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Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the 2 nations. The inaugural Norway-UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.
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Envejecimiento , Demencia , Humanos , Anciano , Longevidad , Demencia/prevención & control , Demencia/epidemiología , Reino Unido , NoruegaRESUMEN
Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we identify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arachnoid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology.
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Aracnoides , Meninges , Ratones , Animales , Aracnoides/anatomía & histología , Piamadre , Plexo Coroideo , EncéfaloRESUMEN
The lactate receptor HCAR1 (hydroxycarboxylic acid receptor 1) is highly expressed in pancreatic ductal adenocarcinoma (PDAC), where it regulates lactate transport between the cancer cells. Little is known about the underlying cause of high HCAR1 expression in PDAC, and in the present study, we investigated whether HCAR1 could be a target of miRNA regulation. By searching for predicted miRNA candidates in silico, we identified miR-431-5p as a possible regulator of HCAR1. We found miR-431-5p to repress HCAR1 expression through direct binding to the 3' UTR. The endogenous expression of miR-431-5p and HCAR1 was found to be negatively related in the PDAC cell lines BxPC-3, Capan-2, and PANC-1. Overexpression of miR-431-5p inhibited cell proliferation in all the cell lines, and a shift in cell cycle progression and induction of apoptosis were found in the BxPC-3 cells. Transcriptomic analysis of mRNA from BxPC-3 cells revealed numerous differentially expressed genes (DEGs), including HCAR1, in response to miR-431-5p overexpression. A significant proportion of these DEGs was enriched in cancer-related processes and signalling pathways. Among the most significantly repressed DEGs was ATP6V0E1, encoding the integral subunit e of vacuolar ATPase (V-ATPase), an enzyme that is important for cancer cell survival. Small interfering RNA (siRNA)-mediated knockdown of HCAR1 and ATP6V0E1 showed that only knockdown of ATP6V0E1 mimicked the effect of miR-431-5p overexpression on cell viability. Our findings indicate that miR-431-5p acts as a tumour suppressor in PDAC cells, with BxPC-3 cells being most responsive.
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Carcinoma Ductal Pancreático/genética , MicroARNs/genética , Neoplasias Pancreáticas/genética , Receptores Acoplados a Proteínas G/genética , ATPasas de Translocación de Protón Vacuolares/genética , Regiones no Traducidas 3' , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Invasividad NeoplásicaRESUMEN
This is a summary of the 2022 Nansen Neuroscience Lectures. On 10 October 2022, Professors Henriette van Praag and David Gems gave the 2022 Nansen Neuroscience Lectures on the theme "Is ageing inevitable?" in the Norwegian Academy of Science and Letters, Oslo, Norway. While van Praag gave a lecture entitled "The benefits of exercise for brain function", Gems gave the 2nd lecture discussing "What causes ageing? Lessons from The Worm". Understanding the fundamental mechanisms of ageing will pave the way to the development of future interventions to pre-empt the development of the diseases, including Alzheimer's disease and other dementias, of later life.
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AIM: Adult neurogenesis occurs in two major niches in the brain: the subgranular zone of the hippocampal formation and the ventricular-subventricular zone. Neurogenesis in both niches is reduced in ageing and neurological disease involving dementia. Exercise can rescue memory by enhancing hippocampal neurogenesis, but whether exercise affects adult neurogenesis in the ventricular-subventricular zone remains unresolved. Previously, we reported that exercise induces angiogenesis through activation of the lactate receptor HCA1. The aim of the present study is to investigate HCA1 -dependent effects on neurogenesis in the two main neurogenic niches. METHODS: Wild-type and HCA1 knock-out mice received high intensity interval exercise, subcutaneous injections of L-lactate, or saline injections, five days per week for seven weeks. Well-established markers for proliferating cells (Ki-67) and immature neurons (doublecortin), were used to investigate neurogenesis in the subgranular zone and the ventricular-subventricular zone. RESULTS: We demonstrated that neurogenesis in the ventricular-subventricular zone is enhanced by HCA1 activation: Treatment with exercise or lactate resulted in increased neurogenesis in wild-type, but not in HCA1 knock-out mice. In the subgranular zone, neurogenesis was induced by exercise in both genotypes, but unaffected by lactate treatment. CONCLUSION: Our study demonstrates that neurogenesis in the two main neurogenic niches in the brain is regulated differently: Neurogenesis in both niches was induced by exercise, but only in the ventricular-subventricular zone was neurogenesis induced by lactate through HCA1 activation. This opens for a role of HCA1 in the physiological control of neurogenesis, and potentially in counteracting age-related cognitive decline.
