Adult microglia,by continuously sensing changes in their environment and communicating with nearly all brain cell types,are considered to be the immune sentinels of the brain.In the healthy central nervous system(CNS)...Adult microglia,by continuously sensing changes in their environment and communicating with nearly all brain cell types,are considered to be the immune sentinels of the brain.In the healthy central nervous system(CNS),microglia display a unique molecular homeostatic signature(i.e.,Tmem119,P2ry12,Sall1,Siglech,Gpr34,and Hexb)(Figure 1A).展开更多
Traumatic brain injury(TBI)is a public health problem with an undue economic burden that impacts nearly every age,ethnic,and gender group across the globe(Capizzi et al.,2020).TBIs are often sustained during a dynamic...Traumatic brain injury(TBI)is a public health problem with an undue economic burden that impacts nearly every age,ethnic,and gender group across the globe(Capizzi et al.,2020).TBIs are often sustained during a dynamic range of exposures to energetic environmental forces and as such outcomes are typically heterogeneous regarding severity and pathology(Capizzi et al.,2020).展开更多
Alzheimer's disease (AD) is characterized by an imbalance between excitatory and inhibitory brain networks,leading to aberrant homeostatic synaptic plasticity.AD has progressively been recognized as syna ptopathy ...Alzheimer's disease (AD) is characterized by an imbalance between excitatory and inhibitory brain networks,leading to aberrant homeostatic synaptic plasticity.AD has progressively been recognized as syna ptopathy and syna ptic dysfunction has been identified as a key component of its pathogenesis (Schirinzi et al.,2020).Syna ptic dysfunction is believed to precede synapse loss,a primary biological correlate of cognitive decline in AD,inevita bly associated with neuronal death.展开更多
Adult neurogenesis continuously produces new neurons critical for cognitive plasticity in adult rodents.While it is known transforming growth factor-βsignaling is important in embryonic neurogenesis,its role in postn...Adult neurogenesis continuously produces new neurons critical for cognitive plasticity in adult rodents.While it is known transforming growth factor-βsignaling is important in embryonic neurogenesis,its role in postnatal neurogenesis remains unclear.In this study,to define the precise role of transforming growth factor-βsignaling in postnatal neurogenesis at distinct stages of the neurogenic cascade both in vitro and in vivo,we developed two novel inducible and cell type-specific mouse models to specifically silence transforming growth factor-βsignaling in neural stem cells in(mGFAPcre-ALK5fl/fl-Ai9)or immature neuroblasts in(DCXcreERT2-ALK5fl/fl-Ai9).Our data showed that exogenous transforming growth factor-βtreatment led to inhibition of the proliferation of primary neural stem cells while stimulating their migration.These effects were abolished in activin-like kinase 5(ALK5)knockout primary neural stem cells.Consistent with this,inhibition of transforming growth factor-βsignaling with SB-431542 in wild-type neural stem cells stimulated proliferation while inhibited the migration of neural stem cells.Interestingly,deletion of transforming growth factor-βreceptor in neural stem cells in vivo inhibited the migration of postnatal born neurons in mGFAPcre-ALK5fl/fl-Ai9 mice,while abolishment of transforming growth factor-βsignaling in immature neuroblasts in DCXcreERT2-ALK5fl/fl-Ai9 mice did not affect the migration of these cells in the hippocampus.In summary,our data supports a dual role of transforming growth factor-βsignaling in the proliferation and migration of neural stem cells in vitro.Moreover,our data provides novel insights on cell type-specific-dependent requirements of transforming growth factor-βsignaling on neural stem cell proliferation and migration in vivo.展开更多
Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival a...Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival and integration of neural stem cells into the host neural circuit remains a formidable challenge.Here,we investigated whether modifying the intrinsic properties of neural stem cells could enhance their integration post-transplantation.We focused on phosphatase and tensin homolog(PTEN),a well-characterized tumor suppressor known to critically regulate neuronal survival and axonal regeneration.By deleting Pten in mouse neural stem cells,we observed increased neurite outgrowth and enhanced resistance to neurotoxic environments in culture.Upon transplantation into injured spinal cords,Pten-deficient neural stem cells exhibited higher survival and more extensive rostrocaudal distribution.To examine the potential influence of partial PTEN suppression,rat neural stem cells were treated with short hairpin RNA targeting PTEN,and the PTEN knockdown resulted in significant improvements in neurite growth,survival,and neurosphere motility in vitro.Transplantation of sh PTEN-treated neural stem cells into the injured spinal cord also led to an increase in graft survival and migration to an extent similar to that of complete deletion.Moreover,PTEN suppression facilitated neurite elongation from NSC-derived neurons migrating from the lesion epicenter.These findings suggest that modifying intrinsic signaling pathways,such as PTEN,within neural stem cells could bolster their therapeutic efficacy,offering potential avenues for future regenerative strategies for spinal cord injury.展开更多
