Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and...Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and differentiation.This neurogenic potential may be a relevant factor to fight neurodegeneration and aging.In the last years,we can find growing evidence suggesting that melatonin may be a potential modulator of adult hippocampal neurogenesis.The lack of therapeutic strategies targeting neurogenesis led researchers to explore new molecules.Numerous preclinical studies with melatonin observed how melatonin can modulate and enhance molecular and signaling pathways involved in neurogenesis.We made a special focus on the connection between these modulation mechanisms and their implication in neurodegeneration,to summarize the current knowledge and highlight the therapeutic potential of melatonin.展开更多
Adult hippocampal neurogenesis is a finely tuned process regulated by extrinsic factors. Neuroinflammation is a hallmark of several pathological conditions underlying dysregulation of neurogenesis. In animal models, l...Adult hippocampal neurogenesis is a finely tuned process regulated by extrinsic factors. Neuroinflammation is a hallmark of several pathological conditions underlying dysregulation of neurogenesis. In animal models, lipopolysaccharide(LPS)-induced neuroinflammation leads to a neurogenic decrease mainly associated to the early inflammatory response. However, it is not well understood how the neuroinflammatory response progresses over time and if neurogenesis continues to be diminished during the late neuroinflammatory response. Moreover, it is unknown if repeated intermittent administration of LPS along time induces a greater reduction in neurogenesis. We administered one single intraperitoneal injection of LPS or saline or four repeated injections(one per week) of LPS or saline to young-adult mice. A cohort of new cells was labeled with three 5-bromo-2-deoxyuridine injections(one per day) 4 days after the last LPS injection. We evaluated systemic and neuroinflammation-associated parameters and compared the effects of the late neuroinflammatory response on neurogenesis induced by each protocol. Our results show that 1) a single LPS injection leads to a late pro-inflammatory response characterized by microglial activation, moderate astrocytic reaction and increased interleukin-6 levels. This response correlates in time with decreased neurogenesis and 2) a repeated intermittent injection of LPS does not elicit a late pro-inflammatory response although activated microglia persists. The latter profile is not accompanied by a continued longterm hippocampal neurogenic decrease. Hereby, we provide evidence that the neuroinflammatory response is a dynamic process that progresses in a milieu-dependent manner and does not necessarily lead to a neurogenic decrease, highlighting the complex interaction between the immune system and neurogenesis.展开更多
Several lines of evidence have established that proliferation and differentiation of neural stem cells into neurons within the sub-granular zone of the dentate gyrus,a process named adult hippocampal neurogenesis,cont...Several lines of evidence have established that proliferation and differentiation of neural stem cells into neurons within the sub-granular zone of the dentate gyrus,a process named adult hippocampal neurogenesis,contribute to maintaining healthy cognitive functions throughout life.The rate of adult hippocampal neurogenesis decreases with aging and a premature impairment of adult hippocampal neurogenesis has been observed both in animal models of Alzheimer’s disease and human post-mortem tissues.The causal relationship between adult hippocampal neurogenesis and the development of Alzheimer’s disease pathology has,however,not been established.This is partly due to the limitation of recapitulating the development of Alzheimer’s disease pathology in rodent models and the lack of translatable biomarkers to identify tractable targets in humans.While it is tempting to postulate that adult hippocampal neurogenesis could be leveraged to improve cognitive deficits in Alzheimer’s disease,consensual results have yet to be reached to fully explore this hypothesis.In this review,we discuss how the recent progress in identifying molecular pathways in adult hippocampal neurogenesis provides a good framework to initiate strategies for drug-based intervention in neurodegenerative diseases,especially in Alzheimer’s disease.We outline how discrepancies in pre-clinical disease models and experimental methodology have resulted in contradictory findings and propose a shift towards using more translatable approaches to model neurogenesis in Alzheimer’s disease.In particular,we review how exploring novel experimental paradigms including the use of human induced pluripotent stem cells and more complex cell culture systems,as well as standardizing protocols used to investigate evidence of neurogenesis in human tissues,could deliver deeper mechanistic insights that would kick-start innovative drug discovery efforts to promote healthy aging and cellular rejuvenation.展开更多
Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain.Recent evidence suggests that adult hippocampal neurogenesis(AHN)persists throughout life in mammal...Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain.Recent evidence suggests that adult hippocampal neurogenesis(AHN)persists throughout life in mammals,including humans.These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory.Importantly,studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases.Alzheimer’s disease(AD)is one of the most common forms of dementia affecting millions of people.Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus.Therefore,there has been growing interest in identifying how hippocampal neurogenesis is affected in AD.However,the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood.In this review,we summarized the recent literature on AHN and its impairments in AD.展开更多
OBJECTIVE Cranial radiotherapy is clinically used in the treatment of brain tumors;however,the consequent cognitive and emotional dysfunctions seriously impair the life quality of patients.LW-AFC,an active fraction co...OBJECTIVE Cranial radiotherapy is clinically used in the treatment of brain tumors;however,the consequent cognitive and emotional dysfunctions seriously impair the life quality of patients.LW-AFC,an active fraction combination extracted from classical traditional Chinese medicine prescription Liuwei Dihuang decoction,can improve cognitive and emotional dysfunctions in many animal models;however,the protective effect of LW-AFC on cranial irradiation-induced cognitive and emotional dysfunctions has not been reported.Recent studies indicate that impairment of adult hippocampal neurogenesis(AHN)and alterations of the neurogenic microenvironment in the hippocampus constitute critical factors in cognitive and emotional dysfunctions following cranial irradiation.Here,our research further investigated the potential protective effects and mechanisms of LW-AFC on cranial irradiation-induced cognitive and emotional dysfunctions in mice.METHODS LW-AFC(1.6 g·kg^(-1))was intragastrically administered to mice for 14 d before cranial irradiation(7 Gyγ-ray).AHN was examined by quantifying the number of proliferative neural stem cells and immature neurons in the dorsal and ventral hippocampus.The contextual fear conditioning test,open field test,and tail suspension test were used to assess cognitive and emotional functions in mice.To detect the change of the neurogenic microenvironment,colorimetry and multiplex bead analysis were performed to measure the level of oxidative stress,neurotrophic and growth factors,and inflammation in the hippocampus.RESULTS LW-AFC exerted beneficial effects on the contextual fear memory,anxiety behavior,and depression behavior in irradiated mice.Moreover,LW-AFC increased the number of proliferative neural stem cells and immature neurons in the dorsal hippocampus,displaying a regional specificity of neurogenic response.For the neurogenic microenvironment,LW-AFC significantly increased the contents of superoxide dismutase,glutathione peroxidase,glutathione,and catalase and decreased the content of malondialdehyde in the hippocampus of irradiated mice,accompanied by the increase in brain-derived neurotrophic factor,insulin-like growth factor-1,and interleukin-4 content.Together,LW-AFC improved cognitive and emotional dysfunctions,promoted AHN preferentially in the dorsal hippocampus,and ameliorated disturbance in the neurogenic microenvironment in irradiated mice.CONCLUSION LW-AFC ameliorates cranial irradiation-induced cognitive and emotional dysfunctions,and the underlying mechanisms are mediated by promoting AHN in the dorsal hippocampus and improving the neurogenic microenvironment.LW-AFC might be a promising therapeutic agent to treat cognitive and emotional dysfunctions in patients receiving cranial radiotherapy.展开更多
Diet is an important health factor and it has been recently associated with neurodegenerative diseases and cognitive decline. Here it was investigated the effect of fatty acid or cholesterol rich diets with the possib...Diet is an important health factor and it has been recently associated with neurodegenerative diseases and cognitive decline. Here it was investigated the effect of fatty acid or cholesterol rich diets with the possible acceleration of the biological decline in adult hippocampal neurogenesis associated with aging in middle-age rats, and its impact on anxiety and memory function. It was found that a diet of 10 weeks with saturated fatty acids and cholesterol has a detrimental effect on memory function, exerts like-anxiety behavior and diminishes the presence of new generated neurons in the hippocampus in six months old rats.展开更多
