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
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
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
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
Subcortical ischemic white matter injury(SIWMI),pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging,is a common cause of cognitive decline in elderly.Despite its high...Subcortical ischemic white matter injury(SIWMI),pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging,is a common cause of cognitive decline in elderly.Despite its high prevalence,it remains unknown how various components of the white matter degenerate in response to chronic ischemia.This incomplete knowledge is in part due to a lack of adequate animal model.The current review introduces various SIWMI animal models and aims to scrutinize their advantages and disadvantages primarily in regard to the pathological manifestations of white matter components.The SIWMI animal models are categorized into 1)chemically induced SIWMI models,2)vascular occlusive SIWMI models,and 3)SIWMI models with comorbid vascular risk factors.Chemically induced models display consistent lesions in predetermined areas of the white matter,but the abrupt evolution of lesions does not appropriately reflect the progressive pathological processes in human white matter hyperintensities.Vascular occlusive SIWMI models often do not exhibit white matter lesions that are sufficiently unequivocal to be quantified.When combined with comorbid vascular risk factors(specifically hypertension),however,they can produce progressive and definitive white matter lesions including diffuse rarefaction,demyelination,loss of oligodendrocytes,and glial activation,which are by far the closest to those found in human white matter hyperintensities lesions.However,considerable surgical mortality and unpredictable natural deaths during a follow-up period would necessitate further refinements in these models.In the meantime,in vitro SIWMI models that recapitulate myelinated white matter track may be utilized to study molecular mechanisms of the ischemic white matter injury.Appropriate in vivo and in vitro SIWMI models will contribute in a complementary manner to making a breakthrough in developing effective treatment to prevent progression of white matter hyperintensities.展开更多
Traumatic injuries to spinal cord elicit diverse signaling pathways leading to unselective and complex pathological outcomes：death of multiple classes of neural cells,formation of cystic cavities and glial scars,disr...Traumatic injuries to spinal cord elicit diverse signaling pathways leading to unselective and complex pathological outcomes：death of multiple classes of neural cells,formation of cystic cavities and glial scars,disruption of axonal connections,and demyelination of spared axons,all of which can contribute more or less to debilitating functional impairments found in patients with spinal cord injury.展开更多
Axons in central nervous system （CNS） do not regenerate spontaneously after injuries such as stroke and traumatic spinal cord iniury. Both intrinsic and extrinsic factors are responsible for the regeneration fail- u...Axons in central nervous system （CNS） do not regenerate spontaneously after injuries such as stroke and traumatic spinal cord iniury. Both intrinsic and extrinsic factors are responsible for the regeneration fail- ure, Although intensive research efforts have been invested on extrinsic regeneration inhibitors, the extent to which glial inhibitors contribute to the regeneration failure in viva still remains elusive. Recent exper- imental evidence has rekindled interests in intrinsic factors for the regulation of regeneration capacity in adult mammals. In this review, we propose that activating macrophages with pro-regenerative molecular signatures could be a novel approach for boosting intrinsic regenerative capacity of CNS neurons. Using a conditioning injury model in which regeneration of central branches of dorsal root ganglia sensory neu- rons is enhanced by a preceding injury to the peripheral branches, we have demonstrated that perineuronal macrophages surrounding dorsal root ganglia neurons are critically involved in the maintenance of en- hanced regeneration capacity. Neuron-derived chemokine （C-C motif） ligand 2 （CCL2） seems to mediate neuron-macrophage interactions conveying injury signals to perineuronal macrophages taking on a soley pro-regenerative phenotype, which we designate as regeneration-associated macrophages （RAMs）. Ma- nipulation of the CCL2 signaling could boost regeneration potential mimicking the conditioning injury, suggesting that the chemokine-mediated RAM activation could be utilized as a regenerative therapeutic strategy for CNS injuries.展开更多
