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
Vascular endothelial growth factor(VEGF)was discovered by its angiogenic activity.However,during evolution,it appeared earlier as a neurotrophic factor required for the development of the nervous system in invertebrat...Vascular endothelial growth factor(VEGF)was discovered by its angiogenic activity.However,during evolution,it appeared earlier as a neurotrophic factor required for the development of the nervous system in invertebrates lacking a circulatory system.We aimed at reviewing recent evidence indicating that VEGF has neuroprotective effects in neurons exposed to a variety of insults.Of particular interest is the link established between VEGF and motoneurons,especially after the design of the VEGFδ/δmutant mice.These mice are characterized by low levels of VEGF and develop muscle weakness and motoneuron degeneration resembling amyotrophic lateral sclerosis.The administration of VEGF through several routes to animal models of amyotrophic lateral sclerosis delays motor impairment and motoneuron degeneration and increases life expectancy.There are new recent advances in the role of VEGF in the physiology of motoneurons.Our experimental aims use the extraocular(abducens)motoneurons lesioned by axotomy as a model for studying VEGF actions.Axotomized abducens motoneurons exhibit severe alterations in their discharge activity and a loss of synaptic boutons.The exogenous administration of VEGF to axotomized abducens motoneurons,either from the transected nerve or intraventricularly,fully restores the synaptic and discharge properties of abducens motoneurons,despite being axotomized.In addition,when an anti-VEGF neutralizing antibody is delivered from the muscle to intact,uninjured abducens motoneurons,these cells display alterations in their discharge pattern and a loss of synaptic boutons that resemble the state of axotomy.All these data indicate that VEGF is an essential neurotrophic factor for motoneurons.展开更多
The consequences of neonatal white matter injury are devastating and represent a major societal problem as currently there is no cure.Prematurity,low weight birth and maternal pre-natal infection are the most frequent...The consequences of neonatal white matter injury are devastating and represent a major societal problem as currently there is no cure.Prematurity,low weight birth and maternal pre-natal infection are the most frequent causes of acquired myelin deficiency in the human neonate leading to cerebral palsy and cognitive impairment.In the developing brain,oligodendrocyte(OL)maturation occurs perinatally,and immature OLs are particularly vulnerable.Cell replacement therapy is often considered a viable option to replace progenitors that die due to glutamate excitotoxicity.We previously reported directed specification and mobilization of endogenous committed and uncommitted neural progenitors by the combination of transferrin and insulin growth factor 1(TSC1).Here,considering cell replacement and integration as therapeutic goals,we examined if OL progenitors(OLPs)grafted into the brain parenchyma of mice that were subjected to an excitotoxic insult could rescue white matter injury.For that purpose,we used a well-established model of glutamate excitotoxic injury.Four-day-old mice received a single intraparenchymal injection of the glutamate receptor agonist N-methyl-D-aspartate alone or in conjunction with TSC1 in the presence or absence of OLPs grafted into the brain parenchyma.Energetics and expression of stress proteins and OL developmental specific markers were examined.A comparison of the proteomic profile per treatment was also ascertained.We found that OLPs did not survive in the excitotoxic environment when grafted alone.In contrast,when combined with TSC1,survival and integration of grafted OLPs was observed.Further,energy metabolism in OLPs was significantly increased by N-methyl-D-aspartate and modulated by TSC1.The proteomic profile after the various treatments showed elevated ubiquitination and stress/heat shock protein 90 in response to N-methyl-D-aspartate.These changes were reversed in the presence of TSC1 and ubiquitination was decreased.The results obtained in this pre-clinical study indicate that the use of a combinatorial intervention including both trophic support and healthy OLPs constitutes a promising approach for long-term survival and successful graft integration.We established optimal conditioning of the host brain environment to promote long-term survival and integration of grafted OLPs into an inflamed neonate host brain.Experimental procedures were performed under the United States Public Health Service Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care Committee at(UCLA)(ARC#1992-034-61)on July 1,2010.展开更多