Central and peripheral nervous systems are lipid rich tissues. Lipids, in the context of lipid-protein complexes, surround neurons and provide electrical insulation for transmission of signals allowing neurons to rema...Central and peripheral nervous systems are lipid rich tissues. Lipids, in the context of lipid-protein complexes, surround neurons and provide electrical insulation for transmission of signals allowing neurons to remain embedded within a conducting environment. Lipids play a key role in vesicle formation and fusion in synapses. They provide means of rapid signaling, cell motility and migration for astrocytes and other cell types that surround and play supporting roles neurons. Unlike many other signaling molecules, lipids are capable of multiple signaling events based on the different fragments generated from a single precursor during each event. Lipidomics, until recently suffered from two major disadvantages:(1) level of expertise required an overwhelming amount of chemical detail to correctly identify a vast number of different lipids which could be close in their chemical reactivity; and(2) high amount of purified compounds needed by analytical techniques to determine their structures. Advances in mass spectrometry have enabled overcoming these two limitations. Mass spectrometry offers a great degree of simplicity in identification and quantification of lipids directly extracted from complex biological mixtures. Mass spectrometers can be regarded to as mass analyzers. There are those that separate and analyze the product ion fragments in space(spatial) and those which separate product ions in time in the same space(temporal). Databases and standardized instrument parameters have further aided the capabilities of the spatial instruments while recent advances in bioinformatics have made the identification and quantification possible using temporal instruments.展开更多
The primary assumption of Neuroscience is that all experiences are strongly correlated with or caused by the specifics of brain structures and their particular dynamics. The profound experiences attributed to the “se...The primary assumption of Neuroscience is that all experiences are strongly correlated with or caused by the specifics of brain structures and their particular dynamics. The profound experiences attributed to the “sensed presence” and their cultural anthropomorphisms such as deities and gods are persistent reports in human populations that are frequently associated with permanent changes in behavior, reduced depression and alleviation of pain. The majority of traditional clinical observations and modern imaging techniques have emphasized the central role of right temporal lobe structures and their directly related networks. The experimental simulation of sensed presences which can result in attributions to spiritual, deity-based or mystical sources within the clinical laboratory by the application of physiologically-patterned magnetic fields across the temporal lobes through our God Helmet requires the same precision of technology that is essential for synthesizing molecular treatments for modifying anomalous behavior, depression and pain. Despite the clinical utility of these simulated conditions within Neuroscience and Medicine, misinformation concerning the bases and efficacy of this new technology persist. Here we present detailed technical clarifications and rebuttals to refute these misconceptions. A Hegelian approach to this delay of development and impedance provides a context through which the ultimate synthesis and application of this technology may be accommodated in the near future.展开更多
Striatal interneurons play a key role in modulating striatal-dependent behaviors,including motor activity and reward and emotional processing.Interneurons not only provide modulation to the basal ganglia circuitry und...Striatal interneurons play a key role in modulating striatal-dependent behaviors,including motor activity and reward and emotional processing.Interneurons not only provide modulation to the basal ganglia circuitry under homeostasis but are also involved in changes to plasticity and adaptation during disease conditions such as Parkinson's or Huntington's disease.This review aims to summarize recent findings regarding the role of striatal cholinergic and GABAergic interneurons in providing circuit modulation to the basal ganglia in both homeostatic and disease conditions.In addition to direct circuit modulation,striatal interneurons have also been shown to provide trophic support to maintain neuron populations in adulthood.We discuss this interesting and novel role of striatal interneurons,with a focus on the maintenance of adult dopaminergic neurons from interneuronderived sonic-hedgehog.展开更多
Structural plasticity is critical for the functional diversity of neurons in the brain.Experimental autoimmune encephalomyelitis(EAE)is the most commonly used model for multiple sclerosis(MS),successfully mimicking it...Structural plasticity is critical for the functional diversity of neurons in the brain.Experimental autoimmune encephalomyelitis(EAE)is the most commonly used model for multiple sclerosis(MS),successfully mimicking its key pathological features(inflammation,demyelination,axonal loss,and gliosis)and clinical symptoms(motor and non-motordysfunctions).Recentstudieshave demonstrated the importance of synaptic plasticity in EAE pathogenesis.In the present study,we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase(11 days post-immunization,DPI)and chronic phase(28DPI).EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases.Dendritic complexity was largely affected in the cornu ammonis 1(CA1)and CA3 apical and dentate gyrus(DG)subregions of the hippocampus during the chronic phase,while this effect was only noted in the CA1 apical subregion in the early phase.Moreover,dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE,but only reduced in the DG subregion during the chronic phase.Furthermore,mRNA levels of proinflammatory cytokines(Il1β,Tnfα,and Ifnγ)and glial cell markers(Gfap and Cd68)were significantly increased,whereas the expression of activity-regulated cytoskeletonassociated protein(ARC)was reduced during the chronic phase.Similarly,exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression.Primary cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase(ERK)phosphorylation upon treatment with proinflammatory cytokines.Collectively,these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus,possibly through the ERK-ARC pathway,indicating that this alteration may be associated with hippocampal dysfunctions in EAE.展开更多
