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
G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR3...G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR37 undergoes proteolysis under normal physiological conditions,resulting in the formation of cleaved receptor forms and the release of its ectodomain(ecto-GPR37)into the extracellular milieu(Mattila et al.,2021).Importantly,ecto-GPR37 density is increased in cerebrospinal fluid(CSF)of patients suffering from sporadic Parkinson’s disease(PD),together with an abnormal GPR37 processing in post-mortem PD substantia nigra(Moratóet al.,2021;Figure 1A).展开更多
Glutamate receptors and schizophrenia:Schizophrenia is a chronic mental disorder affecting approximately 1%of the global population,with 70%-80%heritability.It has a multifactorial etiology involving both environmenta...Glutamate receptors and schizophrenia:Schizophrenia is a chronic mental disorder affecting approximately 1%of the global population,with 70%-80%heritability.It has a multifactorial etiology involving both environmental factors and a complex polygenic genetic architecture.Over the last two decades,large-scale genome-wide approaches revealed contributions of common variants with individually small effect sizes and of rare copy number variants with a large effect size.N-methy l-D-a spar tat e receptor(NMDAR)hypofunction has been implicated as a central mechanism in the pathophysiology of schizophrenia(Coyle et al.,2020).展开更多
Neurodegenerative disorde rs such as Alzheimer's and Parkinson s diseases are increasingly associated with metabolic dysfunction,including obesity,type 2 diabetes,and metabolic dysfunction-associated steatotic liv...Neurodegenerative disorde rs such as Alzheimer's and Parkinson s diseases are increasingly associated with metabolic dysfunction,including obesity,type 2 diabetes,and metabolic dysfunction-associated steatotic liver disease.Central to this connection is the dysregulation of lipid metabolism,which extends beyond peripheral tissues to the brain,defective autolysosomal function,oxidative stress,inflammation,and insulin resistance.Lipids,which constitute over half of dry weight of the brain,play critical roles in ene rgy provisio n,structural integrity,and synaptic function.Dys regulation of lipid metabolism contributes to neuroinflammation,impaired neuronal function,and disrupted blood-brain barrier integrity.Palmitic acid,a saturated fatty acid abundant in high-fat diets,serves as a key model for studying lipid-induced toxicity(lipotoxicity)in the brain.Palmitic acid disrupts autophagy and lysosomal function,mitochondrial function,trigge ring oxidative stress,contributing to neuroinflammation and neurodegeneration.These effects are particularly pronounced in neurons,which are highly susceptible to lipid-induced toxicity due to their high metabolic demands.Glial cells,including astrocytes,microglia,and oligodendrocytes,also exhibit distinct vulnerabilities and adaptive responses to lipid metabolism dysregulation,further contributing to neuroinflammation and demyelination.Therapeutic strategies,such as supplementation with polyunsaturated fatty acids,AMP-activated protein kinase activation,and lysosome-ta rgeted interventions,show promise in mitigating palmitic acid-induced lipotoxicity and restoring cellular homeostasis.This review comprehensively examines palmitic acid-induced lipotoxicity and its impact on autolysosomal dysfunction across various central nervous system cell types,including neurons,astrocytes,microglia,and oligodendrocytes.Additionally,it highlights therapeutic approaches to restore autolysosomal function under lipotoxic conditions.Advances in multi-omics technologies and a deeper unde rstanding of intercellular crosstalk offer new avenues for develo ping targeted the rapies to resto re autolysosomal function,and attenuate neuroinflammation and neurodegeneration.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
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
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
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