Late-onset Alzheimer 's disease(LOAD), the most common cause of dementia, currently affects 5.6 million Americans ages 65 and older.LOAD is a neurodegenerative disorder characterized by progressive loss in synapti...Late-onset Alzheimer 's disease(LOAD), the most common cause of dementia, currently affects 5.6 million Americans ages 65 and older.LOAD is a neurodegenerative disorder characterized by progressive loss in synaptic function, notable bioenergetic decline, increased neuronal death and brain atrophy, and significant cognitive impairment.Because the etiology of LOAD remains unknown, a treatment for LOAD has not yet been formulated, a fact that is clearly demonstrated by the more than 200 failed clinical trials.展开更多
α-Synuclein accumulation causes synaptic vesicle trafficking defects and may underlie neurodegenerative disorders:Neurodegenerative disorders,such as Parkinson’s disease(PD)and other synucleinopathies,impact the liv...α-Synuclein accumulation causes synaptic vesicle trafficking defects and may underlie neurodegenerative disorders:Neurodegenerative disorders,such as Parkinson’s disease(PD)and other synucleinopathies,impact the lives of millions of patients and their caregivers.Synucleinopathies include PD,dementia with Lewy Bodies(DLB),multiple system atrophy,and several Alzheimer’s Disease variants.They are clinically characterized by intracellular inclusions called Lewy Bodies,which are rich in atypical aggregates of the protein α-synuclein.While dopaminergic neurons in the substantia nigra are particularly susceptible toα-synuclein-induced aggregation and neurodegeneration,glutamatergic neurons in other brain regions(e.g.cortex)are also frequently affected in PD and other synucleinopathies(Schulz-Schaeffer 2010).展开更多
The dentate gyrus subregion of the mammalian hippocampus is an adult neural stem cell niche and site of lifelong neurogenesis.Hypotheses regarding the role of adult-born neuron synaptic integration in hippocampal circ...The dentate gyrus subregion of the mammalian hippocampus is an adult neural stem cell niche and site of lifelong neurogenesis.Hypotheses regarding the role of adult-born neuron synaptic integration in hippocampal circuit function are framed by robust estimations of adultborn versus pre/perinatally-born neuron number.In contrast,the non-neurogenic functions of adult neural stem cells and their immediate progeny,such as secretion of bioactive growth factors and expression of extracellular matrix-modifying proteins,lack similar framing due to few estimates of their number versus other prominent secretory cells.Here,we apply immunohistochemical methods to estimate cell density of neural stem/progenitor cells versus other major classes of glial and endothelial cell types that are potentially secretory in the dentate gyrus of adult mice.Of the cell types quantified,we found that GFAP^(+)SOX2^(+)stellate astrocytes were the most numerous,followed by CD31^(+)endothelia,GFAP-SOX2^(+)intermediate progenitors,Olig2^(+)oligodendrocytes,Iba1+microglia,and GFAP^(+)SOX2^(+)radial glia-like neural stem cells.We did not observe any significant sex differences in density of any cell population.Notably,neural stem/progenitor cells were present at a similar density as several cell types known to have potent functional roles via their secretome.These findings may be useful for refining hypotheses regarding the contributions of these cell types to regulating hippocampal function and their potential therapeutic uses.All experimental protocols were approved by the Ohio State University Institutional Animal Care and Use Committee(protocol#2016A00000068)on July 14,2016.展开更多
Alzheimer’s disease（AD）is the most common form of dementia among the elderly.It currently affects approximately 5.1 million Americans,a number predicted to triple by 2050.AD is clinically manifested as progressive ...Alzheimer’s disease（AD）is the most common form of dementia among the elderly.It currently affects approximately 5.1 million Americans,a number predicted to triple by 2050.AD is clinically manifested as progressive loss of memory and cognitive function,and is characterized pathologically by the formation of amyloid-beta（Aβ）plaques and neurofibrillary tangles（NFT）.Since its discovery in 1906,展开更多
The limited axonal growth after central nervous system （CNS） injury such as spinal cord injury presents a major challenge in promoting repair and recovery. The literature in axonal repair has focused mostly on frank...The limited axonal growth after central nervous system （CNS） injury such as spinal cord injury presents a major challenge in promoting repair and recovery. The literature in axonal repair has focused mostly on frank regeneration of injured axons. Here, we argue that sprouting of uninjured axons, an innate repair mech- anism of the CNS, might be more amenable to modulation in order to promote functional repair. Extrinsic inhibitors of axonal growth modulate axon sprouting after injury and may serve as the first group of therapeutic targets to promote functional repair.展开更多