Traumatic brain injury(TBI)is a major cause of mortality and morbidity in the pediatric population.With advances in medical care,the mortality rate of pediatric TBI has declined.However,more children and adolescents a...Traumatic brain injury(TBI)is a major cause of mortality and morbidity in the pediatric population.With advances in medical care,the mortality rate of pediatric TBI has declined.However,more children and adolescents are living with TBI-related cognitive and emotional impairments,which negatively affects the quality of their life.Adult hippocampal neurogenesis plays an important role in cognition and mood regulation.Alterations in adult hippocampal neurogenesis are associated with a variety of neurological and neurodegenerative diseases,including TBI.Promoting endogenous hippocampal neurogenesis after TBI merits significant attention.However,TBI affects the function of neural stem/progenitor cells in the dentate gyrus of hippocampus,which results in aberrant migration and impaired dendrite development of adult-born neurons.Therefore,a better understanding of adult hippocampal neurogenesis after TBI can facilitate a more successful neuro-restoration of damage in immature brains.Secondary injuries,such as neuroinflammation and oxidative stress,exert a significant impact on hippocampal neurogenesis.Currently,a variety of therapeutic approaches have been proposed for ameliorating secondary TBI injuries.In this review,we discuss the uniqueness of pediatric TBI,adult hippocampal neurogenesis after pediatric TBI,and current efforts that promote neuroprotection to the developing brains,which can be leveraged to facilitate neuroregeneration.展开更多
Schizophrenia(SCZ)is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits.Although many genetic risk factors have been identified,SCZ is also cons...Schizophrenia(SCZ)is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits.Although many genetic risk factors have been identified,SCZ is also considered as a neurodevelopmental disorder.Elucidation of the pathogenesis and the development of treatment is challenging because complex interactions occur between these genetic risk factors and environment in essential neurodevelopmental processes.Adult neural stem cells share a lot of similarities with embryonic neural stem cells and provide a promising model for studying neuronal development in adulthood.These adult neural stem cells also play an important role in cognitive functions including temporal and spatial memory encoding and context discrimination,which have been shown to be closely linked with many psychiatric disorders,such as SCZ.Here in this review,we focus on the SCZ risk genes and the key components in related signaling pathways in adult hippocampal neural stem cells and summarize their roles in adult neurogenesis and animal behaviors.We hope that this would be helpful for the understanding of the contribution of dysregulated adult neural stem cells in the pathogenesis of SCZ and for the identification of potential therapeutic targets,which could facilitate the development of novel medication and treatment.展开更多
Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rode...Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.展开更多
Heat stress has multiple potential effects on the brain,such as neuroinflammation,neurogenesis defects,and cog-nitive impairment.β-hydroxybutyric acid(BHBA)has been demonstrated to play neuroprotective roles in vario...Heat stress has multiple potential effects on the brain,such as neuroinflammation,neurogenesis defects,and cog-nitive impairment.β-hydroxybutyric acid(BHBA)has been demonstrated to play neuroprotective roles in various models of neurological diseases.In the present study,we investigated the efficacy of BHBA in alleviating heat stress-induced impairments of adult hippocampal neurogenesis and cognitive function,as well as the underlying mecha-nisms.Mice were exposed to 43℃for 15 min for 14 days after administration with saline,BHBA,or minocycline.Here,we showed for the first time that BHBA normalized memory ability in the heat stress-treated mice and attenuated heat stress-impaired hippocampal neurogenesis.Consistently,BHBA noticeably improved the synaptic plasticity in the heat stress-treated hippocampal neurons by inhibiting the decrease of synapse-associated proteins and the density of dendritic spines.Moreover,BHBA inhibited the expression of cleaved caspase-3 by suppressing endoplasmic reticu-lum(ER)stress,and increased the expression of brain-derived neurotrophic factor(BDNF)in the heat stress-treated hippocampus by activating the protein kinase B(Akt)/cAMP response element binding protein(CREB)and methyl-CpG binding protein 2(MeCP2)pathways.These findings indicate that BHBA is a potential agent for improving cogni-tive functions in heat stress-treated mice.The action may be mediated by ER stress,and Akt-CREB-BDNF and MeCP2 pathways to improve adult hippocampal neurogenesis and synaptic plasticity.展开更多
文摘Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and differentiation.This neurogenic potential may be a relevant factor to fight neurodegeneration and aging.In the last years,we can find growing evidence suggesting that melatonin may be a potential modulator of adult hippocampal neurogenesis.The lack of therapeutic strategies targeting neurogenesis led researchers to explore new molecules.Numerous preclinical studies with melatonin observed how melatonin can modulate and enhance molecular and signaling pathways involved in neurogenesis.We made a special focus on the connection between these modulation mechanisms and their implication in neurodegeneration,to summarize the current knowledge and highlight the therapeutic potential of melatonin.
