1.IntroductionPassive movement is a 200+year-old manipulation involving the external movement of an individuals’limbs or body absent voluntary effort or muscle contraction.1The original application of passive movemen...1.IntroductionPassive movement is a 200+year-old manipulation involving the external movement of an individuals’limbs or body absent voluntary effort or muscle contraction.1The original application of passive movement was therapist-guided limb manipulation to increase range of motion and blood supply following acute and chronic injury.展开更多
Exposure to explosive shockwave often leads to blast-induced traumatic brain injury in military and civilian populations.Unprotected ears are most often damaged following exposure to blasts.Although there is an associ...Exposure to explosive shockwave often leads to blast-induced traumatic brain injury in military and civilian populations.Unprotected ears are most often damaged following exposure to blasts.Although there is an association between tympanic membrane perforation and TBI in blast exposure victims,little is known about how and to what extent blast energy is transmitted to the central nervous system via the external ear canal.The present study investigated whether exposure to blasts directed through the ear canal causes brain injury in LongEvans rats.Animals were exposed to a single blast(0–30 pounds per square inch(psi))through the ear canal,and brain injury was evaluated by histological and behavioral outcomes at multiple time-points.Blast exposure not only caused tympanic membrane perforation but also produced substantial neuropathological changes in the brain,including increased expression of c-Fos,induction of a profound chronic neuroinflammatory response,and apoptosis of neurons.The blast-induced injury was not limited only to the brainstem most proximal to the source of the blast,but also affected the forebrain including the hippocampus,amygdala and the habenula,which are all involved in cognitive functions.Indeed,the animals exhibited long-term neurological deficits,including signs of anxiety in open field tests 2 months following blast exposure,and impaired learning and memory in an 8-arm maze 12 months following blast exposure.These results suggest that the unprotected ear canal provides a locus for blast waves to cause TBI.This study was approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center(Animal protocol#0932 E,approval date:September 30,2016 and 0932 F,approval date:September 27,2019).展开更多
Previous reports showed that decreased histone deacetylase activity significantly potentiated the rewarding effects of psychostimulants, and that encoding of the 5-HT3 receptor by the htr3a gene was related to ethanol...Previous reports showed that decreased histone deacetylase activity significantly potentiated the rewarding effects of psychostimulants, and that encoding of the 5-HT3 receptor by the htr3a gene was related to ethanol-seeking behavior. However, the effects of a histone deacetylase inhibitor on ethanol-seeking behavior and epigenetic regulation of htr3a mRNA expression after chronic ethanol exposure are not fully understood. Using quantitative reverse transcription-polymerase chain reaction and chromatin immunoprecipitation analysis, we investigated the effects of chronic ethanol exposure and its interaction with a histone deacetylase inhibitor on histone-acetylation-mediated changes in htr3a mRNA expression in the htr3a promoter region. The conditioned place preference procedure was used to evaluate ethanol-seeking behavior. Chronic exposure to ethanol effectively elicited place conditioning. In the prefrontal cortex, the acetylation of H3K9 and htr3a mRNA expression in the htr3a promoter region were significantly higher in the ethanol group than in the saline group. The histone deacetylase inhibitor sodium butyrate potentiated the effects of ethanol on htr3a mRNA expression and enhanced ethanol-induced conditioned place preferences. These results suggest that ethanol upregulates htr3a levels through mechanisms involving H3K9 acetylation, and that histone acetylation may be a therapeutic target for treating ethanol abuse.展开更多
Blast overpressure has become an increasing cause of brain injuries in both military and civilian populations. Though blast＇s direct effects on the cochlea and vestibular organs are active areas of study, little atte...Blast overpressure has become an increasing cause of brain injuries in both military and civilian populations. Though blast＇s direct effects on the cochlea and vestibular organs are active areas of study, little attention has been given to the ear＇s contribution to the overall spectrum of blast injury. Acute auto- nomic responses to blast exposure, including bradycardia and hypotension, can cause hypoxia and contribute to blast-induced neurotrauma. Existing literature suggests that these autonomic responses are elicited through blast impacting the thorax and lungs. We hypothesize that the unprotected ear also provides a vulnerable locus for blast to cause autonomic responses. We designed a blast generator that delivers controlled overpressure waves into the ear canal without impacting surrounding tissues in order to study the ear＇s specific contribution to blast injury. Anesthetized adult rats＇ left ears were exposed to a single blast wave ranging from 0 to 110 PSI （0-758 kPa）. Blast exposed rats exhibited decreased heart rates and blood pressures with increased blast intensity, similar to results gathered using shock tubes and whole-body exposure in the literature. While rats exposed to blasts below 50 PSI （345 kPa） exhibited increased respiratory rate with increased blast intensity, some rats exposed to blasts higher than 50 PSI （345 kPa） stopped breathing immediately and ultimately died. These autonomic responses were significantly reduced in vagally denervated rats, again similar to whole-body exposure literature. These results support the hypothesis that the unprotected ear contributes to the autonomic responses to blast.展开更多