Glial cells in the central nervous system （CNS） contribute to formation of the extracellular matrix, which provides adhesive sites, signaling molecules, and a diffusion barrier to enhance efficient on and axon poten...Glial cells in the central nervous system （CNS） contribute to formation of the extracellular matrix, which provides adhesive sites, signaling molecules, and a diffusion barrier to enhance efficient on and axon potential propagation. In the normal adult CNS, the extracellular matrix （ECM） is relatively stable except in selected regions characterized by dynamic remodeling. However, after trauma such as a spinal cord injury or cortical contusion, the lesion epicenter becomes a focus of acute neuroinflammation. The activation of the surrounding glial cells leads to a dramatic change in the composition of the ECM at the edges of the lesion, creating a perilesion environment dominated by growth inhibitory molecules and restoration of the peripheral/ central nervous system border. An advantage of this response is to limit the invasion of damaging cells and diffusion of toxic molecules into the spared tissue regions, but this occurs at the cost of inhibiting migration of endogenous repair cells and preventing axonal regrowth. The following review was prepared by reading and discussing over 200 research articles in the field published in PubMed and selecting those with significant impact and/or controversial points. This article highlights structural and functional features of the normal adult CNS ECM and then focuses on the reactions of glial cells and changes in the perilesion border that occur following spinal cord or contusive brain injury. Current research strategies directed at modifying the inhibitory perilesion microenvironment without eliminating the protective functions of glial cell activation are discussed.展开更多
Edema formation is a major problem following traumatic spinal cord injury(SCI) that acts to exacerbate secondary damage.Severity of edema correlates with reduced neurological outcome in human patients.To date, there a...Edema formation is a major problem following traumatic spinal cord injury(SCI) that acts to exacerbate secondary damage.Severity of edema correlates with reduced neurological outcome in human patients.To date, there are no effective treatments to directly resolve edema within the spinal cord.The aquaporin-4(AQP4) water channel is found on membranes of astrocytic endfeet in direct contact with blood vessels, the glia limitans in contact with the cerebrospinal fluid and ependyma around the central canal.Being so locally expressed at the interface between fluid and tissue allow AQP4 channels to play an important role in the bidirectional regulation of water homeostasis under normal conditions and following trauma.With the need to better understand the pathophysiology underlying the devastating cellular events in SCI, animal models have become an integral part of exploration.Inevitably, several injury models have been developed(contusion, compression, transection) resulting in difficult interpretation between studies with conflicting results.This is true in the case of understanding the role of AQP4 in the progression and resolution of edema following SCI, whose role is still not completely understood and is highly dependent on the type of edema present(vasogenic vs cytotoxic).Here, we discuss regulation of AQP4 in varying injury models and the effects of potential therapeutic interventions on expression, edema formation and functional recovery.Better understanding of the precise role of AQP4 following a wide range of injuries will help to understand optimal treatment timing following human SCI for prime therapeutic benefit and enhanced neurological outcome.展开更多
The regeneration of peripheral nervous system and central nervous system(CNS)neurons after injury remains challenging.We have come a long way since the identification of a 37 k Da protein specific for regenerating per...The regeneration of peripheral nervous system and central nervous system(CNS)neurons after injury remains challenging.We have come a long way since the identification of a 37 k Da protein specific for regenerating peripheral nervous system and CNS nerves(Muller et al.,1985).展开更多
Vasculature is the interface between tissue and circulation.It consists of endothelial cells,mural cells including vascular smooth muscle cells and pericytes,and other perivascular cells including macrophages and fibr...Vasculature is the interface between tissue and circulation.It consists of endothelial cells,mural cells including vascular smooth muscle cells and pericytes,and other perivascular cells including macrophages and fibroblasts(Sweeney et al.,2019).The vascular system not only delivers oxygen and nutrients,but also shuttles the immune cells around.As the first line of defense,the vascular system also senses the changes in surrounding tissue,particularly inflammation.Vascular inflammation can occur in blood vessels of all sizes in any organ.It has a complex etiology,including infections such as coronavirus disease-19(COVID-19),and chronic condi t ions such as diabetes,hypertension and neurodegenerative diseases(Hanafi et al.,2020).Excessive vascular inflammation is clinically known as vasculitis,diagnosed by blood test,imaging and biopsy.Vasculitis not only thickens the blood vessel wall,causing blood flow reduction and insufficient delivery of oxygen and nutrients,but also triggers inflammatory responses in secondary sites,or even the whole body.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).