Neural stem/progenitor cells (NSCs) can spontaneously differentiate into neurons and glial cells in the absence of mitogen fibroblast growth factor-2 (FGF-2) or epidermal growth factor (EGF) in medium and the spontane...Neural stem/progenitor cells (NSCs) can spontaneously differentiate into neurons and glial cells in the absence of mitogen fibroblast growth factor-2 (FGF-2) or epidermal growth factor (EGF) in medium and the spontaneous differentiation of NSCs is mediated partially by endogenous ciliary neuro-trophic factor (CNTF). This study examined the relationship of FGF-2 and CNTF in the spontaneous differentiation of adult hippocampal progenitor cells (AHPs). AHPs were cultured in the medium containing different concentration of FGF-2 (1–100 ng/mL). Western blotting and immunofluorescence staining were applied to detect the expression of the astrocytic marker GFAP, the neuronal marker Tuj1, the oligodendrocytic marker CNPase and, Nestin, the marker of AHPs. The expression of endogenous CNTF in AHPs at early (passage 4) and late stage (passage 22) was also measured by Western blotting. The results showed that FGF-2 increased the expression of Nestin, dramatically inhibited the expression of GFAP and Tuj1 and slightly suppressed the expression of CNPase. FGF-2 down-regulated the expression of endogenous CNTF in AHPs at both early (passage 4) and late stage (passage 22). These results suggested that FGF-2 could inhibit the spontaneous differentiation of cultured AHPs by negatively regulating the expression of endogenous CNTF in AHPs.展开更多
The carotid body (CB) is a small neural crest-derived organ that registers oxygen and glucose levels in blood and regulates ventilation. The most abundant cell type in the CB glomeruli is glomus or type I cells, which...The carotid body (CB) is a small neural crest-derived organ that registers oxygen and glucose levels in blood and regulates ventilation. The most abundant cell type in the CB glomeruli is glomus or type I cells, which is enveloped by processes of sustentacular or type II cells. Growth and neurotrophic factors have been established as signaling molecules played an important role in the development of the CB. To gain insight whether these signaling molecules are present in the adult rat CB, we examined the expression and cellular localization of some neurotrophic factors and their corresponding receptors in this organ by immunohistochemistry. The results showed the presence of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) as well as p75NTR, tyrosine kinase A receptor (TrkA), tyrosine kinase B receptor (TrkB) and GDNF family receptor alpha1 (GFRα1) in the adult CB. At the light-microscopical level, the immunoreactivity for NGF and both its low-affinity (p75) and high-affinity (TrkA) receptors was detected in the majority of glomus cells and also in a subset of sustentacular cells. BDNF and its receptors, p75 and TrkB, were observed in the glomus cells, too. Remarkably, the immunohistochemical analysis revealed that the neuron-like glomus cells, but not the glial-like sustentacular cells, expressed GDNF and GFRα1. Taken together with prior results, it can be inferred that neurotrophins may be involved in the CB cell differentiation and survival in adulthood, and may exert a potent glomic protective action as well. It is also presumable that GDNF production by glomus cells plays a pivotal role in permitting long-term viability of CB grafts, which permits their potential applicability in cell therapy as a promising tool in neurodegenerative disorders.展开更多
The gastrointestinal tract(GIT) is a complex system, which changes in response to requirements of the body. GIT represents a barrier to the external environment. To achieve this, epithelial cells must renew rapidly. T...The gastrointestinal tract(GIT) is a complex system, which changes in response to requirements of the body. GIT represents a barrier to the external environment. To achieve this, epithelial cells must renew rapidly. This renewal of epithelial cells starts in the fetal life under the influence of many GIT peptides by swallowing amniotic fluid(AF). Development and maturation of GIT is a very complex cascade that begins long before birth and continues during infancy and childhood by breastfeeding. Many factors like genetic preprogramming, local and systemic endocrine secretions and many trophic factors(TF) from swallowed AF contribute and modulate the development and growth of the GIT. GIT morphogenesis, differentiation and functional development depend on the activity of various TF in the AF. This manuscript will review the role of AF borne TF in the development of GIT.展开更多