Elevated levels of γ-synuclein(γ-syn)expression have been noted in the progression of glioblastomas,and also in the cerebrospinal fluid of patients diagnosed with neurodegenerative diseases.γ-Syn can be either inte...Elevated levels of γ-synuclein(γ-syn)expression have been noted in the progression of glioblastomas,and also in the cerebrospinal fluid of patients diagnosed with neurodegenerative diseases.γ-Syn can be either internalized from the extracellular milieu or expressed endogenously by human cortical astrocytes.Internalizedγ-syn results in increased cellular proliferation,brain derived neurotrophic factor release and astroprotection.However,the function of endogenousγ-syn in primary astrocytes,and the relationship to these two opposing disease states are unknown.γ-Syn is expressed by astrocytes in the human cortex,and to gain a better understanding of the role of endogenous γ-syn,primary human cortical astrocytes were treated with chimera RNA interference(RNAi)targeting γ-syn after release from cell synchronization.Quantitative polymerase chain reaction analysis demonstrated an increase in endogenousγ-syn expression 48 hours after release from cell synchronization,while RNAi reduced γ-syn expression to control levels.Immunocytochemistry of Ki67 and 5-bromodeoxyuridine showed chimera RNAi γ-syn knockdown reduced cellular proliferation at 24 and 48 hours after release from cell synchronization.To further investigate the consequence of γ-syn knockdown on the astrocytic cell cycle,phosphorylated histone H3 pSer10(pHH3)and phosphorylated cyclin dependent kinase-2 pTyr15(pCDK2)levels were observed via western blot analysis.The results revealed an elevated expression of pHH3,but not pCDK2,indicating γ-syn knockdown leads to disruption of the cell cycle and chromosomal compaction after 48 hours.Subsequently,flow cytometry with propidium iodide determined that increases in apoptosis coincided with γ-syn knockdown.Therefore,γ-syn exerts its effect to allow normal astrocytic progression through the cell cycle,as evidenced by decreased proliferation marker expression,increased pHH3,and mitotic catastrophe after knockdown.In this study,we demonstrated that the knockdown of γ-syn within primary human cortical astrocytes using chimera RNAi leads to cell cycle disruption and apoptosis,indicating an essential role for γ-syn in regulating normal cell division in astrocytes.Therefore,disruption to γ-syn function would influence astrocytic proliferation,and could be an important contributor to neurological diseases.展开更多
Acquired neurological injuries initiate a pathological cascade of secondary injury processes,including inflammation,which continue for days to weeks following injury.Injury-induced neuroinflammation acts as a host def...Acquired neurological injuries initiate a pathological cascade of secondary injury processes,including inflammation,which continue for days to weeks following injury.Injury-induced neuroinflammation acts as a host defense mechanism contributing to the neutralization of the insult（removing offending factors）and restoring structure and function of the brain（establish homeostasis）.The timing of these protective functions of the immune response is vital,since chronic inflammation展开更多
Background:There is a growing interest to understand the neurobiological mechanisms that drive the positive associations of physical activity and fitness with measures of cognitive performance.To better understand tho...Background:There is a growing interest to understand the neurobiological mechanisms that drive the positive associations of physical activity and fitness with measures of cognitive performance.To better understand those mechanisms,several studies have employed eye-based measures(e.g., eye movement measures such as saccades,pupillary measures such as pupil dilation,and vascular measures such as retinal vessel diameter)deemed to be proxies for specific neurobiological mechanisms.However,there is currently no systematic review providing a comprehensive overview of these studies in the field of exercise-cognition science.Thus,this review aimed to address that gap in the literature.Methods:To identify eligible studies,we searched 5 electronic databases on October 23,2022.Two researchers independently extracted data and assessed the risk of bias using a modified version of the Tool for the assEssment of Study qualiTy and reporting in EXercise(TESTEX scale,for interventional studies) and the critical appraisal tool from the Joanna Briggs Institute(for cross-sectional studies).Results:Our systematic review(n=35 studies) offers the following main findings:(a) there is insufficient evidence available to draw solid conclusions concerning gaze-fixation-based measures;(b) the evidence that