基金supported by grants from Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica(PAPIIT):203015,208518Consejo Nacional de Ciencia y Tecnología(CONACyT):282470(all to AZ)
文摘Adult hippocampal neurogenesis is a finely tuned process regulated by extrinsic factors. Neuroinflammation is a hallmark of several pathological conditions underlying dysregulation of neurogenesis. In animal models, lipopolysaccharide(LPS)-induced neuroinflammation leads to a neurogenic decrease mainly associated to the early inflammatory response. However, it is not well understood how the neuroinflammatory response progresses over time and if neurogenesis continues to be diminished during the late neuroinflammatory response. Moreover, it is unknown if repeated intermittent administration of LPS along time induces a greater reduction in neurogenesis. We administered one single intraperitoneal injection of LPS or saline or four repeated injections(one per week) of LPS or saline to young-adult mice. A cohort of new cells was labeled with three 5-bromo-2-deoxyuridine injections(one per day) 4 days after the last LPS injection. We evaluated systemic and neuroinflammation-associated parameters and compared the effects of the late neuroinflammatory response on neurogenesis induced by each protocol. Our results show that 1) a single LPS injection leads to a late pro-inflammatory response characterized by microglial activation, moderate astrocytic reaction and increased interleukin-6 levels. This response correlates in time with decreased neurogenesis and 2) a repeated intermittent injection of LPS does not elicit a late pro-inflammatory response although activated microglia persists. The latter profile is not accompanied by a continued longterm hippocampal neurogenic decrease. Hereby, we provide evidence that the neuroinflammatory response is a dynamic process that progresses in a milieu-dependent manner and does not necessarily lead to a neurogenic decrease, highlighting the complex interaction between the immune system and neurogenesis.
文摘Several lines of evidence have established that proliferation and differentiation of neural stem cells into neurons within the sub-granular zone of the dentate gyrus,a process named adult hippocampal neurogenesis,contribute to maintaining healthy cognitive functions throughout life.The rate of adult hippocampal neurogenesis decreases with aging and a premature impairment of adult hippocampal neurogenesis has been observed both in animal models of Alzheimer’s disease and human post-mortem tissues.The causal relationship between adult hippocampal neurogenesis and the development of Alzheimer’s disease pathology has,however,not been established.This is partly due to the limitation of recapitulating the development of Alzheimer’s disease pathology in rodent models and the lack of translatable biomarkers to identify tractable targets in humans.While it is tempting to postulate that adult hippocampal neurogenesis could be leveraged to improve cognitive deficits in Alzheimer’s disease,consensual results have yet to be reached to fully explore this hypothesis.In this review,we discuss how the recent progress in identifying molecular pathways in adult hippocampal neurogenesis provides a good framework to initiate strategies for drug-based intervention in neurodegenerative diseases,especially in Alzheimer’s disease.We outline how discrepancies in pre-clinical disease models and experimental methodology have resulted in contradictory findings and propose a shift towards using more translatable approaches to model neurogenesis in Alzheimer’s disease.In particular,we review how exploring novel experimental paradigms including the use of human induced pluripotent stem cells and more complex cell culture systems,as well as standardizing protocols used to investigate evidence of neurogenesis in human tissues,could deliver deeper mechanistic insights that would kick-start innovative drug discovery efforts to promote healthy aging and cellular rejuvenation.