Plaques of amyloid-β(Aβ)and neurofibrillary tangles are the main pathological characteristics of Alzheimer’s disease(AD).However,some older adult people with AD pathological hallmarks can retain cognitive function....Plaques of amyloid-β(Aβ)and neurofibrillary tangles are the main pathological characteristics of Alzheimer’s disease(AD).However,some older adult people with AD pathological hallmarks can retain cognitive function.Unraveling the factors that lead to this cognitive resilience to AD offers promising prospects for identifying new therapeutic targets.Our hypothesis focuses on the contribution of resilience to changes in excitatory synapses at the structural and molecular levels,which may underlie healthy cognitive performance in aged AD animals.Utilizing the Morris Water Maze test,we selected resilient(asymptomatic)and cognitively impaired aged Tg2576 mice.While the enzyme-linked immunosorbent assay showed similar levels of Aβ42 in both experimental groups,western blot analysis revealed differences in tau pathology in the pre-synaptic supernatant fraction.To further investigate the density of synapses in the hippocampus of 16-18 month-old Tg2576 mice,we employed stereological and electron microscopic methods.Our findings indicated a decrease in the density of excitatory synapses in the stratum radiatum of the hippocampal CA1 in cognitively impaired Tg2576 mice compared with age-matched resilient Tg2576 and non-transgenic controls.Intriguingly,through quantitative immunoelectron microscopy in the hippocampus of impaired and resilient Tg2576 transgenic AD mice,we uncovered differences in the subcellular localization of glutamate receptors.Specifically,the density of GluA1,GluA2/3,and mGlu5 in spines and dendritic shafts of CA1 pyramidal cells in impaired Tg2576 mice was significantly reduced compared with age-matched resilient Tg2576 and non-transgenic controls.Notably,the density of GluA2/3 in resilient Tg2576 mice was significantly increased in spines but not in dendritic shafts compared with impaired Tg2576 and non-transgenic mice.These subcellular findings strongly support the hypothesis that dendritic spine plasticity and synaptic machinery in the hippocampus play crucial roles in the mechanisms of cognitive resilience in Tg2576 mice.展开更多
Chemically engineered agricultural products such as pesticides, insecticides, and herbicides, although used considerably for both industrialized and personal agricultural use, have recently been associated with a numb...Chemically engineered agricultural products such as pesticides, insecticides, and herbicides, although used considerably for both industrialized and personal agricultural use, have recently been associated with a number of serious human health disorders. This rapid literature review aims to accumulate and analyze research from the last ten years, focusing specifically on the effects of exposure to glyphosate-based herbicide products such as Roundup as associated with the formation of various neurological disorders. Specifically, this review focuses on laboratory research using animal models or human cell cultures as well as human population-based epidemiological studies. It associates exposure to glyphosate or glyphosate-based products with the formation or exacerbation of neurological disorders such as Parkinson’s disease, Alzheimer’s disease, seizures, and autism spectrum disorder. In addition, it examines the correlation between the gut-brain axis, exposure to glyphosate, and neurodegeneration.展开更多
Glial cells have often been referred to as the support cells of the brain.While they do have numerous supportive functions,there is emerging research showing they play an active role in shaping the brain and behaviour...Glial cells have often been referred to as the support cells of the brain.While they do have numerous supportive functions,there is emerging research showing they play an active role in shaping the brain and behaviour.Studying the cellular and molecular crosstalk between brain cell types is immensely valuable as this research topic continues to demonstrate that many brain functions are a result of a system of cells working together,rather than any cell type independently.展开更多
Objectives To assess the feasibility of methods and estimate the potential effect of interrupting sedentary behaviour,with intermittent or continuous physical activity breaks,on cognitive performance in young people w...Objectives To assess the feasibility of methods and estimate the potential effect of interrupting sedentary behaviour,with intermittent or continuous physical activity breaks,on cognitive performance in young people with Cerebral Palsy.Methods A randomised three-arm exposure response cross-over design with process evaluation.Participants were recruited throughout the Thames Valley,UK between 01/11/2018 to 31/03/2020.The three 2 h activity exposure visits included:(i)sitting only(controls),(ii)sitting plus 20 min of moderate-to-vigorous activity burst,or(iii)4×5 min of moderate-to-vigorous activity bursts,during a 2.5 h sedentary session.Measures of feasibility were sought.Cognitive performance outcomes(using the Eriksen Flanker task and Forward and Backward Digit Span)were delivered before and after the 2 h testing period.Results 36 participants were randomised(age 13.2±2.7,Gross-Motor Functional Classification System 1–3).Study retention was 83%across all three interventions and overall missing data for measures was 4%.A small intervention effect was found in reaction time in the 4×5 min physical activity exposure session compared to the sedentary control condition(0.42;95%CI 0.40 to 0.79).There were two research-related minor adverse effects,an allergic reaction to the FreeStyle Libre and feeling faint and vomiting after consumption of glucose solution.Both events were resolved and participants continued with the study.Conclusions The study design and intervention implementing short bursts of physical activity was feasible and indicated a potential effect on reaction time as a measure of cognitive performance in young people with cerebral palsy.展开更多