pupillometric measures,which are a proxy for the noradrenergic system,can explain the positive effect of acute exercise and cardiorespiratory fitness on cognitive performance is mixed;(c) physical training-or fitness-related changes of the cerebrovascular system(operationalized via changes in retinal vasculature) are,in general,positively associated with cognitive performance improvements;(d) acute and chronic physical exercises show a positive effect based on an oculomotor-based measure function(operationalized via antisaccade tasks);and(e) the positive association between cardiorespiratory fitness and cognitive performance is partly mediated by the dopaminergic system(operationalized via spontaneous eye-blink rate).Conclusion:This systematic review offers confirmation that eye-based measures can provide valuable insigt into the neurobiological mechanisms that may drive positive associations between physical activity and fitness and measures of cognitive performance.However,due to the limited number of studies utilizing specific methods for obtaining eye-based measures(e.g.,pupillometry,retinal vessel analysis,spontaneous eye blink rate) or investigating a possible dose-response relationship,further research is necessary before more nuanced conclusions can be drawn.Given that eye-based measures are economical and non-invasive,we hope this review will foster the future application of eye-based measures in the field of exercise-cognition science.展开更多
Spinal cord injury can lead to severe motor,sensory and autonomic dysfunction.Currently,there is no effective treatment for the injured spinalcord.The transplantation of Schwann cells,neural stem cells or progenitor c...Spinal cord injury can lead to severe motor,sensory and autonomic dysfunction.Currently,there is no effective treatment for the injured spinalcord.The transplantation of Schwann cells,neural stem cells or progenitor cells,olfactory ensheathing cells,oligodendrocyte precursor cells and mesenchymal stem cells has been investigated as potential therapies for spinal cord injury.However,little is known about the mechanisms through which these individual cell types promote repair and functional improvements.The five most commonly proposed mechanisms include neuroprotection,immunomodulation,axon regeneration,neuronal relay formation and myelin regeneration.A better understanding of the mechanisms whereby these cells promote functional improvements,as well as an appreciation of the obstacles in implementing these therapies and effectively modeling spinal cord injury,will be important to make cell transplantation a viable clinical option and may lead to the development of more targeted therapies.展开更多
Most conceptual and computational models assume that synaptic transmission is reliable, a simplification rarely substantiated by data. The functional consequences of the recruitment of high and low initial release pro...Most conceptual and computational models assume that synaptic transmission is reliable, a simplification rarely substantiated by data. The functional consequences of the recruitment of high and low initial release probability synapses on the reliability and precision of their postsynaptic targets are studied in a multi-compartmental model of a hippocampal CA1 pyramidal cell. We show that changes in the firing rate of CA3 afferent inputs (rate remapping) are not reflected in the firing rate of the CA1 cell but in the reliability and precise timing of some of its action potentials, suggesting that a signature of remapping may be found in the precise spike timing of CA1. Our results suggest that about half of the action potentials produced by a CA1 cell can potentially carry reliable information in their precise timing with about 25 ms precision, a time scale on the order of the gamma cycle. We show further that reliable events were primarily elicited by CA3 synapses in a state of low probability of release. Overall, our results suggest that the non-uniform distribution of initial release probabilities observed experimentally achieves an optimum yielding simultaneously high precision and high reliability, and allows large populations of CA3 synapses to contribute to the production of reliable CA1 spiking events.展开更多
Obesity and aging are two important epidemic factors for metabolic syndrome and many other health issues,which contribute to devastating diseases such as cardiovascular diseases,stroke and cancers.The brain plays a ce...Obesity and aging are two important epidemic factors for metabolic syndrome and many other health issues,which contribute to devastating diseases such as cardiovascular diseases,stroke and cancers.The brain plays a central role in controlling metabolic physiology in that it integrates information from other metabolic organs,sends regulatory projections and orchestrates the whole-body function.Emerging studies suggest that brain dysfunction in sensing various internal cues or processing external cues may have profound effects on metabolic and other physiological functions.This review highlights brain dysfunction linked to genetic mutations,sex,brain inflammation,microbiota,stress as causes for whole-body pathophysiology,arguing brain dysfunction as a root cause for the epidemic of aging and obesity-related disorders.We also speculate key issues that need to be addressed on how to reveal relevant brain dysfunction that underlines the development of these disorders and diseases in order to develop new treatment strategies against these health problems.展开更多