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 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This work was supported by the National Research Foundation of Korea(NRF)grants funded by the Korea government(MSIT,Ministry of Science and ICT)(NRF-2018M3A9E8023853(to JYC)NRF-2018R1C1B6006145(to JYC)NRF-2018R1A2A1A05020292(to BGK)and NRF-2019R1A5A2026045(to JYC and BGK).
文摘Subcortical ischemic white matter injury(SIWMI),pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging,is a common cause of cognitive decline in elderly.Despite its high prevalence,it remains unknown how various components of the white matter degenerate in response to chronic ischemia.This incomplete knowledge is in part due to a lack of adequate animal model.The current review introduces various SIWMI animal models and aims to scrutinize their advantages and disadvantages primarily in regard to the pathological manifestations of white matter components.The SIWMI animal models are categorized into 1)chemically induced SIWMI models,2)vascular occlusive SIWMI models,and 3)SIWMI models with comorbid vascular risk factors.Chemically induced models display consistent lesions in predetermined areas of the white matter,but the abrupt evolution of lesions does not appropriately reflect the progressive pathological processes in human white matter hyperintensities.Vascular occlusive SIWMI models often do not exhibit white matter lesions that are sufficiently unequivocal to be quantified.When combined with comorbid vascular risk factors(specifically hypertension),however,they can produce progressive and definitive white matter lesions including diffuse rarefaction,demyelination,loss of oligodendrocytes,and glial activation,which are by far the closest to those found in human white matter hyperintensities lesions.However,considerable surgical mortality and unpredictable natural deaths during a follow-up period would necessitate further refinements in these models.In the meantime,in vitro SIWMI models that recapitulate myelinated white matter track may be utilized to study molecular mechanisms of the ischemic white matter injury.Appropriate in vivo and in vitro SIWMI models will contribute in a complementary manner to making a breakthrough in developing effective treatment to prevent progression of white matter hyperintensities.
基金supported by a National Research Foundation of Korea grant funded by the Korean Government(NRF-2014R1A1A2056452 to D.H.H.and NRF-2014M3A9B6034224 to BGK)
文摘Traumatic injuries to spinal cord elicit diverse signaling pathways leading to unselective and complex pathological outcomes：death of multiple classes of neural cells,formation of cystic cavities and glial scars,disruption of axonal connections,and demyelination of spared axons,all of which can contribute more or less to debilitating functional impairments found in patients with spinal cord injury.
文摘Axons in central nervous system （CNS） do not regenerate spontaneously after injuries such as stroke and traumatic spinal cord iniury. Both intrinsic and extrinsic factors are responsible for the regeneration fail- ure, Although intensive research efforts have been invested on extrinsic regeneration inhibitors, the extent to which glial inhibitors contribute to the regeneration failure in viva still remains elusive. Recent exper- imental evidence has rekindled interests in intrinsic factors for the regulation of regeneration capacity in adult mammals. In this review, we propose that activating macrophages with pro-regenerative molecular signatures could be a novel approach for boosting intrinsic regenerative capacity of CNS neurons. Using a conditioning injury model in which regeneration of central branches of dorsal root ganglia sensory neu- rons is enhanced by a preceding injury to the peripheral branches, we have demonstrated that perineuronal macrophages surrounding dorsal root ganglia neurons are critically involved in the maintenance of en- hanced regeneration capacity. Neuron-derived chemokine （C-C motif） ligand 2 （CCL2） seems to mediate neuron-macrophage interactions conveying injury signals to perineuronal macrophages taking on a soley pro-regenerative phenotype, which we designate as regeneration-associated macrophages （RAMs）. Ma- nipulation of the CCL2 signaling could boost regeneration potential mimicking the conditioning injury, suggesting that the chemokine-mediated RAM activation could be utilized as a regenerative therapeutic strategy for CNS injuries.
基金supported by the National Institutes of Health(NIHR21 AG055964, R21 AG059177, R01 AG061038 to LZ)。
文摘Late-onset Alzheimer 's disease(LOAD), the most common cause of dementia, currently affects 5.6 million Americans ages 65 and older.LOAD is a neurodegenerative disorder characterized by progressive loss in synaptic function, notable bioenergetic decline, increased neuronal death and brain atrophy, and significant cognitive impairment.Because the etiology of LOAD remains unknown, a treatment for LOAD has not yet been formulated, a fact that is clearly demonstrated by the more than 200 failed clinical trials.