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Ventrículos Laterales , Células-Madre Neurales , Animales , Proliferación Celular , Ácido Láctico , Ratones , Ratones Noqueados , NeurogénesisRESUMEN
PURPOSE: Degenerative 'microdot' deposits in healthy and hypoxic corneas are believed to represent lipofuscin-like material aggregation in the stroma. To accurately assess microdot deposits in a clinical setting, we sought to quantify these deposits for the first time using the non-invasive clinical imaging technique of in vivo confocal microscopy (IVCM). METHODS: The corneas of 102 healthy subjects aged 15-88 years were examined by IVCM and microdot density was quantified using a 6-point grading scale by two masked, trained examiners. Microdot density was analyzed with respect to age, sex and stromal depth, and inter-eye and inter-observer differences were evaluated. RESULTS: In healthy subjects, microdot density decreased from the anterior to posterior stroma, with the greatest accumulation observed in the most anterior stroma (subepithelial region). In this region, microdot density correlated strongly with age (P < .0001), with increased microdot deposition in older subjects (>60 years) relative to younger ones (<45 years) (P < .001). Microdot density between eyes of the same subject was highly correlated (r = 0.92, P < .0001), while no association with sex was noted (P ≥ 0.05). The mean inter-observer difference in microdot assessment was 0.62 ± 0.09 grades, with a high correlation of grading between observers (r = 0.77, P < .0001). CONCLUSIONS: IVCM can be used to non-invasively quantify microdot deposits in the subepithelial corneal stroma with good inter-observer reproducibility. Microdot assessment may provide a novel means of quantifying age-related or pathologic degeneration of the corneal stroma in a clinical setting.
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Envejecimiento/fisiología , Córnea/metabolismo , Lipofuscina/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Sustancia Propia/metabolismo , Epitelio Corneal/metabolismo , Femenino , Humanos , Masculino , Microscopía Confocal , Persona de Mediana EdadRESUMEN
Glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) carry the bulk of excitatory synaptic transmission. Their modulation plays key roles in synaptic plasticity, which underlies hippocampal learning and memory. A dysfunctional glutamatergic system may negatively affect learning abilities and underlie symptoms of attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate whether the expression and function of AMPARs were altered in ADHD. We recorded AMPAR mediated synaptic transmission at hippocampal excitatory synapses and quantified immunogold labelling density of AMPAR subunits GluA1 and GluA2/3 in a rat model for ADHD; the spontaneously hypertensive rat (SHR). Electrophysiological recordings showed significantly reduced AMPAR mediated synaptic transmission at the CA3-to-CA1 pyramidal cell synapses in stratum radiatum and stratum oriens in SHRs compared to control rats. Electronmicroscopic immunogold quantifications did not show any statistically significant changes in labelling densities of the GluA1 subunit of the AMPAR on dendritic spines in stratum radiatum or in stratum oriens. However, there was a significant increase of the GluA2/3 subunit intracellularly in stratum oriens in SHR compared to control, interpreted as a compensatory effect. The proportion of synapses lacking AMPAR subunit labelling was the same in the two genotypes. In addition, electronmicroscopic examination of tissue morphology showed the density of this type of synapse (i.e., asymmetric synapses on spines), and the average size of the synaptic membranes, to be the same. AMPAR dysfunction, possibly involving molecular changes, in hippocampus may in part reflect altered learning in individuals with ADHD.