Objective:Glioblastoma(GBM)is the most prevalent and aggressive adult primary cancer in the central nervous system.Therapeutic approaches for GBM treatment are under intense investigation,including the use of emerging...Objective:Glioblastoma(GBM)is the most prevalent and aggressive adult primary cancer in the central nervous system.Therapeutic approaches for GBM treatment are under intense investigation,including the use of emerging immunotherapies.Here,we propose an alternative approach to treat GBM through reprogramming proliferative GBM cells into non-proliferative neurons.Methods:Retroviruses were used to target highly proliferative human GBM cells through overexpression of neural transcription factors.Immunostaining,electrophysiological recording,and bulk RNA-seq were performed to investigate the mechanisms underlying the neuronal conversion of human GBM cells.An in vivo intracranial xenograft mouse model was used to examine the neuronal conversion of human GBM cells.Results:We report efficient neuronal conversion from human GBM cells by overexpressing single neural transcription factor Neurogenic differentiation 1(Neuro D1),Neurogenin-2(Neurog2),or Achaete-scute homolog 1(Ascl1).Subtype characterization showed that the majority of Neurog2-and Neuro D1-converted neurons were glutamatergic,while Ascl1 favored GABAergic neuron generation.The GBM cell-converted neurons not only showed pan-neuronal markers but also exhibited neuron-specific electrophysiological activities.Transcriptome analyses revealed that neuronal genes were activated in glioma cells after overexpression of neural transcription factors,and different signaling pathways were activated by different neural transcription factors.Importantly,the neuronal conversion of GBM cells was accompanied by significant inhibition of GBM cell proliferation in both in vitro and in vivo models.Conclusions:These results suggest that GBM cells can be reprogrammed into different subtypes of neurons,leading to a potential alternative approach to treat brain tumors using in vivo cell conversion technology.展开更多
[Objective] The aim was to study the relationship between chlorophyll-a and environmental impact factors in deep reservoir in Karst Areas.[Method] Taking Aha Reservoir for example,the changes of chlorophyll-a content ...[Objective] The aim was to study the relationship between chlorophyll-a and environmental impact factors in deep reservoir in Karst Areas.[Method] Taking Aha Reservoir for example,the changes of chlorophyll-a content and its relationship with environmental impact factors were researched,and the water quality of Aha Reservoir was assessed by means of modified Carlson trophic state index.[Result] Chlorophyll-a content in Aha Reservoir was higher in March,April,May and September and lower from June to August,and there was obvious seasonal variation,namely its variation trend was spring>summer>autumn>winter.In addition,chlorophyll-a content showed extremely significant correlation with transparency and dissolved oxygen (P<0.01) and significant correlation with ammonia nitrogen (P<0.05).Meanwhile,trophic state index was higher in whole year in Aha Reservoir which was in moderate trophic state in August,October and November and eutrophic state in other months.[Conclusion] The study could provide scientific reference for discussing the mechanism of lake eutrophication.展开更多
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 I+D+i project P20_00529 Consejería de Transformación Económica Industria y Conocimiento,Junta de Andalucía-FEDERsupported by project PGC2018-094654-B-100 and PID2021-124300NB-I00 funded by MCIN/AEI/FEDER“A way of making Europe”+1 种基金P.M.C.was a scholar of Ministerio de Educación y Ciencia(BES-2016-077912)in Spain and is now a“Margarita Salas”postdoctoral fellowRGH is a postdoctoral fellow from PAIDI-2019,“Talento Doctores”Junta de Andalucía in Spain,and is now a“Ramón y Cajal”fellow in Spain。
文摘Vascular endothelial growth factor(VEGF)was discovered by its angiogenic activity.However,during evolution,it appeared earlier as a neurotrophic factor required for the development of the nervous system in invertebrates lacking a circulatory system.We aimed at reviewing recent evidence indicating that VEGF has neuroprotective effects in neurons exposed to a variety of insults.Of particular interest is the link established between VEGF and motoneurons,especially after the design of the VEGFδ/δmutant mice.These mice are characterized by low levels of VEGF and develop muscle weakness and motoneuron degeneration resembling amyotrophic lateral sclerosis.The administration of VEGF through several routes to animal models of amyotrophic lateral sclerosis delays motor impairment and motoneuron degeneration and increases life expectancy.There are new recent advances in the role of VEGF in the physiology of motoneurons.Our experimental aims use the extraocular(abducens)motoneurons lesioned by axotomy as a model for studying VEGF actions.Axotomized abducens motoneurons exhibit severe alterations in their discharge activity and a loss of synaptic boutons.The exogenous administration of VEGF to axotomized abducens motoneurons,either from the transected nerve or intraventricularly,fully restores the synaptic and discharge properties of abducens motoneurons,despite being axotomized.In addition,when an anti-VEGF neutralizing antibody is delivered from the muscle to intact,uninjured abducens motoneurons,these cells display alterations in their discharge pattern and a loss of synaptic boutons that resemble the state of axotomy.All these data indicate that VEGF is an essential neurotrophic factor for motoneurons.
