The concept of the brain cognitive reserve is derived from the well-acknowledged notion that the degree of brain damage does not always match the severity of clinical symptoms and neurological/cognitive outcomes.It ha...The concept of the brain cognitive reserve is derived from the well-acknowledged notion that the degree of brain damage does not always match the severity of clinical symptoms and neurological/cognitive outcomes.It has been suggested that the size of the brain(brain reserve) and the extent of neural connections acquired through life(neural reserve) set a threshold beyond which noticeable impairments occur.In contrast,cognitive reserve refers to the brain's ability to adapt and reo rganize stru cturally and functionally to resist damage and maintain function,including neural reserve and brain maintenance,resilience,and compensation(Verkhratsky and Zorec,2024).展开更多
Inflammatory reflex and cholinergic anti-inflammatory pathway:Innate immune system triggers a local inflammatory response following an injury or a pathogen invasion.Likewise,this inflammatory response is limited by ra...Inflammatory reflex and cholinergic anti-inflammatory pathway:Innate immune system triggers a local inflammatory response following an injury or a pathogen invasion.Likewise,this inflammatory response is limited by rapid,localized,and adaptive anti-inflammatory responses which are crucial for maintaining homeostasis.Hence,the loss of these responses converts a limited and protective inflammatory response into an excessive and harmful response.Anti-inflammatory responses are integrated into the central nervous system,since the central nervous system accumulates information about harmful events,activates defenses,and builds memory for survival.At the same time,it has been demonstrated that hypothalamic neuronal signaling can be altered by inflammation in peripheral tissues.Additionally,immune cells release neuropeptides and neurotransmitters such as acetylcholine(ACh),the main neurotransmitter of the parasympathetic autonomic nervous system,evidencing the communication between the immune and nervous systems(Tracey,2002).展开更多
Apoptosis is a widespread phenomenon that occurs in the brain in both physiological and pathological conditions. Dead ceils must be quickly removed to avoid the further toxic effects they exert in the pa- renchyma, a ...Apoptosis is a widespread phenomenon that occurs in the brain in both physiological and pathological conditions. Dead ceils must be quickly removed to avoid the further toxic effects they exert in the pa- renchyma, a process executed by microglia, the brain professional phagocytes. Although phagocytosis is critical to maintain tissue homeostasis, it has long been either overlooked or indirectly assessed based on microglial morphology, expression of classical activation markers, or engulfment of artificial phagocytic targets in vitro. Nevertheless, these indirect methods present several limitations and, thus, direct obser- vation and quantification of microglial phagocytosis is still necessary to fully grasp its relevance in the diseased brain. To overcome these caveats and obtain a comprehensive, quantitative picture of microglial phagocytosis we have developed a novel set of parameters. These parameters have allowed us to identify the different strategies utilized by microglia to cope with apoptotic challenges induced by excitotoxicity or inflammation. In contrast, we discovered that in mouse and human epilepsy microglia failed to find and engulf apoptotic ceils, resulting in accumulation of debris and inflammation. Herein, we advocate that the efficiency of microglial phagocytosis should be routinely tested in neurodegenerative and neuro- logical disorders, in order to determine the extent to which it contributes to apoptosis and inflammation found in these conditions. Finally, our findings point towards enhancing microglial phagocytosis as a novel therapeutic strategy to control tissue damage and inflammation, and accelerate recovery in brain diseases.展开更多
Glial proliferation:For the last decades,glial cells have been wrongly believed to have a mere passive supporting role for neurons.Nevertheless,this notion has clearly changed and it is now admitted that these cells a...Glial proliferation:For the last decades,glial cells have been wrongly believed to have a mere passive supporting role for neurons.Nevertheless,this notion has clearly changed and it is now admitted that these cells are essential for the correct development and regulation of the nervous system.Glia cell population are commonly subdivided in astrocytes,oligodendrocytes and microglia.During the development,neural stem cells(NSCs)(called neuroepithelial progenitor cells or NPCs)transform into radial glia,the primary progenitor cells for neurons,astrocytes and oligodendrocytes(Zuchero and Barres,2015).Microglial cells,however,derive from a mesenchymal precursor infiltration,meaning that during brain development,precursors generated in the bone narrow invade the nervous parenchyma and differentiate into microglial cells(Zuchero and Barres,2015).This proliferative capacity is preserved in the adult mammalian brain,and neurogenic NSCs are stored in two restricted regions of the central nervous system(CNS),the forebrain subventricular zone(SVZ)and the hippocampal dentate gyrus(subgranular zone).These cells continue to produce neurons and glial cells during the adulthood,being activated after certain signals and leaving the quiescent state(Urbán et al.,2019).This process,in which glial progenitor cells differentiate into mature glia during development and in the adult brain to maintain and regulate brain function,is called gliogenesis(Ardaya et al.,2020).展开更多