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Trastorno por Déficit de Atención con Hiperactividad/patología , Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/metabolismo , Hipocampo/patología , Receptores AMPA/metabolismo , Animales , Animales Recién Nacidos , Trastorno por Déficit de Atención con Hiperactividad/genética , Espinas Dendríticas , Modelos Animales de Enfermedad , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Hipocampo/efectos de los fármacos , Inmunohistoquímica , Técnicas In Vitro , Masculino , Microscopía Electrónica , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Células Piramidales/ultraestructura , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores AMPA/ultraestructura , Membranas Sinápticas/metabolismo , Membranas Sinápticas/ultraestructuraRESUMEN
The energy deficit hypothesis of attention-deficit/hyperactivity disorder (ADHD) suggests that low lactate production by brain astrocytes causes the symptoms of the disorder. Astrocytes are the main producers of lactate in the brain; however, skeletal muscles can produce the most lactate in the body. The lactate production by skeletal muscles increases with physical activity, as does the expression of the lactate transporter monocarboxylate transporter 1 (MCT1) at the blood-brain barrier (BBB). We hypothesise that children with ADHD, by being hyperactive, increase lactate production by skeletal muscles and transport it into the brain to compensate for low supply by astrocytes. The aim of this study was to explore whether the level of MCT1 is altered in the brain in an animal model of ADHD. The MCT1 expression was quantified on hippocampal brain sections from the best available rat model of ADHD, i.e., the spontaneously hypertensive rat (SHR) (n = 12), and the relevant control, the Wistar Kyoto rat (WKY) (n = 12), by the use of quantitative immunofluorescence laser scanning microscopy and postembedding immunogold electron microscopy. The results revealed significantly higher levels of hippocampal MCT1 immunoreactivity in SHR compared to WKY, particularly at the BBB. These results indicate that lactate flux through MCT1 between the body and the brain could be upregulated in children with ADHD. This study adds to previous research suggesting hyperactivity may be beneficial in ADHD; Children with ADHD possibly display a hyperactive behaviour in order to raise skeletal muscle lactate production, MCT1 expression and flux over the BBB to supply the brain with lactate.
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Trastorno por Déficit de Atención con Hiperactividad/patología , Barrera Hematoencefálica/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Regulación hacia Arriba/fisiología , Animales , Trastorno por Déficit de Atención con Hiperactividad/genética , Barrera Hematoencefálica/ultraestructura , Modelos Animales de Enfermedad , Masculino , Microscopía Confocal , Microscopía Inmunoelectrónica , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/ultraestructura , Neurópilo/metabolismo , Neurópilo/ultraestructura , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Análisis de Regresión , Especificidad de la Especie , Regulación hacia Arriba/genéticaRESUMEN
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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Brain aging is accompanied by declining mitochondrial respiration. We hypothesized that mitochondrial morphology and dynamics would reflect this decline. Using hippocampus and frontal cortex of a segmental progeroid mouse model lacking Cockayne syndrome protein B (CSBm/m) and C57Bl/6 (WT) controls and comparing young (2-5 months) to middle-aged mice (13-14 months), we found that complex I-linked state 3 respiration (CI) was reduced at middle age in CSBm/m hippocampus, but not in CSBm/m cortex or WT brain. In hippocampus of both genotypes, mitochondrial size heterogeneity increased with age. Notably, an inverse correlation between heterogeneity and CI was found in both genotypes, indicating that heterogeneity reflects mitochondrial dysfunction. The ratio between fission and fusion gene expression reflected age-related alterations in mitochondrial morphology but not heterogeneity. Mitochondrial DNA content was lower, and hypoxia-induced factor 1α mRNA was greater at both ages in CSBm/m compared to WT brain. Our findings show that decreased CI and increased mitochondrial size heterogeneity are highly associated and point to declining mitochondrial quality control as an initial event in brain aging.
