Since the pioneering work by Broca and Wernicke in the 19th century,who examined individuals with brain lesions to associate them with specific behaviors,it was evident that behaviors are complex and cannot be fully a...Since the pioneering work by Broca and Wernicke in the 19th century,who examined individuals with brain lesions to associate them with specific behaviors,it was evident that behaviors are complex and cannot be fully attributable to specific brain areas alone.Instead,they involve connectivity among brain areas,whether close or distant.At that time,this approach was considered the optimal way to dissect brain circuitry and function.These pioneering efforts opened the field to explore the necessity or sufficiency of brain areas in controlling behavior and hence dissecting brain function.However,the connectivity of the brain and the mechanisms through which various brain regions regulate specific behaviors,either individually or collaboratively,remain largely elusive.Utilizing animal models,researchers have endeavored to unravel the necessity or sufficiency of specific brain areas in influencing behavior;however,no clear associations have been firmly established.展开更多
Neuroscience is the ultimate frontier in our quest for a comprehensive understanding of human behavior. Since its launch in 2009, the Human Connectome Project has emerged as a pioneering force, making heroic strides i...Neuroscience is the ultimate frontier in our quest for a comprehensive understanding of human behavior. Since its launch in 2009, the Human Connectome Project has emerged as a pioneering force, making heroic strides in elucidating the intricate correlation between structural information and the functioning of the human brain.展开更多
The feasibility of manufacturing Ti-6Al-4V samples through a combination of laser-aided additive manufacturing with powder(LAAM_(p))and wire(LAAM_(w))was explored.A process study was first conducted to successfully ci...The feasibility of manufacturing Ti-6Al-4V samples through a combination of laser-aided additive manufacturing with powder(LAAM_(p))and wire(LAAM_(w))was explored.A process study was first conducted to successfully circumvent defects in Ti-6Al-4V deposits for LAAM_(p) and LAAM_(w),respectively.With the optimized process parameters,robust interfaces were achieved between powder/wire deposits and the forged substrate,as well as between powder and wire deposits.Microstructure characterization results revealed the epitaxial prior β grains in the deposited Ti-6Al-4V,wherein the powder deposit was dominated by a finerα′microstructure and the wire deposit was characterized by lamellar α phases.The mechanisms of microstructure formation and correlation with mechanical behavior were analyzed and discussed.The mechanical properties of the interfacial samples can meet the requirements of the relevant Aerospace Material Specifications(AMS 6932)even without post heat treatment.No fracture occurred within the interfacial area,further suggesting the robust interface.The findings of this study highlighted the feasibility of combining LAAM_(p) and LAAM_(w) in the direct manufacturing of Ti-6Al-4V parts in accordance with the required dimensional resolution and deposition rate,together with sound strength and ductility balance in the as-built condition.展开更多
In engineering practice,it is often necessary to determine functional relationships between dependent and independent variables.These relationships can be highly nonlinear,and classical regression approaches cannot al...In engineering practice,it is often necessary to determine functional relationships between dependent and independent variables.These relationships can be highly nonlinear,and classical regression approaches cannot always provide sufficiently reliable solutions.Nevertheless,Machine Learning(ML)techniques,which offer advanced regression tools to address complicated engineering issues,have been developed and widely explored.This study investigates the selected ML techniques to evaluate their suitability for application in the hot deformation behavior of metallic materials.The ML-based regression methods of Artificial Neural Networks(ANNs),Support Vector Machine(SVM),Decision Tree Regression(DTR),and Gaussian Process Regression(GPR)are applied to mathematically describe hot flow stress curve datasets acquired experimentally for a medium-carbon steel.Although the GPR method has not been used for such a regression task before,the results showed that its performance is the most favorable and practically unrivaled;neither the ANN method nor the other studied ML techniques provide such precise results of the solved regression analysis.展开更多
Spinal cord injury necessitates effective rehabilitation strategies, with exercise therapies showing promise in promoting recovery. This study investigated the impact of rehabilitation exercise on functional recovery ...Spinal cord injury necessitates effective rehabilitation strategies, with exercise therapies showing promise in promoting recovery. This study investigated the impact of rehabilitation exercise on functional recovery and morphological changes following thoracic contusive spinal cord injury. After a 7-day recovery period after spinal cord injury, mice were assigned to either a trained group(10 weeks of voluntary running wheel or forced treadmill exercise) or an untrained group. Bi-weekly assessments revealed that the exercise-trained group, particularly the voluntary wheel exercise subgroup, displayed significantly improved locomotor recovery, more plasticity of dopaminergic and serotonin modulation compared with the untrained group. Additionally, exercise interventions led to gait pattern restoration and enhanced transcranial magnetic motor-evoked potentials. Despite consistent injury areas across groups, exercise training promoted terminal innervation of descending axons. In summary, voluntary wheel exercise shows promise for enhancing outcomes after thoracic contusive spinal cord injury, emphasizing the role of exercise modality in promoting recovery and morphological changes in spinal cord injuries. Our findings will influence future strategies for rehabilitation exercises, restoring functional movement after spinal cord injury.展开更多