基金supported by the Medical Scientist Training Program(T32 GM008444)Mechanistic Study of Declining Hippocampal Neurogenesis in the Aging Brain(R01AG066912 to S.G.)。
文摘Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain.Recent evidence suggests that adult hippocampal neurogenesis(AHN)persists throughout life in mammals,including humans.These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory.Importantly,studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases.Alzheimer’s disease(AD)is one of the most common forms of dementia affecting millions of people.Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus.Therefore,there has been growing interest in identifying how hippocampal neurogenesis is affected in AD.However,the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood.In this review,we summarized the recent literature on AHN and its impairments in AD.
文摘OBJECTIVE Cranial radiotherapy is clinically used in the treatment of brain tumors;however,the consequent cognitive and emotional dysfunctions seriously impair the life quality of patients.LW-AFC,an active fraction combination extracted from classical traditional Chinese medicine prescription Liuwei Dihuang decoction,can improve cognitive and emotional dysfunctions in many animal models;however,the protective effect of LW-AFC on cranial irradiation-induced cognitive and emotional dysfunctions has not been reported.Recent studies indicate that impairment of adult hippocampal neurogenesis(AHN)and alterations of the neurogenic microenvironment in the hippocampus constitute critical factors in cognitive and emotional dysfunctions following cranial irradiation.Here,our research further investigated the potential protective effects and mechanisms of LW-AFC on cranial irradiation-induced cognitive and emotional dysfunctions in mice.METHODS LW-AFC(1.6 g·kg^(-1))was intragastrically administered to mice for 14 d before cranial irradiation(7 Gyγ-ray).AHN was examined by quantifying the number of proliferative neural stem cells and immature neurons in the dorsal and ventral hippocampus.The contextual fear conditioning test,open field test,and tail suspension test were used to assess cognitive and emotional functions in mice.To detect the change of the neurogenic microenvironment,colorimetry and multiplex bead analysis were performed to measure the level of oxidative stress,neurotrophic and growth factors,and inflammation in the hippocampus.RESULTS LW-AFC exerted beneficial effects on the contextual fear memory,anxiety behavior,and depression behavior in irradiated mice.Moreover,LW-AFC increased the number of proliferative neural stem cells and immature neurons in the dorsal hippocampus,displaying a regional specificity of neurogenic response.For the neurogenic microenvironment,LW-AFC significantly increased the contents of superoxide dismutase,glutathione peroxidase,glutathione,and catalase and decreased the content of malondialdehyde in the hippocampus of irradiated mice,accompanied by the increase in brain-derived neurotrophic factor,insulin-like growth factor-1,and interleukin-4 content.Together,LW-AFC improved cognitive and emotional dysfunctions,promoted AHN preferentially in the dorsal hippocampus,and ameliorated disturbance in the neurogenic microenvironment in irradiated mice.CONCLUSION LW-AFC ameliorates cranial irradiation-induced cognitive and emotional dysfunctions,and the underlying mechanisms are mediated by promoting AHN in the dorsal hippocampus and improving the neurogenic microenvironment.LW-AFC might be a promising therapeutic agent to treat cognitive and emotional dysfunctions in patients receiving cranial radiotherapy.
文摘Diet is an important health factor and it has been recently associated with neurodegenerative diseases and cognitive decline. Here it was investigated the effect of fatty acid or cholesterol rich diets with the possible acceleration of the biological decline in adult hippocampal neurogenesis associated with aging in middle-age rats, and its impact on anxiety and memory function. It was found that a diet of 10 weeks with saturated fatty acids and cholesterol has a detrimental effect on memory function, exerts like-anxiety behavior and diminishes the presence of new generated neurons in the hippocampus in six months old rats.
基金This work was supported by the Startup Grant for ZZ from the Department of Natural Sciences,University of Michigan-Dearborn and“CASL Faculty Summer Research Grant”for ZZ from Office of Research&Sponsored Programs,University of Michigan-Dearborn.