Presenilins(PSs)are the catalytic core of γ-secretase complex.However,the mechanism of FAD-associated PS mutations in AD pathogenesis still remains elusive.Here we review the general biology and mechanism of γ-secre...Presenilins(PSs)are the catalytic core of γ-secretase complex.However,the mechanism of FAD-associated PS mutations in AD pathogenesis still remains elusive.Here we review the general biology and mechanism of γ-secretase and focus on the catalytic components–presenilins and their biological functions and contributions to the AD pathogenesis.The functions of presenilins are divided into γ-secretase dependent and γ-secretase independent ones.The γ-secretase dependent functions of presenilins are exemplified by the sequential cleavages in the processing of APP and Notch;the γ-secretase independent functions of presenilins include stabilizing β-catenin in Wnt signaling pathway,regulating calcium homeostasis and their interaction with synaptic transmission.展开更多
There has been a surge of diagnosis of autism spectrum disorders （ASD） over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, res...There has been a surge of diagnosis of autism spectrum disorders （ASD） over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.展开更多
文摘1.IntroductionPassive movement is a 200+year-old manipulation involving the external movement of an individuals’limbs or body absent voluntary effort or muscle contraction.1The original application of passive movement was therapist-guided limb manipulation to increase range of motion and blood supply following acute and chronic injury.
基金supported by the National Institutes of Health(NIH)grants R21 DC017293(to HZ,WZ),R01 DC018919(to HZ,WZ),AG050049(to FF),AG057842(to FF),P20GM104357(to FF,RJR),and HL138685(to RJR)。
文摘Exposure to explosive shockwave often leads to blast-induced traumatic brain injury in military and civilian populations.Unprotected ears are most often damaged following exposure to blasts.Although there is an association between tympanic membrane perforation and TBI in blast exposure victims,little is known about how and to what extent blast energy is transmitted to the central nervous system via the external ear canal.The present study investigated whether exposure to blasts directed through the ear canal causes brain injury in LongEvans rats.Animals were exposed to a single blast(0–30 pounds per square inch(psi))through the ear canal,and brain injury was evaluated by histological and behavioral outcomes at multiple time-points.Blast exposure not only caused tympanic membrane perforation but also produced substantial neuropathological changes in the brain,including increased expression of c-Fos,induction of a profound chronic neuroinflammatory response,and apoptosis of neurons.The blast-induced injury was not limited only to the brainstem most proximal to the source of the blast,but also affected the forebrain including the hippocampus,amygdala and the habenula,which are all involved in cognitive functions.Indeed,the animals exhibited long-term neurological deficits,including signs of anxiety in open field tests 2 months following blast exposure,and impaired learning and memory in an 8-arm maze 12 months following blast exposure.These results suggest that the unprotected ear canal provides a locus for blast waves to cause TBI.This study was approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center(Animal protocol#0932 E,approval date:September 30,2016 and 0932 F,approval date:September 27,2019).
基金supported by the National Key Basic Research and Development Program(NKBRDP)of China(No.2009CB522000)the National Natural Science Foundation of China(No.30971050)+1 种基金the State Key Program of the National Natural Science of China(No.81130020)the Key Program on Basic Science of Henan Science and Technology Department(No.094200510005)
文摘Previous reports showed that decreased histone deacetylase activity significantly potentiated the rewarding effects of psychostimulants, and that encoding of the 5-HT3 receptor by the htr3a gene was related to ethanol-seeking behavior. However, the effects of a histone deacetylase inhibitor on ethanol-seeking behavior and epigenetic regulation of htr3a mRNA expression after chronic ethanol exposure are not fully understood. Using quantitative reverse transcription-polymerase chain reaction and chromatin immunoprecipitation analysis, we investigated the effects of chronic ethanol exposure and its interaction with a histone deacetylase inhibitor on histone-acetylation-mediated changes in htr3a mRNA expression in the htr3a promoter region. The conditioned place preference procedure was used to evaluate ethanol-seeking behavior. Chronic exposure to ethanol effectively elicited place conditioning. In the prefrontal cortex, the acetylation of H3K9 and htr3a mRNA expression in the htr3a promoter region were significantly higher in the ethanol group than in the saline group. The histone deacetylase inhibitor sodium butyrate potentiated the effects of ethanol on htr3a mRNA expression and enhanced ethanol-induced conditioned place preferences. These results suggest that ethanol upregulates htr3a levels through mechanisms involving H3K9 acetylation, and that histone acetylation may be a therapeutic target for treating ethanol abuse.