The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain functio...The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain function and encoding behaviors associated with emotions.Specifically, astrocytes in the basolateral amygdala have been found to play a role in the modulation of anxiety-like behaviors triggered by chronic stress. Nevertheless, the precise molecular mechanisms by which basolateral amygdala astrocytes regulate chronic stress–induced anxiety-like behaviors remain to be fully elucidated. In this study, we found that in a mouse model of anxiety triggered by unpredictable chronic mild stress, the expression of excitatory amino acid transporter 2 was upregulated in the basolateral amygdala. Interestingly, our findings indicate that the targeted knockdown of excitatory amino acid transporter 2 specifically within the basolateral amygdala astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of excitatory amino acid transporter 2 in the basolateral amygdala, whether achieved through intracranial administration of excitatory amino acid transporter 2agonists or through injection of excitatory amino acid transporter 2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our single-nucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of excitatory amino acid transporter 2 specifically in astrocytes in the basolateral amygdala. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the basolateral amygdala of mice subjected to chronic stress was higher compared with normal mice.After knocking down the expression of excitatory amino acid transporter 2 in the basolateral amygdala, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was obviously mitigated. Additionally, administration of an excitatory amino acid transporter 2 inhibitor in the basolateral amygdala yielded a notable reduction in anxiety level among mice subjected to stress. These results suggest that basolateral amygdala astrocytic excitatory amino acid transporter 2 plays a role in in the regulation of unpredictable chronic mild stress-induced anxiety-like behavior by impacting the activity of local glutamatergic neurons, and targeting excitatory amino acid transporter 2 in the basolateral amygdala holds therapeutic promise for addressing anxiety disorders.展开更多
BACKGROUND Emotional reactions,such as anxiety,irritability,and aggressive behavior,have attracted clinical attention as behavioral and emotional problems in preschool-age children.AIM To investigate the current statu...BACKGROUND Emotional reactions,such as anxiety,irritability,and aggressive behavior,have attracted clinical attention as behavioral and emotional problems in preschool-age children.AIM To investigate the current status of family rearing,parental stress,and behavioral and emotional problems of preschool children and to analyze the mediating effect of the current status of family rearing on parental stress and behavioral/emo-tional problems.METHODS We use convenience sampling to select 258 preschool children in the physical examination center of our hospital from October 2021 to September 2023.The children and their parents were evaluated using a questionnaire survey.Pearson's correlation was used to analyze the correlation between child behavioral and emotional problems and parental stress and family rearing,and the structural equation model was constructed to test the mediating effect.RESULTS The score for behavioral/emotional problems of 258 preschool children was(27.54±3.63),the score for parental stress was(87.64±11.34),and the score for parental family rearing was(31.54±5.24).There was a positive correlation between the behavioral and emotional problems of the children and the“hostile/mandatory”parenting style;meanwhile,showed a negative correlation with the“support/participation”parenting style(all P<0.05).The intermediary effect value between the family upbringing of parents in parental stress and children's behavior problems was 29.89%.CONCLUSION Parental family upbringing has a mediating effect between parental stress and behavioral and emotional problems of children.Despite paying attention to the behavioral and emotional problems of preschool-age children,clinical medical staff should provide correct and reasonable parenting advice to their parents to promote the mental health of preschool-age children.展开更多
This letter provides a concise review of the pertinent literature on visual and tactile hallucinations in elderly patients.The discussion addresses differential diagnoses and potential underlying mechanisms,as well as...This letter provides a concise review of the pertinent literature on visual and tactile hallucinations in elderly patients.The discussion addresses differential diagnoses and potential underlying mechanisms,as well as the psychopathology associated with tactile hallucinations,and emphasizes the necessity for invest-igation into the possibility of coexisting delusional infestation(parasitosis).These symptoms frequently manifest in patients with primary psychotic disorders,organic mental disorders,and substance use disorders.The proposed pathophy-siological mechanisms may involve dopaminergic imbalances and dysfunction of the striatal dopamine transporter.展开更多