We review the physics of monolayer graphene in a strong magnetic field,with emphasis on highly collective states that emerge from the weakly interacting system because of correlations(emergent states).After reviewing ...We review the physics of monolayer graphene in a strong magnetic field,with emphasis on highly collective states that emerge from the weakly interacting system because of correlations(emergent states).After reviewing the general properties of graphene and of electrons in a magnetic field,we give a brief introduction to the integer quantum Hall effect(IQHE)and the fractional quantum Hall effect(FQHE)in a 2D electron gas as foundation to show that monolayer graphene in a magnetic field exhibits both effects,but with properties modified by the influence of the graphene crystal.After giving an introduction to standard methods of dealing with emergent states for this system,we show that an SO(8)fermion dynamical symmetry governs the emergent degrees of freedom and that the algebraic and group properties of the dynamical symmetry provide a new view of strongly correlated states observed in monolayer graphene subject to a strong magnetic field.展开更多
Background:Multiple sclerosis(MS)is a chronic demyelinating disease characterized by autoimmune attacks on myelin sheaths.Its deleterious effects may be reversed by remyelination,a process that restores the integrity ...Background:Multiple sclerosis(MS)is a chronic demyelinating disease characterized by autoimmune attacks on myelin sheaths.Its deleterious effects may be reversed by remyelination,a process that restores the integrity of myelin sheaths and,consequently,neuronal function.However,the functional implications of demyelination and remyelination in MS,as well as the potential impact of therapeutic interventions,remain incompletely understood.We used noninvasive longitudinal resting-state functional magnetic resonance imaging in a cuprizone murine model of demyelination to investigate these unsolved questions.Methods:Three groups of(n=6)animals were studied.A control group was fed with standard food for 5 weeks while two treatment groups(cuprizone and clemastine)suffered progressive demyelination by feeding them with 2%cuprizone.At Week 5(W5),all animals returned to the standard diet and studied for another 5-week period to compare controls vs spontaneous(cuprizone group)vs clemastine-aided(clemastine group)remyelination group.Group clemastine was treated with this antihistaminic(oral gavage)during the remyelination period(Weeks 5–10).Anatomical magnetic resonance imaging(T2w-MRI)and resting state functional MRI(rs-FMRI)studies were conducted on weeks W0,W2,W5(maximal demyelination)W7 and W10(remyelination).MRI images were processed with the FMRIB Software Library,involving seed-free functional imaging and seed-based correlation.This study uses the t-test and the D'Agostino–Pearson normality test to make an assessment.Results:The principal findings of our research include:(1)cuprizone-treated animals suffer an initial phase of elevated connectivity at Week 2 with respect to controls,transitioning to reduced connectivity at Week 5;(2)different temporal trajectories across brain regions,reflecting varying susceptibility to demyelination;(3)while spontaneous remyelination normalizes connectivity in most networks at Week 10(5 weeks after ceasing cuprizone intoxication),the thalamocortical axis exhibits lasting disruption even 6 months after normalization of diet;and(4)on the contrary,clemastine-aided remyelination re-establishes normal thalamocortical connectivity at 6 months after demyelination.Conclusion:This approach provides insights into the dynamic processes of demyelination and remyelination,informing the development of more effective interventions for MS.展开更多
文摘The concept of the brain cognitive reserve is derived from the well-acknowledged notion that the degree of brain damage does not always match the severity of clinical symptoms and neurological/cognitive outcomes.It has been suggested that the size of the brain(brain reserve) and the extent of neural connections acquired through life(neural reserve) set a threshold beyond which noticeable impairments occur.In contrast,cognitive reserve refers to the brain's ability to adapt and reo rganize stru cturally and functionally to resist damage and maintain function,including neural reserve and brain maintenance,resilience,and compensation(Verkhratsky and Zorec,2024).