基金supported by a grant from the National Institutes of Health National Institute of Neurological Disorders and Stroke/National Institute on Aging(NIH NINDS/NIA R01NS078165 to JRM)National Institute of General Medical Sciences(NIH/NIGMS Grant R01GM118933 to EML and RS).
文摘α-Synuclein accumulation causes synaptic vesicle trafficking defects and may underlie neurodegenerative disorders:Neurodegenerative disorders,such as Parkinson’s disease(PD)and other synucleinopathies,impact the lives of millions of patients and their caregivers.Synucleinopathies include PD,dementia with Lewy Bodies(DLB),multiple system atrophy,and several Alzheimer’s Disease variants.They are clinically characterized by intracellular inclusions called Lewy Bodies,which are rich in atypical aggregates of the protein α-synuclein.While dopaminergic neurons in the substantia nigra are particularly susceptible toα-synuclein-induced aggregation and neurodegeneration,glutamatergic neurons in other brain regions(e.g.cortex)are also frequently affected in PD and other synucleinopathies(Schulz-Schaeffer 2010).
基金a R00 Pathway to Independence Award from NIH/NINDS(R00NS089938to EDK).
文摘The dentate gyrus subregion of the mammalian hippocampus is an adult neural stem cell niche and site of lifelong neurogenesis.Hypotheses regarding the role of adult-born neuron synaptic integration in hippocampal circuit function are framed by robust estimations of adultborn versus pre/perinatally-born neuron number.In contrast,the non-neurogenic functions of adult neural stem cells and their immediate progeny,such as secretion of bioactive growth factors and expression of extracellular matrix-modifying proteins,lack similar framing due to few estimates of their number versus other prominent secretory cells.Here,we apply immunohistochemical methods to estimate cell density of neural stem/progenitor cells versus other major classes of glial and endothelial cell types that are potentially secretory in the dentate gyrus of adult mice.Of the cell types quantified,we found that GFAP^(+)SOX2^(+)stellate astrocytes were the most numerous,followed by CD31^(+)endothelia,GFAP-SOX2^(+)intermediate progenitors,Olig2^(+)oligodendrocytes,Iba1+microglia,and GFAP^(+)SOX2^(+)radial glia-like neural stem cells.We did not observe any significant sex differences in density of any cell population.Notably,neural stem/progenitor cells were present at a similar density as several cell types known to have potent functional roles via their secretome.These findings may be useful for refining hypotheses regarding the contributions of these cell types to regulating hippocampal function and their potential therapeutic uses.All experimental protocols were approved by the Ohio State University Institutional Animal Care and Use Committee(protocol#2016A00000068)on July 14,2016.
基金supported by the Alzheimer’s Association Investigator-Initiated Research Grant(IIRG-10-172459)the NIH-funded Institutional Development Award(P20GM103418)+2 种基金the NIH-funded University of Kansas Alzheimer’s Disease Center(P30AG035982)the University of Kansas Institute for Reproductive Health and Regenerative Medicinethe University of Kansas general research and startup funds to LZ
文摘Alzheimer’s disease（AD）is the most common form of dementia among the elderly.It currently affects approximately 5.1 million Americans,a number predicted to triple by 2050.AD is clinically manifested as progressive loss of memory and cognitive function,and is characterized pathologically by the formation of amyloid-beta（Aβ）plaques and neurofibrillary tangles（NFT）.Since its discovery in 1906,
基金supported by grants from NIH/ NINDS (R01NS054734)the California Institute for Regenerative Medicinethe Craig H. Neilsen Foundation and Wings for Life Spinal Cord Research Foundation
文摘The limited axonal growth after central nervous system （CNS） injury such as spinal cord injury presents a major challenge in promoting repair and recovery. The literature in axonal repair has focused mostly on frank regeneration of injured axons. Here, we argue that sprouting of uninjured axons, an innate repair mech- anism of the CNS, might be more amenable to modulation in order to promote functional repair. Extrinsic inhibitors of axonal growth modulate axon sprouting after injury and may serve as the first group of therapeutic targets to promote functional repair.