A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease.Consequently,enhancing adult neurogenesis represents a promising therapeutic approach for mitigati...A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease.Consequently,enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression.Nonetheless,nonpharmacological interventions aimed at inducing adult neurogenesis are currently limited.Although individual non-pharmacological interventions,such as aerobic exercise,acousto-optic stimulation,and olfactory stimulation,have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease,the therapeutic effect of a strategy that combines these interventions has not been fully explored.In this study,we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months.Amyloid deposition became evident at 4 months,while neurogenesis declined by 6 months,further deteriorating as the disease progressed.However,following a 4-week multifactor stimulation protocol,which encompassed treadmill running(46 min/d,10 m/min,6 days per week),40 Hz acousto-optic stimulation(1 hour/day,6 days/week),and olfactory stimulation(1 hour/day,6 days/week),we found a significant increase in the number of newborn cells(5'-bromo-2'-deoxyuridine-positive cells),immature neurons(doublecortin-positive cells),newborn immature neurons(5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells),and newborn astrocytes(5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells).Additionally,the amyloid-beta load in the hippocampus decreased.These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice.Furthermore,cognitive abilities were improved,and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation,as evidenced by Morris water maze,novel object recognition,forced swimming test,and tail suspension test results.Notably,the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2weeks after treatment cessation.At the molecular level,multifactor stimulation upregulated the expression of neuron-related proteins(NeuN,doublecortin,postsynaptic density protein-95,and synaptophysin),anti-apoptosis-related proteins(Bcl-2 and PARP),and an autophagyassociated protein(LC3B),while decreasing the expression of apoptosis-related proteins(BAX and caspase-9),in the hippocampus of amyloid precursor protein/presenilin 1 mice.These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways.Furthermore,serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis,oxidative damage,and cognition.Collectively,these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer's disease.展开更多
Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem ce...Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem cell therapy and advancing the frontiers of stem cell-derived treatments.This lays a foundation for the development of potentially potent new treatment modalities for ischemic stroke.However,the precise mechanisms underlying the efficacy and safety of human neural stem cell-derived extracellular vesicles remain unclear,presenting challenges for clinical translation.To promote the translation of therapy based on human neural stem cell-derived extracellular vesicles from the bench to the bedside,we conducted a comprehensive preclinical study to evaluate the efficacy and safety of human neural stem cell-derived extracellular vesicles in the treatment of ischemic stroke.We found that administration of human neural stem cell-derived extracellular vesicles to an ischemic stroke rat model reduced the volume of cerebral infarction and promoted functional recovery by alleviating neuronal apoptosis.The human neural stem cell-derived extracellular vesicles reduced neuronal apoptosis by enhancing phosphorylation of phosphoinositide 3-kinase,mammalian target of rapamycin,and protein kinase B,and these effects were reversed by treatment with a phosphoinositide 3-kinase inhibitor.These findings suggest that human neural stem cell-derived extracellular vesicles play a neuroprotective role in ischemic stroke through activation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.Finally,we showed that human neural stem cell-derived extracellular vesicles have a good in vivo safety profile.Therefore,human neural stem cell-derived extracellular vesicles are a promising potential agent for the treatment of ischemic stroke.展开更多
基金supported by ANID Fondecyt Iniciacion 11180540(to FJB)ANID PAI 77180077(to FJB)+2 种基金UNAB DI-02-22/REG(to FJB)Exploración-ANID 13220203(to FJB)ANID-MILENIO(NCN2023_23,to FJB)。
文摘Since the pioneering work by Broca and Wernicke in the 19th century,who examined individuals with brain lesions to associate them with specific behaviors,it was evident that behaviors are complex and cannot be fully attributable to specific brain areas alone.Instead,they involve connectivity among brain areas,whether close or distant.At that time,this approach was considered the optimal way to dissect brain circuitry and function.These pioneering efforts opened the field to explore the necessity or sufficiency of brain areas in controlling behavior and hence dissecting brain function.However,the connectivity of the brain and the mechanisms through which various brain regions regulate specific behaviors,either individually or collaboratively,remain largely elusive.Utilizing animal models,researchers have endeavored to unravel the necessity or sufficiency of specific brain areas in influencing behavior;however,no clear associations have been firmly established.