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Envejecimiento/metabolismo , Encéfalo/metabolismo , Respiración de la Célula , Complejo I de Transporte de Electrón/metabolismo , Lóbulo Frontal/metabolismo , Hipocampo/metabolismo , Mitocondrias/metabolismo , Tamaño Mitocondrial , Animales , ADN Helicasas , Enzimas Reparadoras del ADN , ADN Mitocondrial/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Ratones Transgénicos , Mitocondrias/patología , Proteínas de Unión a Poli-ADP-Ribosa , ARN Mensajero/metabolismoRESUMEN
Nucleic acids, which constitute the genetic material of all organisms, are continuously exposed to endogenous and exogenous damaging agents, representing a significant challenge to genome stability and genome integrity over the life of a cell or organism. Unrepaired DNA lesions, such as single- and double-stranded DNA breaks (SSBs and DSBs), and single-stranded gaps can block progression of the DNA replication fork, causing replicative stress and/or cell cycle arrest. However, translesion synthesis (TLS) DNA polymerases, such as Rev1, have the ability to bypass some DNA lesions, which can circumvent the process leading to replication fork arrest and minimize replicative stress. Here, we show that Rev1-deficiency in mouse embryo fibroblasts or mouse liver tissue is associated with replicative stress and mitochondrial dysfunction. In addition, Rev1-deficiency is associated with high poly(ADP) ribose polymerase 1 (PARP1) activity, low endogenous NAD+, low expression of SIRT1 and PGC1α and low adenosine monophosphate (AMP)-activated kinase (AMPK) activity. We conclude that replication stress via Rev1-deficiency contributes to metabolic stress caused by compromized mitochondrial function via the PARP-NAD+-SIRT1-PGC1α axis.
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Adenosina Trifosfato/metabolismo , Mitocondrias Hepáticas/genética , Nucleotidiltransferasas/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Poli(ADP-Ribosa) Polimerasas/genética , Sirtuina 1/genética , Animales , ADN Polimerasa Dirigida por ADN , Embrión de Mamíferos , Femenino , Fibroblastos/citología , Fibroblastos/enzimología , Regulación de la Expresión Génica , Hígado/enzimología , Masculino , Potencial de la Membrana Mitocondrial/fisiología , Ratones , Ratones Noqueados , Mitocondrias Hepáticas/enzimología , NAD/metabolismo , Nucleotidiltransferasas/deficiencia , Fosforilación Oxidativa , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Cultivo Primario de Células , Transducción de Señal , Sirtuina 1/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismoRESUMEN
Neuroglia, the "glue" that fills the space between neurons in the central nervous system, takes active part in nerve cell signaling. Neuroglial cells, astroglia, oligodendroglia, and microglia, are together about as numerous as neurons in the brain as a whole, and in the cerebral cortex grey matter, but the proportion varies widely among brain regions. Glial volume, however, is less than one-fifth of the tissue volume in grey matter. When stimulated by neurons or other cells, neuroglial cells release gliotransmitters by exocytosis, similar to neurotransmitter release from nerve endings, or by carrier-mediated transport or channel flux through the plasma membrane. Gliotransmitters include the common neurotransmitters glutamate and GABA, the nonstandard amino acid d-serine, the high-energy phosphate ATP, and l-lactate. The latter molecule is a "buffer" between glycolytic and oxidative metabolism as well as a signaling substance recently shown to act on specific lactate receptors in the brain. Complementing neurotransmission at a synapse, neuroglial transmission often implies diffusion of the transmitter over a longer distance and concurs with the concept of volume transmission. Transmission from glia modulates synaptic neurotransmission based on energetic and other local conditions in a volume of tissue surrounding the individual synapse. Neuroglial transmission appears to contribute significantly to brain functions such as memory, as well as to prevalent neuropathologies.