基金supported by grants from the Spanish Ministry of Education and Science(RYC-2017-22412,PID2019-107989RB-I00 and MDM-2017-0720)FundacióTV3(248/C/2020)(to AM).
文摘Inflammatory reflex and cholinergic anti-inflammatory pathway:Innate immune system triggers a local inflammatory response following an injury or a pathogen invasion.Likewise,this inflammatory response is limited by rapid,localized,and adaptive anti-inflammatory responses which are crucial for maintaining homeostasis.Hence,the loss of these responses converts a limited and protective inflammatory response into an excessive and harmful response.Anti-inflammatory responses are integrated into the central nervous system,since the central nervous system accumulates information about harmful events,activates defenses,and builds memory for survival.At the same time,it has been demonstrated that hypothalamic neuronal signaling can be altered by inflammation in peripheral tissues.Additionally,immune cells release neuropeptides and neurotransmitters such as acetylcholine(ACh),the main neurotransmitter of the parasympathetic autonomic nervous system,evidencing the communication between the immune and nervous systems(Tracey,2002).
基金supported by grants from the Spanish Ministry of Economy and Competitiveness with FEDER funds to AS(BFU2015-66689,RYC-2013-12817)OA is recipient of a predoctoral fellowship from the Basque GovernmentIDA is recipient of a predoctoral fellowship from the University of the Basque Country EHU/UPV
文摘Apoptosis is a widespread phenomenon that occurs in the brain in both physiological and pathological conditions. Dead ceils must be quickly removed to avoid the further toxic effects they exert in the pa- renchyma, a process executed by microglia, the brain professional phagocytes. Although phagocytosis is critical to maintain tissue homeostasis, it has long been either overlooked or indirectly assessed based on microglial morphology, expression of classical activation markers, or engulfment of artificial phagocytic targets in vitro. Nevertheless, these indirect methods present several limitations and, thus, direct obser- vation and quantification of microglial phagocytosis is still necessary to fully grasp its relevance in the diseased brain. To overcome these caveats and obtain a comprehensive, quantitative picture of microglial phagocytosis we have developed a novel set of parameters. These parameters have allowed us to identify the different strategies utilized by microglia to cope with apoptotic challenges induced by excitotoxicity or inflammation. In contrast, we discovered that in mouse and human epilepsy microglia failed to find and engulf apoptotic ceils, resulting in accumulation of debris and inflammation. Herein, we advocate that the efficiency of microglial phagocytosis should be routinely tested in neurodegenerative and neuro- logical disorders, in order to determine the extent to which it contributes to apoptosis and inflammation found in these conditions. Finally, our findings point towards enhancing microglial phagocytosis as a novel therapeutic strategy to control tissue damage and inflammation, and accelerate recovery in brain diseases.
基金supported by grants from the Spanish Ministry of Education and Science(RYC-2017-22412,PID2019-107989RB-I00and MDM-2017-0720)the Basque Government(BIO18/IC/006)and FundacióLa Maratóde TV3(17/C/2017).