文摘Neuroscience is the ultimate frontier in our quest for a comprehensive understanding of human behavior. Since its launch in 2009, the Human Connectome Project has emerged as a pioneering force, making heroic strides in elucidating the intricate correlation between structural information and the functioning of the human brain.
基金financially supported by the Agency for Science,Technology and Research(A*Star),Republic of Singapore,under the Aerospace Consortium Cycle 12“Characterization of the Effect of Wire and Powder Deposited Materials”(No.A1815a0078)。
文摘The feasibility of manufacturing Ti-6Al-4V samples through a combination of laser-aided additive manufacturing with powder(LAAM_(p))and wire(LAAM_(w))was explored.A process study was first conducted to successfully circumvent defects in Ti-6Al-4V deposits for LAAM_(p) and LAAM_(w),respectively.With the optimized process parameters,robust interfaces were achieved between powder/wire deposits and the forged substrate,as well as between powder and wire deposits.Microstructure characterization results revealed the epitaxial prior β grains in the deposited Ti-6Al-4V,wherein the powder deposit was dominated by a finerα′microstructure and the wire deposit was characterized by lamellar α phases.The mechanisms of microstructure formation and correlation with mechanical behavior were analyzed and discussed.The mechanical properties of the interfacial samples can meet the requirements of the relevant Aerospace Material Specifications(AMS 6932)even without post heat treatment.No fracture occurred within the interfacial area,further suggesting the robust interface.The findings of this study highlighted the feasibility of combining LAAM_(p) and LAAM_(w) in the direct manufacturing of Ti-6Al-4V parts in accordance with the required dimensional resolution and deposition rate,together with sound strength and ductility balance in the as-built condition.
基金supported by the SP2024/089 Project by the Faculty of Materials Science and Technology,VˇSB-Technical University of Ostrava.
文摘In engineering practice,it is often necessary to determine functional relationships between dependent and independent variables.These relationships can be highly nonlinear,and classical regression approaches cannot always provide sufficiently reliable solutions.Nevertheless,Machine Learning(ML)techniques,which offer advanced regression tools to address complicated engineering issues,have been developed and widely explored.This study investigates the selected ML techniques to evaluate their suitability for application in the hot deformation behavior of metallic materials.The ML-based regression methods of Artificial Neural Networks(ANNs),Support Vector Machine(SVM),Decision Tree Regression(DTR),and Gaussian Process Regression(GPR)are applied to mathematically describe hot flow stress curve datasets acquired experimentally for a medium-carbon steel.Although the GPR method has not been used for such a regression task before,the results showed that its performance is the most favorable and practically unrivaled;neither the ANN method nor the other studied ML techniques provide such precise results of the solved regression analysis.
基金supported by the NIH (R01NS103481, R01NS111776, and R01NS131489)Indiana Department of Health (ISDH58180)(all to WW)。
文摘Spinal cord injury necessitates effective rehabilitation strategies, with exercise therapies showing promise in promoting recovery. This study investigated the impact of rehabilitation exercise on functional recovery and morphological changes following thoracic contusive spinal cord injury. After a 7-day recovery period after spinal cord injury, mice were assigned to either a trained group(10 weeks of voluntary running wheel or forced treadmill exercise) or an untrained group. Bi-weekly assessments revealed that the exercise-trained group, particularly the voluntary wheel exercise subgroup, displayed significantly improved locomotor recovery, more plasticity of dopaminergic and serotonin modulation compared with the untrained group. Additionally, exercise interventions led to gait pattern restoration and enhanced transcranial magnetic motor-evoked potentials. Despite consistent injury areas across groups, exercise training promoted terminal innervation of descending axons. In summary, voluntary wheel exercise shows promise for enhancing outcomes after thoracic contusive spinal cord injury, emphasizing the role of exercise modality in promoting recovery and morphological changes in spinal cord injuries. Our findings will influence future strategies for rehabilitation exercises, restoring functional movement after spinal cord injury.
