improve diagnosis/therapy for ALS and AD. This perspective article describes the role of EAAT2 in physio/pathological processes and provides a structure–activity relationship of EAAT2-binders, bringing two perspectives: therapy (activators) and diagnosis (molecular imaging tools).
Postoperative cognitive dysfunction (POCD) is a multifactorial adverse event most frequently in elderly patients. This study evaluated the effect of dexamethasone on POCD incidence after noncardiac ...and nonneurologic surgery.
One hundred and forty patients (ASA I-II; age 60-87 years) took part in a prospective phase III, double blind, randomized study involving the administration or not of 8 mg of IV dexamethasone before general anesthesia under bispectral index (BIS) between 35-45 or 46-55. Neuropsychological tests were applied preoperatively and on the 3rd, 7th, 21st, 90th and 180th days after surgery and compared with normative data. S100β was evaluated before and 12 hours after induction of anesthesia. The generalized estimating equations (GEE) method was applied, followed by the posthoc Bonferroni test considering P<0.05 as significant.
On the 3rd postoperative day, POCD was diagnosed in 25.2% and 15.3% of patients receiving dexamethasone, BIS 35-45, and BIS 46-55 groups, respectively. Meanwhile, POCD was present in 68.2% and 27.2% of patients without dexamethasone, BIS 35-45 and BIS 46-55 groups (p<0.0001). Neuropsychological tests showed that dexamethasone associated to BIS 46-55 decreased the incidence of POCD, especially memory and executive function. The administration of dexamethasone might have prevented the postoperative increase in S100β serum levels.
Dexamethasone can reduce the incidence of POCD in elderly patients undergoing surgery, especially when associated with BIS 46-55. The effect of dexamethasone on S100β might be related with some degree of neuroprotection.
www.clinicaltrials.gov NCT01332812.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sirt1 has been associated with various effects of calorie restriction, including an increase in lifespan. Here we show in mice that a central regulatory component in energy metabolism, the ...hypothalamic melanocortin system, is affected by Sirt1, which promotes the activity and connectivity of this system resulting in negative energy balance. In adult mice, the pharmacological inhibition of brain Sirt1 activity decreased Agrp neuronal activity and the inhibitory tone on the anorexigenic POMC neurons, as measured by the number of synaptic inputs to these neurons. When a Sirt1 inhibitor (EX-527) was injected either peripherally (i.p., 10 mg/kg) or directly into the brain (i.c.v., 1.5 nmol/mouse), it decreased both food intake during the dark cycle and ghrelin-induced food intake. This effect on feeding is mediated by upstream melanocortin receptors, because the MC4R antagonist, SHU9119, reversed Sirt1's effect on food intake. This action of Sirt1 required an appropriate shift in the mitochondrial redox state: in the absence of such an adaptation enabled by the mitochondrial protein, UCP2, Sirt1-induced cellular and behavioral responses were impaired. In accordance with the pharmacological results, the selective knock-out of Sirt1 in hypothalamic Agrp neurons through the use of Cre-Lox technology decreased electric responses of Agrp neurons to ghrelin and decreased food intake, leading to decreased lean mass, fat mass, and body weight. The present data indicate that Sirt1 has a central mode of action by acting on the NPY/Agrp neurons to affect body metabolism.
Purpose
Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with
18
Ffluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In ...the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug.
Methods
Adult male Wistar rats (control,
n
= 14; CLO,
n
= 12) received CLO (25/35 mg kg
−1
) for 6 weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake).
Results
CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake.
Conclusion
This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism—mimicking the hypometabolic signature seen in people developing dementia—and adds further evidence that astrocytes are key contributors of the FDG-PET signal.
A substantial fraction of coronavirus disease 2019 (COVID-19) patients experience neurological manifestations. Nevertheless, brain changes caused by severe acute respiratory syndrome coronavirus 2 ...(SARS-CoV-2) remain largely unknown. Here, we provide a brief overview of positron emission tomography (PET) applications that could advance current understanding of CNS pathophysiological alterations associated with SARS-CoV-2 infection.
Amyloid‐β (Aβ) dysmetabolism is tightly associated with pathological processes in Alzheimer's disease (AD). Currently, it is thought that, in addition to Aβ fibrils that give rise to plaque ...formation, Aβ aggregates into non‐fibrillar soluble oligomers (AβOs). Soluble AβOs have been extensively studied for their synaptotoxic and neurotoxic properties. In this review, we discuss physicochemical properties of AβOs and their impact on different brain cell types in AD. Additionally, we summarize three decades of studies with AβOs, providing a compelling bulk of evidence regarding cell‐specific mechanisms of toxicity. Cellular models may lead us to a deeper understanding of the detrimental effects of AβOs in neurons and glial cells, putatively shedding light on the development of innovative therapies for AD.
Amyloid‐beta oligomers (AβOs) are synaptotoxins in Alzheimer's disease (AD) and have been firstly characterized in the 90s. Since mechanisms are not fully elucidated, cell culture may hold the key for better understanding AβOs toxic roles in AD pathophysiology. In this review, we briefly revisit AβOs physicochemical properties and toxic mechanism by discussing three decades of research in AβOs cellular models.
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