Animal models are necessary to investigate the pathogenic features underlying motor neuron degeneration and for therapeutic development in amyotrophic lateral sclerosis（ALS）. Measures of model validity allow for a c...Animal models are necessary to investigate the pathogenic features underlying motor neuron degeneration and for therapeutic development in amyotrophic lateral sclerosis（ALS）. Measures of model validity allow for a critical interpretation of results from each model and caution from over-interpretation of experimental models. Face and construct validity refer to the similarity in phenotype and the proposed causal factor to the human disease, respectively. More recently developed models are restricted by limited phenotype characterization, yet new models hold promise for novel disease insights, thus highlighting their importance. In this article, we evaluate the features of face and construct validity of our new zebrafish model of environmentally-induced motor neuron degeneration and discuss this in the context of current environmental and genetic ALS models, including C9 orf72, mutant Cu/Zn superoxide dismutase 1 and TAR DNA-binding protein 43 mouse and zebrafish models. In this mini-review, we discuss the pros and cons to validity criteria in each model. Our zebrafish model of environmentally-induced motor neuron degeneration displays convincing features of face validity with many hallmarks of ALS-like features, and weakness in construct validity. However, the value of this model may lie in its potential to be more representative of the pathogenic features underlying sporadic ALS cases, where environmental factors may be more likely to be involved in disease etiology than single dominant gene mutations. It may be necessary to compare findings between different strains and species modeling specific genes or environmental factors to confirm findings from ALS animal models and tease out arbitrary strain-and overexpression-specific effects.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
AIM:To investigate the effect of quercetin supplementation on the myenteric neurons and glia in the cecum of diabetic rats.METHODS:Total preparations of the muscular tunic were prepared from the ceca of twenty-four ra...AIM:To investigate the effect of quercetin supplementation on the myenteric neurons and glia in the cecum of diabetic rats.METHODS:Total preparations of the muscular tunic were prepared from the ceca of twenty-four rats divided into the following groups:control(C),control supplemented with quercetin(200 mg/kg quercetin body weight)(CQ),diabetic(D)and diabetic supplemented with quercetin(DQ).Immunohistochemical double staining technique was performed with HuC/D(general population)/nitric oxide synthase(nNOS),HuC-D/S-100and VIP.Density analysis of the general neuronal population HuC/D-IR,the nNOS-IR(nitrergic subpopulation)and the enteric glial cells(S-100)was performed,and the morphometry and the reduction in varicosity population(VIP-IR)in these populations were analyzed.RESULTS:Diabetes promoted a significant reduction(25%)in the neuronal density of the HuC/D-IR(general population)and the nNOS-IR(nitrergic subpopulation)compared with the C group.Diabetes also significantly increased the areas of neurons,glial cells and VIP-IR varicosities.Supplementation with quercetin in the DQ group prevented neuronal loss in the general population and increased its area(P<0.001)and the area of nitrergic subpopulation(P<0.001),when compared to C group.Quercetin induced a VIP-IR and glial cells areas(P<0.001)in DQ group when compared to C,CQ and D groups.CONCLUSION:In diabetes,quercetin exhibited a neuroprotective effect by maintaining the density of the general neuronal population but did not affect the density of the nNOS subpopulation.展开更多
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.
基金FEDER/Ministerio de Ciencia,Innovacióny Universidades-Agencia Estatal de Investigación(PID2023-147425OB-I00 to FC)Agència de Gestiód’Ajuts Universitaris i de Recerca(AGAUR)-Generalitat de Catalunya(2021 SGR 00698 to FC).
文摘G protein-coupled receptor 37(GPR37)is an orphan receptor predominantly expressed in the brain,particularly in oligodendrocytes and certain types of neurons.Notably,it has been shown that the N-terminal domain of GPR37 undergoes proteolysis under normal physiological conditions,resulting in the formation of cleaved receptor forms and the release of its ectodomain(ecto-GPR37)into the extracellular milieu(Mattila et al.,2021).Importantly,ecto-GPR37 density is increased in cerebrospinal fluid(CSF)of patients suffering from sporadic Parkinson’s disease(PD),together with an abnormal GPR37 processing in post-mortem PD substantia nigra(Moratóet al.,2021;Figure 1A).
文摘Glutamate receptors and schizophrenia:Schizophrenia is a chronic mental disorder affecting approximately 1%of the global population,with 70%-80%heritability.It has a multifactorial etiology involving both environmental factors and a complex polygenic genetic architecture.Over the last two decades,large-scale genome-wide approaches revealed contributions of common variants with individually small effect sizes and of rare copy number variants with a large effect size.N-methy l-D-a spar tat e receptor(NMDAR)hypofunction has been implicated as a central mechanism in the pathophysiology of schizophrenia(Coyle et al.,2020).