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Encéfalo/metabolismo , Comunicación Celular , Neuroglía/metabolismo , Transducción de Señal , Adenosina Trifosfato/metabolismo , Animales , Astrocitos/metabolismo , Encéfalo/citología , Ácido Glutámico/metabolismo , Humanos , Ácido Láctico/metabolismo , Microglía/metabolismo , Oligodendroglía/metabolismo , Serina/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
We have proposed that lactate is a "volume transmitter" in the brain and underpinned this by showing that the lactate receptor, G-protein-coupled receptor 81 (GPR81, also known as HCA1 or HCAR1), which promotes lipid storage in adipocytes, is also active in the mammalian brain. This includes the cerebral neocortex and the hippocampus, where it can be stimulated by physiological concentrations of lactate and by the HCAR1 agonist 3,5-dihydroxybenzoate to reduce cAMP levels. Cerebral HCAR1 is concentrated on the postsynaptic membranes of excitatory synapses and also is enriched at the blood-brain barrier. In synaptic spines and in adipocytes, HCAR1 immunoreactivity is also located on subplasmalemmal vesicular organelles, suggesting trafficking to and from the plasma membrane. Through activation of HCAR1, lactate can act as a volume transmitter that links neuronal activity, cerebral blood flow, energy metabolism, and energy substrate availability, including a glucose- and glycogen-saving response. HCAR1 may contribute to optimizing the cAMP concentration. For instance, in the prefrontal cortex, excessively high cAMP levels are implicated in impaired cognition in old age, fatigue, stress, and schizophrenia and in the deposition of phosphorylated tau protein in Alzheimer's disease. HCAR1 could serve to ameliorate these conditions and might also act through downstream mechanisms other than cAMP. Lactate exits cells through monocarboxylate transporters in an equilibrating manner and through astrocyte anion channels activated by depolarization. In addition to locally produced lactate, lactate produced by exercising muscle as well as exogenous HCAR1 agonists, e.g., from fruits and berries, might activate the receptor on cerebral blood vessels and brain cells.
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Encéfalo/metabolismo , Ácido Láctico/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Astrocitos/metabolismo , Encéfalo/citología , HumanosRESUMEN
Lactate acts as a 'buffer' between glycolysis and oxidative metabolism. In addition to being exchanged as a fuel by the monocarboxylate transporters (MCTs) between cells and tissues with different glycolytic and oxidative rates, lactate may be a 'volume transmitter' of brain signals. According to some, lactate is a preferred fuel for brain metabolism. Immediately after brain activation, the rate of glycolysis exceeds oxidation, leading to net production of lactate. At physical rest, there is a net efflux of lactate from the brain into the blood stream. But when blood lactate levels rise, such as in physical exercise, there is net influx of lactate from blood to brain, where the lactate is used for energy production and myelin formation. Lactate binds to the lactate receptor GPR81 aka hydroxycarboxylic acid receptor (HCAR1) on brain cells and cerebral blood vessels, and regulates the levels of cAMP. The localization and function of HCAR1 and the three MCTs (MCT1, MCT2, and MCT4) expressed in brain constitute the focus of this review. They are possible targets for new therapeutic drugs and interventions. The author proposes that lactate actions in the brain through MCTs and the lactate receptor underlie part of the favorable effects on the brain resulting from physical exercise.
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Encéfalo/metabolismo , Ejercicio Físico/fisiología , Ácido Láctico/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transducción de Señal/fisiología , Animales , Receptor de Androstano Constitutivo , Regulación de la Expresión Génica/fisiología , Glucólisis/fisiología , Humanos , Oxidación-Reducción , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
During the last years, the concept of gliotransmission has been established. Glutamate has been shown to be released from astrocytes by different mechanisms, e.g., in an exocytotic manner. The authors have previously shown that astrocytes in the dentate-molecular layers express vesicular glutamate transporters on synaptic-like microvesicles (SLMVs). By confocal microscopy, the authors, in this study, show that vesicles by a family of glutamate transporters 1 (VGLUT1) labeling was clearly present within astrocytic processes (diameter > 1 µm) in several brain regions; the dentate-molecular layers, the stratum radiatum of CA1 hippocampus, the frontal cortex, and the striatum. At the electron microscopic level, immunogold cytochemistry showed the presence of VGLUT1 gold particles over SLMVs in delicate astrocytic processes (cross-sectional diameter < 500 nm) in all the above-mentioned brain regions. When measuring the distance from the membrane of SLMVs in astrocytes to the closest VGLUT1 gold particle, it turned out that most gold particles (above 95 %) were located within 25 nm from the membrane, strongly suggesting that VGLUT1 is present in SLMVs in the astrocytes. Finally, electron microscopic immunocytochemistry shows that VGLUT1 labeling was concentrated in astrocytic processes from wild type, and not in VGLUT1 knock out hippocampus. The authors have concluded that astrocytes not only in the dentate-molecular layers but also in stratum radiatum of CA1 hippocampus, frontal cortex, and the striatum possess SLMVs carrying VGLUT1, suggesting that astrocytes in all these brain regions are capable of vesicular release of glutamate.