The high morbidity and mortality rate of ischemic stroke in humans has led to the development of numerous animal models that replicate human stroke to further understand the underlying pathophysiology and to explore p...The high morbidity and mortality rate of ischemic stroke in humans has led to the development of numerous animal models that replicate human stroke to further understand the underlying pathophysiology and to explore potential therapeutic interventions.Although promising therapeutics have been identified using these animal models,with most undergoing significant testing in rodent models,the vast majority of these interventions have failed in human clinical trials.This failure of preclinical translation highlights the critical need for better therapeutic assessment in more clinically relevant ischemic stroke animal models.Large animal models such as non-human primates,sheep,pigs,and dogs are likely more predictive of human responses and outcomes due to brain anatomy and physiology that are more similar to humans-potentially making large animal testing a key step in the stroke therapy translational pipeline.The objective of this review is to highlight key characteristics that potentially make these gyrencephalic,large animal ischemic stroke models more predictive by comparing pathophysiological responses,tissue-level changes,and model limitations.展开更多
Stem cells derived from adult tissues have long been consideredmultipotent, able to differentiate into a limited number of cell typesfound in their tissue of origin. Embryonic stem cells, in contrast,are pluripotent, ...Stem cells derived from adult tissues have long been consideredmultipotent, able to differentiate into a limited number of cell typesfound in their tissue of origin. Embryonic stem cells, in contrast,are pluripotent, which may differentiate into almost all cell types.With the ability to create induced pluripotent stem cells from somaticcells now available, the properties of multipotent stem cellsare being re-evaluated. If adult cells may be reverted to pluripotentstem cells, can multipotent stem cells also be manipulated towardspluripotency? Advancements in biotechnology now allow for bettermethods to investigate stem cell plasticity, such as the relativeinfluence of external versus intrinsic factors on cell fate. Recentstudies indicate that adult neural stem cells (NSCs) demonstrategreater plasticity under certain conditions, resulting in the derivationof a variety of cell types including muscle, hematopoietic, andepithelial cells. This suggests that NSCs may provide a potentialsource of rare cell types for clinical application as an alternative toembryonic stem cells. Producing rare cell types from NSCs ratherthan embryonic stem cells avoids the ethical issues surrounding theuse of this cell type. Further, NSCs may be an advantageous sourcecompared to induced pluripotent stem cells, which are difficult tocreate, expensive, and time-consuming to展开更多
Aggression is a common behavioral trait shared in many animals, including both vertebrates and invertebrates. However, the type and intensity of agonistic encounters and displays can vary widely both across and within...Aggression is a common behavioral trait shared in many animals, including both vertebrates and invertebrates. However, the type and intensity of agonistic encounters and displays can vary widely both across and within species, resulting in complicated or subjective interpretations that create difficulties in developing theoretical models that can be widely applied. The need to easily and objectively identify quantifiable behaviors and their associated morphologies becomes especially important when attempting to decipher the neurological mechanisms underlying this complex behavior. Monoamines, neuropeptides, and pheromones have been implicated as important neuromodulators for agonistic displays in both invertebrates and vertebrates. Ad- ditionally, recent breakthroughs in insect research have revealed exciting proximate mechanisms important in aggression that may be broadly relevant, due to the relatively high conservation of these neurochemical systems across animal taxa. In this review, we present the latest research demonstrating the importance of monoamines, neuropeptides, and pheromones as neuromodulators for aggression across a variety of insect species. Additionally, we describe the stalk-eyed fly as a model system for studying aggres- sion, which integrates physiological, morphological, and neurochemical approaches in exploring detailed mechanisms responsible for this common yet complex behavior. We conclude with our perspective on the most promising lines of future research aimed at understanding the proximate and ultimate mechanisms underlying aggressive behaviors .展开更多
A common remark among laypeople, and notably also among mental health workers, is that individuals with mental illnesses use drugs as self-medication to allay clinical symptoms and the side effects of drug treatments....A common remark among laypeople, and notably also among mental health workers, is that individuals with mental illnesses use drugs as self-medication to allay clinical symptoms and the side effects of drug treatments. Roots of the self-medication concept in psychiatry date back at least to the 1980 s. Observations that rates of smokers in schizophrenic patients are multiple times the rates for regular smoking in the general population, as well as those with other disorders, proved particularly tempting for a self-medication explanation. Additional evidence came from experiments with animal models exposed to nicotine and the identification of neurobiological mechanisms suggesting self-medication with smoking is a plausible idea. More recently, results from studies comparing smoking and non-smoking schizophrenic patients have led to the questioning of the self-medication hypothesis. Closer examination of the literature points to the possibility that smoking is less beneficial on schizophrenic symptomology than generally assumed while clearly increasing the risk of cancer and other smoking-related diseases responsible for early mortality. It is a good time to examine the evidence for the self-medication concept as it relates to smoking. Our approach is to focus on data addressing direct or implied predictions of the hypothesis in schizophrenic smokers.展开更多
基金supported by NIH grants(R01NS125074,R01AG083164,and R21NS127177)(to YL).