基金The Cell Culture Core supported by grant No.PP1498:Neural Cell Culture Core and NIH grant No.04612 Intellectual&Developmental Disabilities.The Cell,Circuits and Systems Analysis Core is supported by NICHD award No.U54HD087101-03
文摘The consequences of neonatal white matter injury are devastating and represent a major societal problem as currently there is no cure.Prematurity,low weight birth and maternal pre-natal infection are the most frequent causes of acquired myelin deficiency in the human neonate leading to cerebral palsy and cognitive impairment.In the developing brain,oligodendrocyte(OL)maturation occurs perinatally,and immature OLs are particularly vulnerable.Cell replacement therapy is often considered a viable option to replace progenitors that die due to glutamate excitotoxicity.We previously reported directed specification and mobilization of endogenous committed and uncommitted neural progenitors by the combination of transferrin and insulin growth factor 1(TSC1).Here,considering cell replacement and integration as therapeutic goals,we examined if OL progenitors(OLPs)grafted into the brain parenchyma of mice that were subjected to an excitotoxic insult could rescue white matter injury.For that purpose,we used a well-established model of glutamate excitotoxic injury.Four-day-old mice received a single intraparenchymal injection of the glutamate receptor agonist N-methyl-D-aspartate alone or in conjunction with TSC1 in the presence or absence of OLPs grafted into the brain parenchyma.Energetics and expression of stress proteins and OL developmental specific markers were examined.A comparison of the proteomic profile per treatment was also ascertained.We found that OLPs did not survive in the excitotoxic environment when grafted alone.In contrast,when combined with TSC1,survival and integration of grafted OLPs was observed.Further,energy metabolism in OLPs was significantly increased by N-methyl-D-aspartate and modulated by TSC1.The proteomic profile after the various treatments showed elevated ubiquitination and stress/heat shock protein 90 in response to N-methyl-D-aspartate.These changes were reversed in the presence of TSC1 and ubiquitination was decreased.The results obtained in this pre-clinical study indicate that the use of a combinatorial intervention including both trophic support and healthy OLPs constitutes a promising approach for long-term survival and successful graft integration.We established optimal conditioning of the host brain environment to promote long-term survival and integration of grafted OLPs into an inflamed neonate host brain.Experimental procedures were performed under the United States Public Health Service Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care Committee at(UCLA)(ARC#1992-034-61)on July 1,2010.
文摘Neural stem/progenitor cells (NSCs) can spontaneously differentiate into neurons and glial cells in the absence of mitogen fibroblast growth factor-2 (FGF-2) or epidermal growth factor (EGF) in medium and the spontaneous differentiation of NSCs is mediated partially by endogenous ciliary neuro-trophic factor (CNTF). This study examined the relationship of FGF-2 and CNTF in the spontaneous differentiation of adult hippocampal progenitor cells (AHPs). AHPs were cultured in the medium containing different concentration of FGF-2 (1–100 ng/mL). Western blotting and immunofluorescence staining were applied to detect the expression of the astrocytic marker GFAP, the neuronal marker Tuj1, the oligodendrocytic marker CNPase and, Nestin, the marker of AHPs. The expression of endogenous CNTF in AHPs at early (passage 4) and late stage (passage 22) was also measured by Western blotting. The results showed that FGF-2 increased the expression of Nestin, dramatically inhibited the expression of GFAP and Tuj1 and slightly suppressed the expression of CNPase. FGF-2 down-regulated the expression of endogenous CNTF in AHPs at both early (passage 4) and late stage (passage 22). These results suggested that FGF-2 could inhibit the spontaneous differentiation of cultured AHPs by negatively regulating the expression of endogenous CNTF in AHPs.