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Astrocitos/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/metabolismo , Animales , Región CA1 Hipocampal/metabolismo , Compartimento Celular/genética , Cuerpo Estriado/metabolismo , Vesículas Citoplasmáticas/genética , Vesículas Citoplasmáticas/metabolismo , Giro Dentado/metabolismo , Lóbulo Frontal/metabolismo , Masculino , Ratones , Ratones Noqueados , Ratas , Ratas Wistar , Proteína 1 de Transporte Vesicular de Glutamato/deficienciaRESUMEN
Eccentric muscle actions are associated with ultrastructural changes. The severity and types of change depend on the nature of the stimulation protocol, and on the method for assessing such changes, and can be regarded as a continuum from mild changes to pathological-like changes. Most studies describing more severe changes have been performed on animals and only a few in humans, some using electrical stimuli. Hence, a debate has emerged on whether voluntary actions are associated with the pathological-like end of the continuum. The aim of this study was to determine whether severe muscle damage, i.e., extensive ultrastructural changes, is confined to animal studies and studies on humans using electrical stimuli. Second, because there is no generally approved method to quantify the degree of muscle damage, we compared two published methods, analyzing the Z disks or sarcomeres, as well as novel analyses of pathological-like changes. A group of untrained subjects performed 70 voluntary maximal eccentric muscle actions using the elbow flexors. On the basis of large reductions in maximal force-generating capacity (on average, -62 +/- 3% immediately after exercise, and -35 +/- 6% 9 days later), five subjects were selected for further analysis. Biopsies were taken from m. biceps brachii in both the exercised and nonexercised arm. In exercised muscle, more disrupted (13 +/- 4 vs. 3 +/- 3%) and destroyed (15 +/- 6 vs. 0%) Z disks were found compared with nonexercised muscle. A significant proportion of exercised myofibers had focal (85 +/- 5 vs. 11 +/- 7%), moderate (65 +/- 7 vs. 11 +/- 6%), and extreme (38 +/- 9 vs. 0%) myofibrillar disruptions. Hypercontracted myofibrils, autophagic vacuoles, granular areas, central nuclei, and necrotic fiber segments were found to various degrees. The present study demonstrates that the more severe end of the continuum of ultrastructural changes occurs in humans after voluntary exercise when maximal eccentric muscle actions are involved.
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Contracción Muscular/fisiología , Fibras Musculares Esqueléticas/patología , Fibras Musculares Esqueléticas/ultraestructura , Músculo Esquelético/patología , Músculo Esquelético/ultraestructura , Adulto , Distribución de Chi-Cuadrado , Creatina Quinasa/sangre , Codo/patología , Femenino , Humanos , Masculino , Microscopía Electrónica de Transmisión , Fatiga Muscular , Fibras Musculares Esqueléticas/fisiología , Fuerza Muscular , Músculo Esquelético/fisiología , Necrosis , Sarcómeros , Estadísticas no ParamétricasRESUMEN
Although several molecular and genetic manipulations may produce hyperactive animals, hyperactivity alone is insufficient for the animal to qualify as a model of ADHD. Based on a wider range of criteria - behavioral, genetic and neurobiological - the spontaneously hypertensive rat (SHR) obtained from Charles River, Germany (SHR/NCrl) at present constitutes the best validated animal model of ADHD combined subtype (ADHD-C), and the Wistar Kyoto substrain obtained from Harlan, UK (WKY/NHsd) is its most appropriate control. Although other rat strains may behave like WKY/NHsd rats, genetic results indicate significant differences when compared to the WKY/NHsd substrain, making them less suitable controls for the SHR/NCrl. The use of WKY/NCrl, outbred Wistar, Sprague Dawley or other rat strains as controls for SHRs may produce spurious neurobiological differences. Consequently, data may be misinterpreted if insufficient care is taken in the selection of the control group. It appears likely that the use of different control strains may underlie some of the discrepancies in results and interpretations in studies involving the SHR and WKY. Finally, we argue that WKY rats obtained from Charles River, Germany (WKY/NCrl) provide a promising model for the predominantly inattentive subtype of ADHD (ADHD-PI); in this case also the WKY/NHsd substrain should be used as control.