文摘Adult microglia,by continuously sensing changes in their environment and communicating with nearly all brain cell types,are considered to be the immune sentinels of the brain.In the healthy central nervous system(CNS),microglia display a unique molecular homeostatic signature(i.e.,Tmem119,P2ry12,Sall1,Siglech,Gpr34,and Hexb)(Figure 1A).
文摘Traumatic brain injury(TBI)is a public health problem with an undue economic burden that impacts nearly every age,ethnic,and gender group across the globe(Capizzi et al.,2020).TBIs are often sustained during a dynamic range of exposures to energetic environmental forces and as such outcomes are typically heterogeneous regarding severity and pathology(Capizzi et al.,2020).
文摘Alzheimer's disease (AD) is characterized by an imbalance between excitatory and inhibitory brain networks,leading to aberrant homeostatic synaptic plasticity.AD has progressively been recognized as syna ptopathy and syna ptic dysfunction has been identified as a key component of its pathogenesis (Schirinzi et al.,2020).Syna ptic dysfunction is believed to precede synapse loss,a primary biological correlate of cognitive decline in AD,inevita bly associated with neuronal death.
基金supported by NIH grants,Nos.R01NS125074,R01AG083164,R01NS107365,and R21NS127177(to YL),1F31NS129204-01A1(to KW)and Albert Ryan Fellowship(to KW).
文摘Adult neurogenesis continuously produces new neurons critical for cognitive plasticity in adult rodents.While it is known transforming growth factor-βsignaling is important in embryonic neurogenesis,its role in postnatal neurogenesis remains unclear.In this study,to define the precise role of transforming growth factor-βsignaling in postnatal neurogenesis at distinct stages of the neurogenic cascade both in vitro and in vivo,we developed two novel inducible and cell type-specific mouse models to specifically silence transforming growth factor-βsignaling in neural stem cells in(mGFAPcre-ALK5fl/fl-Ai9)or immature neuroblasts in(DCXcreERT2-ALK5fl/fl-Ai9).Our data showed that exogenous transforming growth factor-βtreatment led to inhibition of the proliferation of primary neural stem cells while stimulating their migration.These effects were abolished in activin-like kinase 5(ALK5)knockout primary neural stem cells.Consistent with this,inhibition of transforming growth factor-βsignaling with SB-431542 in wild-type neural stem cells stimulated proliferation while inhibited the migration of neural stem cells.Interestingly,deletion of transforming growth factor-βreceptor in neural stem cells in vivo inhibited the migration of postnatal born neurons in mGFAPcre-ALK5fl/fl-Ai9 mice,while abolishment of transforming growth factor-βsignaling in immature neuroblasts in DCXcreERT2-ALK5fl/fl-Ai9 mice did not affect the migration of these cells in the hippocampus.In summary,our data supports a dual role of transforming growth factor-βsignaling in the proliferation and migration of neural stem cells in vitro.Moreover,our data provides novel insights on cell type-specific-dependent requirements of transforming growth factor-βsignaling on neural stem cell proliferation and migration in vivo.
基金supported by the National Research Foundation of Korea,Nos.2021R1A2C2006110,2021M3E5D9021364,2019R1A5A2026045(to BGK)the Korea Initiative for Fostering University of Research and Innovation(KIURI)Program of the NRF funded by the MSIT(to HK),No.NRF2021M3H1A104892211(to HSK)。
文摘Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival and integration of neural stem cells into the host neural circuit remains a formidable challenge.Here,we investigated whether modifying the intrinsic properties of neural stem cells could enhance their integration post-transplantation.We focused on phosphatase and tensin homolog(PTEN),a well-characterized tumor suppressor known to critically regulate neuronal survival and axonal regeneration.By deleting Pten in mouse neural stem cells,we observed increased neurite outgrowth and enhanced resistance to neurotoxic environments in culture.Upon transplantation into injured spinal cords,Pten-deficient neural stem cells exhibited higher survival and more extensive rostrocaudal distribution.To examine the potential influence of partial PTEN suppression,rat neural stem cells were treated with short hairpin RNA targeting PTEN,and the PTEN knockdown resulted in significant improvements in neurite growth,survival,and neurosphere motility in vitro.Transplantation of sh PTEN-treated neural stem cells into the injured spinal cord also led to an increase in graft survival and migration to an extent similar to that of complete deletion.Moreover,PTEN suppression facilitated neurite elongation from NSC-derived neurons migrating from the lesion epicenter.These findings suggest that modifying intrinsic signaling pathways,such as PTEN,within neural stem cells could bolster their therapeutic efficacy,offering potential avenues for future regenerative strategies for spinal cord injury.