基金the Department of Biology at Syracuse University(to CHL)a start-up grant from the Department of Biomedical and Chemical Engineering at Syacuse University(to JZ)an NIH grant(R01DK141923)sub-contract to Co-Investigators JZ and CHL from the Principal Investigator Mark W.Grinstaff。
文摘Neurodegenerative disorde rs such as Alzheimer's and Parkinson s diseases are increasingly associated with metabolic dysfunction,including obesity,type 2 diabetes,and metabolic dysfunction-associated steatotic liver disease.Central to this connection is the dysregulation of lipid metabolism,which extends beyond peripheral tissues to the brain,defective autolysosomal function,oxidative stress,inflammation,and insulin resistance.Lipids,which constitute over half of dry weight of the brain,play critical roles in ene rgy provisio n,structural integrity,and synaptic function.Dys regulation of lipid metabolism contributes to neuroinflammation,impaired neuronal function,and disrupted blood-brain barrier integrity.Palmitic acid,a saturated fatty acid abundant in high-fat diets,serves as a key model for studying lipid-induced toxicity(lipotoxicity)in the brain.Palmitic acid disrupts autophagy and lysosomal function,mitochondrial function,trigge ring oxidative stress,contributing to neuroinflammation and neurodegeneration.These effects are particularly pronounced in neurons,which are highly susceptible to lipid-induced toxicity due to their high metabolic demands.Glial cells,including astrocytes,microglia,and oligodendrocytes,also exhibit distinct vulnerabilities and adaptive responses to lipid metabolism dysregulation,further contributing to neuroinflammation and demyelination.Therapeutic strategies,such as supplementation with polyunsaturated fatty acids,AMP-activated protein kinase activation,and lysosome-ta rgeted interventions,show promise in mitigating palmitic acid-induced lipotoxicity and restoring cellular homeostasis.This review comprehensively examines palmitic acid-induced lipotoxicity and its impact on autolysosomal dysfunction across various central nervous system cell types,including neurons,astrocytes,microglia,and oligodendrocytes.Additionally,it highlights therapeutic approaches to restore autolysosomal function under lipotoxic conditions.Advances in multi-omics technologies and a deeper unde rstanding of intercellular crosstalk offer new avenues for develo ping targeted the rapies to resto re autolysosomal function,and attenuate neuroinflammation and neurodegeneration.
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.
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.
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 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 a grant from Estate of Luther Allyn Shourds Dean,No.20R17162(to CAS)
文摘Animal models are necessary to investigate the pathogenic features underlying motor neuron degeneration and for therapeutic development in amyotrophic lateral sclerosis（ALS）. Measures of model validity allow for a critical interpretation of results from each model and caution from over-interpretation of experimental models. Face and construct validity refer to the similarity in phenotype and the proposed causal factor to the human disease, respectively. More recently developed models are restricted by limited phenotype characterization, yet new models hold promise for novel disease insights, thus highlighting their importance. In this article, we evaluate the features of face and construct validity of our new zebrafish model of environmentally-induced motor neuron degeneration and discuss this in the context of current environmental and genetic ALS models, including C9 orf72, mutant Cu/Zn superoxide dismutase 1 and TAR DNA-binding protein 43 mouse and zebrafish models. In this mini-review, we discuss the pros and cons to validity criteria in each model. Our zebrafish model of environmentally-induced motor neuron degeneration displays convincing features of face validity with many hallmarks of ALS-like features, and weakness in construct validity. However, the value of this model may lie in its potential to be more representative of the pathogenic features underlying sporadic ALS cases, where environmental factors may be more likely to be involved in disease etiology than single dominant gene mutations. It may be necessary to compare findings between different strains and species modeling specific genes or environmental factors to confirm findings from ALS animal models and tease out arbitrary strain-and overexpression-specific effects.
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.
基金Supported by Coordena o de Aperfei oamento de Pessoal de Nível Superior,CAPES,BrasilNIH grant,No.DK76665
文摘AIM:To investigate the effect of quercetin supplementation on the myenteric neurons and glia in the cecum of diabetic rats.METHODS:Total preparations of the muscular tunic were prepared from the ceca of twenty-four rats divided into the following groups:control(C),control supplemented with quercetin(200 mg/kg quercetin body weight)(CQ),diabetic(D)and diabetic supplemented with quercetin(DQ).Immunohistochemical double staining technique was performed with HuC/D(general population)/nitric oxide synthase(nNOS),HuC-D/S-100and VIP.Density analysis of the general neuronal population HuC/D-IR,the nNOS-IR(nitrergic subpopulation)and the enteric glial cells(S-100)was performed,and the morphometry and the reduction in varicosity population(VIP-IR)in these populations were analyzed.RESULTS:Diabetes promoted a significant reduction(25%)in the neuronal density of the HuC/D-IR(general population)and the nNOS-IR(nitrergic subpopulation)compared with the C group.Diabetes also significantly increased the areas of neurons,glial cells and VIP-IR varicosities.Supplementation with quercetin in the DQ group prevented neuronal loss in the general population and increased its area(P<0.001)and the area of nitrergic subpopulation(P<0.001),when compared to C group.Quercetin induced a VIP-IR and glial cells areas(P<0.001)in DQ group when compared to C,CQ and D groups.CONCLUSION:In diabetes,quercetin exhibited a neuroprotective effect by maintaining the density of the general neuronal population but did not affect the density of the nNOS subpopulation.