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Trastorno por Déficit de Atención con Hiperactividad , Modelos Animales de Enfermedad , Animales , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Plasticidad Neuronal/genética , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Refuerzo en Psicología , Especificidad de la EspecieAsunto(s)
Encéfalo/fisiología , Ejercicio Físico , Envejecimiento/fisiología , Envejecimiento/psicología , Encéfalo/irrigación sanguínea , Encéfalo/citología , Cognición/fisiología , Ejercicio Físico/fisiología , Ejercicio Físico/psicología , Humanos , Regeneración Nerviosa/fisiología , Enfermedades Neurodegenerativas/prevención & controlRESUMEN
The brain's energy metabolism is considered to be completely aerobic, with glucose as the major energy substrate for neurons during both rest and activation. This view has now been challenged, as other energy metabolites are shown to play a more important role in the brain's energy metabolism. During development of the brain both lactate and ketone bodies are used as energy substrates. Lactate and ketone bodies are shown to be important energy metabolites in situations of starvation, hypoglycemia and diabetes. During intense physical activity the brain uses lactate from the circulating blood. Lactate and other monocarboxylates cross cell membranes by interaction with specific proteins; the monocarboxylate transporters (MCTs). MCTs are trans-membrane proteins that facilitate cotransport of a monocarboxylate ion with a proton. Whether the transport goes in or out of a brain cell depends on the concentration gradient for the monocarboxylates and the pH-gradient. The brain has been shown to express three different MCTs: MCT1, MCT2 and MCT4. MCT1 is expressed in astrocytes and in microvessel endothelial cells, whilst MCT2 is concentrated in neurons and MCT4 is preferentially expressed in astrocytes. Neurons are considered to be the lactate consuming cells whereas astrocytes are the lactate producers. Lactate may be an important energy substrate for neurons, e.g. in tissue surviving ischemia.
Asunto(s)
Encéfalo/metabolismo , Lactatos/metabolismo , Astrocitos/metabolismo , Encéfalo/citología , Metabolismo Energético , Humanos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Neuroglía/metabolismo , Neuronas/metabolismoRESUMEN
MCT2 is the main neuronal monocarboxylate transporter needed by neurons if they are to use lactate as an additional energy substrate. Previous evidence suggested that some MCT2 could be located in postsynaptic elements of glutamatergic synapses. Using post-embedding electron microscopic immunocytochemistry, it is demonstrated that MCT2 is present at postsynaptic density of asymmetric synapses, in the stratum radiatum of both rat hippocampal CA1 and CA3 regions, as well as at parallel fibre-Purkinje cell synapses in mouse cerebellum. MCT2 levels were significantly lower at mossy fibre synapses on CA3 neurons, and MCT2 was almost absent from symmetric synapses on CA1 pyramidal cells. It could also be demonstrated using quantitative double-labeling immunogold cytochemistry that MCT2 and AMPA receptor GluR2/3 subunits have a similar postsynaptic distribution at asymmetric synapses with high levels expressed within the postsynaptic density. In addition, as for AMPA receptors, a significant proportion of MCT2 is located on vesicular membranes within the postsynaptic spine, forming an intracellular pool available for a putative postsynaptic endo/exocytotic trafficking at these excitatory synapses. Altogether, the data presented provide evidence for MCT2 expression in the postsynaptic density area at specific subsets of glutamatergic synapses, and also suggest that MCT2, like AMPA receptors, could undergo membrane trafficking.