文摘Central and peripheral nervous systems are lipid rich tissues. Lipids, in the context of lipid-protein complexes, surround neurons and provide electrical insulation for transmission of signals allowing neurons to remain embedded within a conducting environment. Lipids play a key role in vesicle formation and fusion in synapses. They provide means of rapid signaling, cell motility and migration for astrocytes and other cell types that surround and play supporting roles neurons. Unlike many other signaling molecules, lipids are capable of multiple signaling events based on the different fragments generated from a single precursor during each event. Lipidomics, until recently suffered from two major disadvantages:(1) level of expertise required an overwhelming amount of chemical detail to correctly identify a vast number of different lipids which could be close in their chemical reactivity; and(2) high amount of purified compounds needed by analytical techniques to determine their structures. Advances in mass spectrometry have enabled overcoming these two limitations. Mass spectrometry offers a great degree of simplicity in identification and quantification of lipids directly extracted from complex biological mixtures. Mass spectrometers can be regarded to as mass analyzers. There are those that separate and analyze the product ion fragments in space(spatial) and those which separate product ions in time in the same space(temporal). Databases and standardized instrument parameters have further aided the capabilities of the spatial instruments while recent advances in bioinformatics have made the identification and quantification possible using temporal instruments.
文摘The primary assumption of Neuroscience is that all experiences are strongly correlated with or caused by the specifics of brain structures and their particular dynamics. The profound experiences attributed to the “sensed presence” and their cultural anthropomorphisms such as deities and gods are persistent reports in human populations that are frequently associated with permanent changes in behavior, reduced depression and alleviation of pain. The majority of traditional clinical observations and modern imaging techniques have emphasized the central role of right temporal lobe structures and their directly related networks. The experimental simulation of sensed presences which can result in attributions to spiritual, deity-based or mystical sources within the clinical laboratory by the application of physiologically-patterned magnetic fields across the temporal lobes through our God Helmet requires the same precision of technology that is essential for synthesizing molecular treatments for modifying anomalous behavior, depression and pain. Despite the clinical utility of these simulated conditions within Neuroscience and Medicine, misinformation concerning the bases and efficacy of this new technology persist. Here we present detailed technical clarifications and rebuttals to refute these misconceptions. A Hegelian approach to this delay of development and impedance provides a context through which the ultimate synthesis and application of this technology may be accommodated in the near future.
文摘Striatal interneurons play a key role in modulating striatal-dependent behaviors,including motor activity and reward and emotional processing.Interneurons not only provide modulation to the basal ganglia circuitry under homeostasis but are also involved in changes to plasticity and adaptation during disease conditions such as Parkinson's or Huntington's disease.This review aims to summarize recent findings regarding the role of striatal cholinergic and GABAergic interneurons in providing circuit modulation to the basal ganglia in both homeostatic and disease conditions.In addition to direct circuit modulation,striatal interneurons have also been shown to provide trophic support to maintain neuron populations in adulthood.We discuss this interesting and novel role of striatal interneurons,with a focus on the maintenance of adult dopaminergic neurons from interneuronderived sonic-hedgehog.
基金supported by the National Research Foundation (NRF)of Korea Grant funded by the Korean Government (NRF-2022R1A2C100402212RS-2023-00219517)。
文摘Structural plasticity is critical for the functional diversity of neurons in the brain.Experimental autoimmune encephalomyelitis(EAE)is the most commonly used model for multiple sclerosis(MS),successfully mimicking its key pathological features(inflammation,demyelination,axonal loss,and gliosis)and clinical symptoms(motor and non-motordysfunctions).Recentstudieshave demonstrated the importance of synaptic plasticity in EAE pathogenesis.In the present study,we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase(11 days post-immunization,DPI)and chronic phase(28DPI).EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases.Dendritic complexity was largely affected in the cornu ammonis 1(CA1)and CA3 apical and dentate gyrus(DG)subregions of the hippocampus during the chronic phase,while this effect was only noted in the CA1 apical subregion in the early phase.Moreover,dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE,but only reduced in the DG subregion during the chronic phase.Furthermore,mRNA levels of proinflammatory cytokines(Il1β,Tnfα,and Ifnγ)and glial cell markers(Gfap and Cd68)were significantly increased,whereas the expression of activity-regulated cytoskeletonassociated protein(ARC)was reduced during the chronic phase.Similarly,exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression.Primary cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase(ERK)phosphorylation upon treatment with proinflammatory cytokines.Collectively,these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus,possibly through the ERK-ARC pathway,indicating that this alteration may be associated with hippocampal dysfunctions in EAE.