基金supported by the National Natural Science Foundation of China,Nos.32371070 (to JT),31761163005 (to JT),32100824 (to QX)the Shenzhen Science and Technology Program,Nos.RCBS20210609104606024 (to QX),JCY20210324101813035 (to DL)+4 种基金the Guangdong Provincial Key S&T Program,No.2018B030336001 (to JT)the Key Basic Research Program of Shenzhen Science and Technology Innovation Commission,Nos.JCYJ20200109115405930 (to JT),JCYJ20220818101615033 (to DL),JCYJ20210324115811031 (to QX),JCYJ20200109150717745 (to QX)Shenzhen Key Laboratory of Neuroimmunomodulation for Neurological Diseases,No.ZDSYS20220304163558001 (to JT)Guangdong Provincial Key Laboratory of Brain Connectome and Behavior,No.2023B1212060055 (to JT)the China Postdoctoral Science Foundation,No.2021M693298 (to QX)。
文摘The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain function and encoding behaviors associated with emotions.Specifically, astrocytes in the basolateral amygdala have been found to play a role in the modulation of anxiety-like behaviors triggered by chronic stress. Nevertheless, the precise molecular mechanisms by which basolateral amygdala astrocytes regulate chronic stress–induced anxiety-like behaviors remain to be fully elucidated. In this study, we found that in a mouse model of anxiety triggered by unpredictable chronic mild stress, the expression of excitatory amino acid transporter 2 was upregulated in the basolateral amygdala. Interestingly, our findings indicate that the targeted knockdown of excitatory amino acid transporter 2 specifically within the basolateral amygdala astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of excitatory amino acid transporter 2 in the basolateral amygdala, whether achieved through intracranial administration of excitatory amino acid transporter 2agonists or through injection of excitatory amino acid transporter 2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our single-nucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of excitatory amino acid transporter 2 specifically in astrocytes in the basolateral amygdala. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the basolateral amygdala of mice subjected to chronic stress was higher compared with normal mice.After knocking down the expression of excitatory amino acid transporter 2 in the basolateral amygdala, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was obviously mitigated. Additionally, administration of an excitatory amino acid transporter 2 inhibitor in the basolateral amygdala yielded a notable reduction in anxiety level among mice subjected to stress. These results suggest that basolateral amygdala astrocytic excitatory amino acid transporter 2 plays a role in in the regulation of unpredictable chronic mild stress-induced anxiety-like behavior by impacting the activity of local glutamatergic neurons, and targeting excitatory amino acid transporter 2 in the basolateral amygdala holds therapeutic promise for addressing anxiety disorders.
基金Supported by the Shijiazhuang Science and Technology Research and Development Program,No.221460383.
文摘BACKGROUND Emotional reactions,such as anxiety,irritability,and aggressive behavior,have attracted clinical attention as behavioral and emotional problems in preschool-age children.AIM To investigate the current status of family rearing,parental stress,and behavioral and emotional problems of preschool children and to analyze the mediating effect of the current status of family rearing on parental stress and behavioral/emo-tional problems.METHODS We use convenience sampling to select 258 preschool children in the physical examination center of our hospital from October 2021 to September 2023.The children and their parents were evaluated using a questionnaire survey.Pearson's correlation was used to analyze the correlation between child behavioral and emotional problems and parental stress and family rearing,and the structural equation model was constructed to test the mediating effect.RESULTS The score for behavioral/emotional problems of 258 preschool children was(27.54±3.63),the score for parental stress was(87.64±11.34),and the score for parental family rearing was(31.54±5.24).There was a positive correlation between the behavioral and emotional problems of the children and the“hostile/mandatory”parenting style;meanwhile,showed a negative correlation with the“support/participation”parenting style(all P<0.05).The intermediary effect value between the family upbringing of parents in parental stress and children's behavior problems was 29.89%.CONCLUSION Parental family upbringing has a mediating effect between parental stress and behavioral and emotional problems of children.Despite paying attention to the behavioral and emotional problems of preschool-age children,clinical medical staff should provide correct and reasonable parenting advice to their parents to promote the mental health of preschool-age children.
文摘This letter provides a concise review of the pertinent literature on visual and tactile hallucinations in elderly patients.The discussion addresses differential diagnoses and potential underlying mechanisms,as well as the psychopathology associated with tactile hallucinations,and emphasizes the necessity for invest-igation into the possibility of coexisting delusional infestation(parasitosis).These symptoms frequently manifest in patients with primary psychotic disorders,organic mental disorders,and substance use disorders.The proposed pathophy-siological mechanisms may involve dopaminergic imbalances and dysfunction of the striatal dopamine transporter.