基金supported by NIH/NINDS R01-NS043246,P30-NS045758,the International Spinal Research Trust(STR-100)the Ohio State University College of Medicine
文摘Glial cells in the central nervous system （CNS） contribute to formation of the extracellular matrix, which provides adhesive sites, signaling molecules, and a diffusion barrier to enhance efficient on and axon potential propagation. In the normal adult CNS, the extracellular matrix （ECM） is relatively stable except in selected regions characterized by dynamic remodeling. However, after trauma such as a spinal cord injury or cortical contusion, the lesion epicenter becomes a focus of acute neuroinflammation. The activation of the surrounding glial cells leads to a dramatic change in the composition of the ECM at the edges of the lesion, creating a perilesion environment dominated by growth inhibitory molecules and restoration of the peripheral/ central nervous system border. An advantage of this response is to limit the invasion of damaging cells and diffusion of toxic molecules into the spared tissue regions, but this occurs at the cost of inhibiting migration of endogenous repair cells and preventing axonal regrowth. The following review was prepared by reading and discussing over 200 research articles in the field published in PubMed and selecting those with significant impact and/or controversial points. This article highlights structural and functional features of the normal adult CNS ECM and then focuses on the reactions of glial cells and changes in the perilesion border that occur following spinal cord or contusive brain injury. Current research strategies directed at modifying the inhibitory perilesion microenvironment without eliminating the protective functions of glial cell activation are discussed.
文摘Edema formation is a major problem following traumatic spinal cord injury(SCI) that acts to exacerbate secondary damage.Severity of edema correlates with reduced neurological outcome in human patients.To date, there are no effective treatments to directly resolve edema within the spinal cord.The aquaporin-4(AQP4) water channel is found on membranes of astrocytic endfeet in direct contact with blood vessels, the glia limitans in contact with the cerebrospinal fluid and ependyma around the central canal.Being so locally expressed at the interface between fluid and tissue allow AQP4 channels to play an important role in the bidirectional regulation of water homeostasis under normal conditions and following trauma.With the need to better understand the pathophysiology underlying the devastating cellular events in SCI, animal models have become an integral part of exploration.Inevitably, several injury models have been developed(contusion, compression, transection) resulting in difficult interpretation between studies with conflicting results.This is true in the case of understanding the role of AQP4 in the progression and resolution of edema following SCI, whose role is still not completely understood and is highly dependent on the type of edema present(vasogenic vs cytotoxic).Here, we discuss regulation of AQP4 in varying injury models and the effects of potential therapeutic interventions on expression, edema formation and functional recovery.Better understanding of the precise role of AQP4 following a wide range of injuries will help to understand optimal treatment timing following human SCI for prime therapeutic benefit and enhanced neurological outcome.
文摘The regeneration of peripheral nervous system and central nervous system(CNS)neurons after injury remains challenging.We have come a long way since the identification of a 37 k Da protein specific for regenerating peripheral nervous system and CNS nerves(Muller et al.,1985).
基金supported by the National Institutes of Health(NIH),Nos.R01AG061288,R03AG063287,R01NS110687,R21AG066090,and 1RF1NS122060Bright Focus Foundation,No.A2019218SU.S.Department of Defense grant No.W81XWH2010424(to ZZ).
文摘Vasculature is the interface between tissue and circulation.It consists of endothelial cells,mural cells including vascular smooth muscle cells and pericytes,and other perivascular cells including macrophages and fibroblasts(Sweeney et al.,2019).The vascular system not only delivers oxygen and nutrients,but also shuttles the immune cells around.As the first line of defense,the vascular system also senses the changes in surrounding tissue,particularly inflammation.Vascular inflammation can occur in blood vessels of all sizes in any organ.It has a complex etiology,including infections such as coronavirus disease-19(COVID-19),and chronic condi t ions such as diabetes,hypertension and neurodegenerative diseases(Hanafi et al.,2020).Excessive vascular inflammation is clinically known as vasculitis,diagnosed by blood test,imaging and biopsy.Vasculitis not only thickens the blood vessel wall,causing blood flow reduction and insufficient delivery of oxygen and nutrients,but also triggers inflammatory responses in secondary sites,or even the whole body.