基金supported by grant PID2021-125875OB-I00 funded by MCIN/AEI/10.13039/501100011033 and by"ERDF A way of making Europe"(to RL)supported by a grant from Junta de Comunidades de Castilla-La Mancha (SBPLY/21/180501/000064)+3 种基金Universidad de Castilla-La Mancha (2023-GRIN-34187)(to RL).Grant PID201 9-104921RB-I00/MCI/AEI/10.13039/501100011033 (to AGO)the Foundation for Applied Medical Research,the University of Navarra (Pamplona,Spain)for financial supporthe Asociación de Amigos of the University of Navarra for the grant (to SB)Margarita Salas fellowship from Ministerio de Universidades and Universidad de Castilla-La Mancha (to AMB)
文摘Plaques of amyloid-β(Aβ)and neurofibrillary tangles are the main pathological characteristics of Alzheimer’s disease(AD).However,some older adult people with AD pathological hallmarks can retain cognitive function.Unraveling the factors that lead to this cognitive resilience to AD offers promising prospects for identifying new therapeutic targets.Our hypothesis focuses on the contribution of resilience to changes in excitatory synapses at the structural and molecular levels,which may underlie healthy cognitive performance in aged AD animals.Utilizing the Morris Water Maze test,we selected resilient(asymptomatic)and cognitively impaired aged Tg2576 mice.While the enzyme-linked immunosorbent assay showed similar levels of Aβ42 in both experimental groups,western blot analysis revealed differences in tau pathology in the pre-synaptic supernatant fraction.To further investigate the density of synapses in the hippocampus of 16-18 month-old Tg2576 mice,we employed stereological and electron microscopic methods.Our findings indicated a decrease in the density of excitatory synapses in the stratum radiatum of the hippocampal CA1 in cognitively impaired Tg2576 mice compared with age-matched resilient Tg2576 and non-transgenic controls.Intriguingly,through quantitative immunoelectron microscopy in the hippocampus of impaired and resilient Tg2576 transgenic AD mice,we uncovered differences in the subcellular localization of glutamate receptors.Specifically,the density of GluA1,GluA2/3,and mGlu5 in spines and dendritic shafts of CA1 pyramidal cells in impaired Tg2576 mice was significantly reduced compared with age-matched resilient Tg2576 and non-transgenic controls.Notably,the density of GluA2/3 in resilient Tg2576 mice was significantly increased in spines but not in dendritic shafts compared with impaired Tg2576 and non-transgenic mice.These subcellular findings strongly support the hypothesis that dendritic spine plasticity and synaptic machinery in the hippocampus play crucial roles in the mechanisms of cognitive resilience in Tg2576 mice.
文摘Chemically engineered agricultural products such as pesticides, insecticides, and herbicides, although used considerably for both industrialized and personal agricultural use, have recently been associated with a number of serious human health disorders. This rapid literature review aims to accumulate and analyze research from the last ten years, focusing specifically on the effects of exposure to glyphosate-based herbicide products such as Roundup as associated with the formation of various neurological disorders. Specifically, this review focuses on laboratory research using animal models or human cell cultures as well as human population-based epidemiological studies. It associates exposure to glyphosate or glyphosate-based products with the formation or exacerbation of neurological disorders such as Parkinson’s disease, Alzheimer’s disease, seizures, and autism spectrum disorder. In addition, it examines the correlation between the gut-brain axis, exposure to glyphosate, and neurodegeneration.
基金supported by Canadian Institutes of Health Research (CIHR)grants awarded to MET.
文摘Glial cells have often been referred to as the support cells of the brain.While they do have numerous supportive functions,there is emerging research showing they play an active role in shaping the brain and behaviour.Studying the cellular and molecular crosstalk between brain cell types is immensely valuable as this research topic continues to demonstrate that many brain functions are a result of a system of cells working together,rather than any cell type independently.
基金supported by the NIHR Exeter Health Biomedical Research Centre.The views expressed are those of the authors and not necessarily those of the NHS,the NIHR or the Department of Health.Johnny Collett is supported NIHR Oxford Health Biomedical research centre。
文摘Objectives To assess the feasibility of methods and estimate the potential effect of interrupting sedentary behaviour,with intermittent or continuous physical activity breaks,on cognitive performance in young people with Cerebral Palsy.Methods A randomised three-arm exposure response cross-over design with process evaluation.Participants were recruited throughout the Thames Valley,UK between 01/11/2018 to 31/03/2020.The three 2 h activity exposure visits included:(i)sitting only(controls),(ii)sitting plus 20 min of moderate-to-vigorous activity burst,or(iii)4×5 min of moderate-to-vigorous activity bursts,during a 2.5 h sedentary session.Measures of feasibility were sought.Cognitive performance outcomes(using the Eriksen Flanker task and Forward and Backward Digit Span)were delivered before and after the 2 h testing period.Results 36 participants were randomised(age 13.2±2.7,Gross-Motor Functional Classification System 1–3).Study retention was 83%across all three interventions and overall missing data for measures was 4%.A small intervention effect was found in reaction time in the 4×5 min physical activity exposure session compared to the sedentary control condition(0.42;95%CI 0.40 to 0.79).There were two research-related minor adverse effects,an allergic reaction to the FreeStyle Libre and feeling faint and vomiting after consumption of glucose solution.Both events were resolved and participants continued with the study.Conclusions The study design and intervention implementing short bursts of physical activity was feasible and indicated a potential effect on reaction time as a measure of cognitive performance in young people with cerebral palsy.