文摘Traumatic brain injury(TBI)is a major cause of mortality and morbidity in the pediatric population.With advances in medical care,the mortality rate of pediatric TBI has declined.However,more children and adolescents are living with TBI-related cognitive and emotional impairments,which negatively affects the quality of their life.Adult hippocampal neurogenesis plays an important role in cognition and mood regulation.Alterations in adult hippocampal neurogenesis are associated with a variety of neurological and neurodegenerative diseases,including TBI.Promoting endogenous hippocampal neurogenesis after TBI merits significant attention.However,TBI affects the function of neural stem/progenitor cells in the dentate gyrus of hippocampus,which results in aberrant migration and impaired dendrite development of adult-born neurons.Therefore,a better understanding of adult hippocampal neurogenesis after TBI can facilitate a more successful neuro-restoration of damage in immature brains.Secondary injuries,such as neuroinflammation and oxidative stress,exert a significant impact on hippocampal neurogenesis.Currently,a variety of therapeutic approaches have been proposed for ameliorating secondary TBI injuries.In this review,we discuss the uniqueness of pediatric TBI,adult hippocampal neurogenesis after pediatric TBI,and current efforts that promote neuroprotection to the developing brains,which can be leveraged to facilitate neuroregeneration.
文摘Schizophrenia(SCZ)is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits.Although many genetic risk factors have been identified,SCZ is also considered as a neurodevelopmental disorder.Elucidation of the pathogenesis and the development of treatment is challenging because complex interactions occur between these genetic risk factors and environment in essential neurodevelopmental processes.Adult neural stem cells share a lot of similarities with embryonic neural stem cells and provide a promising model for studying neuronal development in adulthood.These adult neural stem cells also play an important role in cognitive functions including temporal and spatial memory encoding and context discrimination,which have been shown to be closely linked with many psychiatric disorders,such as SCZ.Here in this review,we focus on the SCZ risk genes and the key components in related signaling pathways in adult hippocampal neural stem cells and summarize their roles in adult neurogenesis and animal behaviors.We hope that this would be helpful for the understanding of the contribution of dysregulated adult neural stem cells in the pathogenesis of SCZ and for the identification of potential therapeutic targets,which could facilitate the development of novel medication and treatment.
基金supported by the National Institutes of Health,Nos.AA025919,AA025919-03S1,and AA025919-05S1(all to RAF).
文摘Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.
基金supported by the National Natural Science Foundation of China(No.32272967)Key Research and Development Projects of Shaanxi Province(No.2021NY-021)+1 种基金National Key Research and Development Program of China(No.2018YFE0127000)Shaanxi Provincial Regional Innovation Capability Guiding Plan Project(No.2020QFY10-04).
文摘Heat stress has multiple potential effects on the brain,such as neuroinflammation,neurogenesis defects,and cog-nitive impairment.β-hydroxybutyric acid(BHBA)has been demonstrated to play neuroprotective roles in various models of neurological diseases.In the present study,we investigated the efficacy of BHBA in alleviating heat stress-induced impairments of adult hippocampal neurogenesis and cognitive function,as well as the underlying mecha-nisms.Mice were exposed to 43℃for 15 min for 14 days after administration with saline,BHBA,or minocycline.Here,we showed for the first time that BHBA normalized memory ability in the heat stress-treated mice and attenuated heat stress-impaired hippocampal neurogenesis.Consistently,BHBA noticeably improved the synaptic plasticity in the heat stress-treated hippocampal neurons by inhibiting the decrease of synapse-associated proteins and the density of dendritic spines.Moreover,BHBA inhibited the expression of cleaved caspase-3 by suppressing endoplasmic reticu-lum(ER)stress,and increased the expression of brain-derived neurotrophic factor(BDNF)in the heat stress-treated hippocampus by activating the protein kinase B(Akt)/cAMP response element binding protein(CREB)and methyl-CpG binding protein 2(MeCP2)pathways.These findings indicate that BHBA is a potential agent for improving cogni-tive functions in heat stress-treated mice.The action may be mediated by ER stress,and Akt-CREB-BDNF and MeCP2 pathways to improve adult hippocampal neurogenesis and synaptic plasticity.
基金supported by the National Natural Science Foundation of China(No.31270027 and 31270034)Science and Technology Commission of Shanghai MunicipalityChina(No.12JC1401000)