文摘The carotid body (CB) is a small neural crest-derived organ that registers oxygen and glucose levels in blood and regulates ventilation. The most abundant cell type in the CB glomeruli is glomus or type I cells, which is enveloped by processes of sustentacular or type II cells. Growth and neurotrophic factors have been established as signaling molecules played an important role in the development of the CB. To gain insight whether these signaling molecules are present in the adult rat CB, we examined the expression and cellular localization of some neurotrophic factors and their corresponding receptors in this organ by immunohistochemistry. The results showed the presence of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) as well as p75NTR, tyrosine kinase A receptor (TrkA), tyrosine kinase B receptor (TrkB) and GDNF family receptor alpha1 (GFRα1) in the adult CB. At the light-microscopical level, the immunoreactivity for NGF and both its low-affinity (p75) and high-affinity (TrkA) receptors was detected in the majority of glomus cells and also in a subset of sustentacular cells. BDNF and its receptors, p75 and TrkB, were observed in the glomus cells, too. Remarkably, the immunohistochemical analysis revealed that the neuron-like glomus cells, but not the glial-like sustentacular cells, expressed GDNF and GFRα1. Taken together with prior results, it can be inferred that neurotrophins may be involved in the CB cell differentiation and survival in adulthood, and may exert a potent glomic protective action as well. It is also presumable that GDNF production by glomus cells plays a pivotal role in permitting long-term viability of CB grafts, which permits their potential applicability in cell therapy as a promising tool in neurodegenerative disorders.
文摘The gastrointestinal tract(GIT) is a complex system, which changes in response to requirements of the body. GIT represents a barrier to the external environment. To achieve this, epithelial cells must renew rapidly. This renewal of epithelial cells starts in the fetal life under the influence of many GIT peptides by swallowing amniotic fluid(AF). Development and maturation of GIT is a very complex cascade that begins long before birth and continues during infancy and childhood by breastfeeding. Many factors like genetic preprogramming, local and systemic endocrine secretions and many trophic factors(TF) from swallowed AF contribute and modulate the development and growth of the GIT. GIT morphogenesis, differentiation and functional development depend on the activity of various TF in the AF. This manuscript will review the role of AF borne TF in the development of GIT.
基金supported by the Charles H.“Skip”Smith Endowment Fund and the Verne M.Willaman Endowment Fund from the Pennsylvania State University to G.C。
文摘Objective:Glioblastoma(GBM)is the most prevalent and aggressive adult primary cancer in the central nervous system.Therapeutic approaches for GBM treatment are under intense investigation,including the use of emerging immunotherapies.Here,we propose an alternative approach to treat GBM through reprogramming proliferative GBM cells into non-proliferative neurons.Methods:Retroviruses were used to target highly proliferative human GBM cells through overexpression of neural transcription factors.Immunostaining,electrophysiological recording,and bulk RNA-seq were performed to investigate the mechanisms underlying the neuronal conversion of human GBM cells.An in vivo intracranial xenograft mouse model was used to examine the neuronal conversion of human GBM cells.Results:We report efficient neuronal conversion from human GBM cells by overexpressing single neural transcription factor Neurogenic differentiation 1(Neuro D1),Neurogenin-2(Neurog2),or Achaete-scute homolog 1(Ascl1).Subtype characterization showed that the majority of Neurog2-and Neuro D1-converted neurons were glutamatergic,while Ascl1 favored GABAergic neuron generation.The GBM cell-converted neurons not only showed pan-neuronal markers but also exhibited neuron-specific electrophysiological activities.Transcriptome analyses revealed that neuronal genes were activated in glioma cells after overexpression of neural transcription factors,and different signaling pathways were activated by different neural transcription factors.Importantly,the neuronal conversion of GBM cells was accompanied by significant inhibition of GBM cell proliferation in both in vitro and in vivo models.Conclusions:These results suggest that GBM cells can be reprogrammed into different subtypes of neurons,leading to a potential alternative approach to treat brain tumors using in vivo cell conversion technology.
基金Supported by Social Development Project of Guiyang City (2009304,2010503)
文摘[Objective] The aim was to study the relationship between chlorophyll-a and environmental impact factors in deep reservoir in Karst Areas.[Method] Taking Aha Reservoir for example,the changes of chlorophyll-a content and its relationship with environmental impact factors were researched,and the water quality of Aha Reservoir was assessed by means of modified Carlson trophic state index.[Result] Chlorophyll-a content in Aha Reservoir was higher in March,April,May and September and lower from June to August,and there was obvious seasonal variation,namely its variation trend was spring>summer>autumn>winter.In addition,chlorophyll-a content showed extremely significant correlation with transparency and dissolved oxygen (P<0.01) and significant correlation with ammonia nitrogen (P<0.05).Meanwhile,trophic state index was higher in whole year in Aha Reservoir which was in moderate trophic state in August,October and November and eutrophic state in other months.[Conclusion] The study could provide scientific reference for discussing the mechanism of lake eutrophication.