文摘Glial proliferation:For the last decades,glial cells have been wrongly believed to have a mere passive supporting role for neurons.Nevertheless,this notion has clearly changed and it is now admitted that these cells are essential for the correct development and regulation of the nervous system.Glia cell population are commonly subdivided in astrocytes,oligodendrocytes and microglia.During the development,neural stem cells(NSCs)(called neuroepithelial progenitor cells or NPCs)transform into radial glia,the primary progenitor cells for neurons,astrocytes and oligodendrocytes(Zuchero and Barres,2015).Microglial cells,however,derive from a mesenchymal precursor infiltration,meaning that during brain development,precursors generated in the bone narrow invade the nervous parenchyma and differentiate into microglial cells(Zuchero and Barres,2015).This proliferative capacity is preserved in the adult mammalian brain,and neurogenic NSCs are stored in two restricted regions of the central nervous system(CNS),the forebrain subventricular zone(SVZ)and the hippocampal dentate gyrus(subgranular zone).These cells continue to produce neurons and glial cells during the adulthood,being activated after certain signals and leaving the quiescent state(Urbán et al.,2019).This process,in which glial progenitor cells differentiate into mature glia during development and in the adult brain to maintain and regulate brain function,is called gliogenesis(Ardaya et al.,2020).
文摘We review the physics of monolayer graphene in a strong magnetic field,with emphasis on highly collective states that emerge from the weakly interacting system because of correlations(emergent states).After reviewing the general properties of graphene and of electrons in a magnetic field,we give a brief introduction to the integer quantum Hall effect(IQHE)and the fractional quantum Hall effect(FQHE)in a 2D electron gas as foundation to show that monolayer graphene in a magnetic field exhibits both effects,but with properties modified by the influence of the graphene crystal.After giving an introduction to standard methods of dealing with emergent states for this system,we show that an SO(8)fermion dynamical symmetry governs the emergent degrees of freedom and that the algebraic and group properties of the dynamical symmetry provide a new view of strongly correlated states observed in monolayer graphene subject to a strong magnetic field.
基金Diputación Foral de Gipuzkoa,Grant/Award Number:2022-CIEN-000090-01NextGenerationEU,Grant/Award Number:2022-CIEN-000090-01+2 种基金Instituto de Salud Carlos III,Grant/Award Number:RD21/0006/0016Agencia Estatal de Investigación,Grant/Award Numbers:PID2020-118546RBI00a,PID2023-152005OB-I00Ikerbasque,Basque Foundation for Science,Grant/Award Number:Ikerbasque Professors Program。
文摘Background:Multiple sclerosis(MS)is a chronic demyelinating disease characterized by autoimmune attacks on myelin sheaths.Its deleterious effects may be reversed by remyelination,a process that restores the integrity of myelin sheaths and,consequently,neuronal function.However,the functional implications of demyelination and remyelination in MS,as well as the potential impact of therapeutic interventions,remain incompletely understood.We used noninvasive longitudinal resting-state functional magnetic resonance imaging in a cuprizone murine model of demyelination to investigate these unsolved questions.Methods:Three groups of(n=6)animals were studied.A control group was fed with standard food for 5 weeks while two treatment groups(cuprizone and clemastine)suffered progressive demyelination by feeding them with 2%cuprizone.At Week 5(W5),all animals returned to the standard diet and studied for another 5-week period to compare controls vs spontaneous(cuprizone group)vs clemastine-aided(clemastine group)remyelination group.Group clemastine was treated with this antihistaminic(oral gavage)during the remyelination period(Weeks 5–10).Anatomical magnetic resonance imaging(T2w-MRI)and resting state functional MRI(rs-FMRI)studies were conducted on weeks W0,W2,W5(maximal demyelination)W7 and W10(remyelination).MRI images were processed with the FMRIB Software Library,involving seed-free functional imaging and seed-based correlation.This study uses the t-test and the D'Agostino–Pearson normality test to make an assessment.Results:The principal findings of our research include:(1)cuprizone-treated animals suffer an initial phase of elevated connectivity at Week 2 with respect to controls,transitioning to reduced connectivity at Week 5;(2)different temporal trajectories across brain regions,reflecting varying susceptibility to demyelination;(3)while spontaneous remyelination normalizes connectivity in most networks at Week 10(5 weeks after ceasing cuprizone intoxication),the thalamocortical axis exhibits lasting disruption even 6 months after normalization of diet;and(4)on the contrary,clemastine-aided remyelination re-establishes normal thalamocortical connectivity at 6 months after demyelination.Conclusion:This approach provides insights into the dynamic processes of demyelination and remyelination,informing the development of more effective interventions for MS.