基金supported by the National Natural Science Foundation of China,No.82001155(to LL)the Natural Science Foundation of Zhejiang Province,No.LY23H090004(to LL)+5 种基金the Natural Science Foundation of Ningbo,No.2023J068(to LL)the Fundamental Research Funds for the Provincial Universities of Zhejiang Province,No.SJLY2023008(to LL)the College Students'Scientific and Technological Innovation Project(Xin Miao Talent Plan)of Zhejiang Province,No.2022R405A045(to CC)the Student ResearchInnovation Program(SRIP)of Ningbo University,Nos.20235RIP1919(to CZ),2023SRIP1938(to YZ)the K.C.Wong Magna Fund in Ningbo University。
文摘A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease.Consequently,enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression.Nonetheless,nonpharmacological interventions aimed at inducing adult neurogenesis are currently limited.Although individual non-pharmacological interventions,such as aerobic exercise,acousto-optic stimulation,and olfactory stimulation,have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease,the therapeutic effect of a strategy that combines these interventions has not been fully explored.In this study,we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months.Amyloid deposition became evident at 4 months,while neurogenesis declined by 6 months,further deteriorating as the disease progressed.However,following a 4-week multifactor stimulation protocol,which encompassed treadmill running(46 min/d,10 m/min,6 days per week),40 Hz acousto-optic stimulation(1 hour/day,6 days/week),and olfactory stimulation(1 hour/day,6 days/week),we found a significant increase in the number of newborn cells(5'-bromo-2'-deoxyuridine-positive cells),immature neurons(doublecortin-positive cells),newborn immature neurons(5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells),and newborn astrocytes(5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells).Additionally,the amyloid-beta load in the hippocampus decreased.These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice.Furthermore,cognitive abilities were improved,and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation,as evidenced by Morris water maze,novel object recognition,forced swimming test,and tail suspension test results.Notably,the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2weeks after treatment cessation.At the molecular level,multifactor stimulation upregulated the expression of neuron-related proteins(NeuN,doublecortin,postsynaptic density protein-95,and synaptophysin),anti-apoptosis-related proteins(Bcl-2 and PARP),and an autophagyassociated protein(LC3B),while decreasing the expression of apoptosis-related proteins(BAX and caspase-9),in the hippocampus of amyloid precursor protein/presenilin 1 mice.These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways.Furthermore,serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis,oxidative damage,and cognition.Collectively,these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer's disease.
基金supported by the National Nature Science Foundation of China,No.81471308(to JL)the Innovative Leading Talents of Liaoning Province,No.XLYC1902031(to JL)+2 种基金Science and Technology Projects in Liaoning Province,No.2022-BS-238(to CH)Young Top Talents of Liaoning Province,No.XLYC1907009(to LW)Dalian Science and Technology Innovation Fund,No.2018J11CY025(to JL)。
文摘Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem cell therapy and advancing the frontiers of stem cell-derived treatments.This lays a foundation for the development of potentially potent new treatment modalities for ischemic stroke.However,the precise mechanisms underlying the efficacy and safety of human neural stem cell-derived extracellular vesicles remain unclear,presenting challenges for clinical translation.To promote the translation of therapy based on human neural stem cell-derived extracellular vesicles from the bench to the bedside,we conducted a comprehensive preclinical study to evaluate the efficacy and safety of human neural stem cell-derived extracellular vesicles in the treatment of ischemic stroke.We found that administration of human neural stem cell-derived extracellular vesicles to an ischemic stroke rat model reduced the volume of cerebral infarction and promoted functional recovery by alleviating neuronal apoptosis.The human neural stem cell-derived extracellular vesicles reduced neuronal apoptosis by enhancing phosphorylation of phosphoinositide 3-kinase,mammalian target of rapamycin,and protein kinase B,and these effects were reversed by treatment with a phosphoinositide 3-kinase inhibitor.These findings suggest that human neural stem cell-derived extracellular vesicles play a neuroprotective role in ischemic stroke through activation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.Finally,we showed that human neural stem cell-derived extracellular vesicles have a good in vivo safety profile.Therefore,human neural stem cell-derived extracellular vesicles are a promising potential agent for the treatment of ischemic stroke.