基金supported by the National Institutes of Health,National Institute of Neurological Disorders and Stroke,No.R01NS093314
文摘The high morbidity and mortality rate of ischemic stroke in humans has led to the development of numerous animal models that replicate human stroke to further understand the underlying pathophysiology and to explore potential therapeutic interventions.Although promising therapeutics have been identified using these animal models,with most undergoing significant testing in rodent models,the vast majority of these interventions have failed in human clinical trials.This failure of preclinical translation highlights the critical need for better therapeutic assessment in more clinically relevant ischemic stroke animal models.Large animal models such as non-human primates,sheep,pigs,and dogs are likely more predictive of human responses and outcomes due to brain anatomy and physiology that are more similar to humans-potentially making large animal testing a key step in the stroke therapy translational pipeline.The objective of this review is to highlight key characteristics that potentially make these gyrencephalic,large animal ischemic stroke models more predictive by comparing pathophysiological responses,tissue-level changes,and model limitations.
文摘Stem cells derived from adult tissues have long been consideredmultipotent, able to differentiate into a limited number of cell typesfound in their tissue of origin. Embryonic stem cells, in contrast,are pluripotent, which may differentiate into almost all cell types.With the ability to create induced pluripotent stem cells from somaticcells now available, the properties of multipotent stem cellsare being re-evaluated. If adult cells may be reverted to pluripotentstem cells, can multipotent stem cells also be manipulated towardspluripotency? Advancements in biotechnology now allow for bettermethods to investigate stem cell plasticity, such as the relativeinfluence of external versus intrinsic factors on cell fate. Recentstudies indicate that adult neural stem cells (NSCs) demonstrategreater plasticity under certain conditions, resulting in the derivationof a variety of cell types including muscle, hematopoietic, andepithelial cells. This suggests that NSCs may provide a potentialsource of rare cell types for clinical application as an alternative toembryonic stem cells. Producing rare cell types from NSCs ratherthan embryonic stem cells avoids the ethical issues surrounding theuse of this cell type. Further, NSCs may be an advantageous sourcecompared to induced pluripotent stem cells, which are difficult tocreate, expensive, and time-consuming to
文摘Aggression is a common behavioral trait shared in many animals, including both vertebrates and invertebrates. However, the type and intensity of agonistic encounters and displays can vary widely both across and within species, resulting in complicated or subjective interpretations that create difficulties in developing theoretical models that can be widely applied. The need to easily and objectively identify quantifiable behaviors and their associated morphologies becomes especially important when attempting to decipher the neurological mechanisms underlying this complex behavior. Monoamines, neuropeptides, and pheromones have been implicated as important neuromodulators for agonistic displays in both invertebrates and vertebrates. Ad- ditionally, recent breakthroughs in insect research have revealed exciting proximate mechanisms important in aggression that may be broadly relevant, due to the relatively high conservation of these neurochemical systems across animal taxa. In this review, we present the latest research demonstrating the importance of monoamines, neuropeptides, and pheromones as neuromodulators for aggression across a variety of insect species. Additionally, we describe the stalk-eyed fly as a model system for studying aggres- sion, which integrates physiological, morphological, and neurochemical approaches in exploring detailed mechanisms responsible for this common yet complex behavior. We conclude with our perspective on the most promising lines of future research aimed at understanding the proximate and ultimate mechanisms underlying aggressive behaviors .
基金Supported by In part by grants from the University of Missouri System,including the UM-Research Board and the Interdisciplinary Intercampus Research Program to GTTfrom the W.M. Keck Foundation to SEM
文摘A common remark among laypeople, and notably also among mental health workers, is that individuals with mental illnesses use drugs as self-medication to allay clinical symptoms and the side effects of drug treatments. Roots of the self-medication concept in psychiatry date back at least to the 1980 s. Observations that rates of smokers in schizophrenic patients are multiple times the rates for regular smoking in the general population, as well as those with other disorders, proved particularly tempting for a self-medication explanation. Additional evidence came from experiments with animal models exposed to nicotine and the identification of neurobiological mechanisms suggesting self-medication with smoking is a plausible idea. More recently, results from studies comparing smoking and non-smoking schizophrenic patients have led to the questioning of the self-medication hypothesis. Closer examination of the literature points to the possibility that smoking is less beneficial on schizophrenic symptomology than generally assumed while clearly increasing the risk of cancer and other smoking-related diseases responsible for early mortality. It is a good time to examine the evidence for the self-medication concept as it relates to smoking. Our approach is to focus on data addressing direct or implied predictions of the hypothesis in schizophrenic smokers.