基金supported by the United States National Institutes of Health[grant numbers:NIDCD R01DC014930(WZ),NIDCD R01DC012060(HZ)]
文摘Blast overpressure has become an increasing cause of brain injuries in both military and civilian populations. Though blast＇s direct effects on the cochlea and vestibular organs are active areas of study, little attention has been given to the ear＇s contribution to the overall spectrum of blast injury. Acute auto- nomic responses to blast exposure, including bradycardia and hypotension, can cause hypoxia and contribute to blast-induced neurotrauma. Existing literature suggests that these autonomic responses are elicited through blast impacting the thorax and lungs. We hypothesize that the unprotected ear also provides a vulnerable locus for blast to cause autonomic responses. We designed a blast generator that delivers controlled overpressure waves into the ear canal without impacting surrounding tissues in order to study the ear＇s specific contribution to blast injury. Anesthetized adult rats＇ left ears were exposed to a single blast wave ranging from 0 to 110 PSI （0-758 kPa）. Blast exposed rats exhibited decreased heart rates and blood pressures with increased blast intensity, similar to results gathered using shock tubes and whole-body exposure in the literature. While rats exposed to blasts below 50 PSI （345 kPa） exhibited increased respiratory rate with increased blast intensity, some rats exposed to blasts higher than 50 PSI （345 kPa） stopped breathing immediately and ultimately died. These autonomic responses were significantly reduced in vagally denervated rats, again similar to whole-body exposure literature. These results support the hypothesis that the unprotected ear contributes to the autonomic responses to blast.
基金supported by grants from the Connecticut Partnership in Innovation and Education(PIE)Fellowship(to TL)the University of Hartford College of Arts and Sciences Dean’s Fund(to TL,FA,AOK)
文摘Elevated levels of γ-synuclein(γ-syn)expression have been noted in the progression of glioblastomas,and also in the cerebrospinal fluid of patients diagnosed with neurodegenerative diseases.γ-Syn can be either internalized from the extracellular milieu or expressed endogenously by human cortical astrocytes.Internalizedγ-syn results in increased cellular proliferation,brain derived neurotrophic factor release and astroprotection.However,the function of endogenousγ-syn in primary astrocytes,and the relationship to these two opposing disease states are unknown.γ-Syn is expressed by astrocytes in the human cortex,and to gain a better understanding of the role of endogenous γ-syn,primary human cortical astrocytes were treated with chimera RNA interference(RNAi)targeting γ-syn after release from cell synchronization.Quantitative polymerase chain reaction analysis demonstrated an increase in endogenousγ-syn expression 48 hours after release from cell synchronization,while RNAi reduced γ-syn expression to control levels.Immunocytochemistry of Ki67 and 5-bromodeoxyuridine showed chimera RNAi γ-syn knockdown reduced cellular proliferation at 24 and 48 hours after release from cell synchronization.To further investigate the consequence of γ-syn knockdown on the astrocytic cell cycle,phosphorylated histone H3 pSer10(pHH3)and phosphorylated cyclin dependent kinase-2 pTyr15(pCDK2)levels were observed via western blot analysis.The results revealed an elevated expression of pHH3,but not pCDK2,indicating γ-syn knockdown leads to disruption of the cell cycle and chromosomal compaction after 48 hours.Subsequently,flow cytometry with propidium iodide determined that increases in apoptosis coincided with γ-syn knockdown.Therefore,γ-syn exerts its effect to allow normal astrocytic progression through the cell cycle,as evidenced by decreased proliferation marker expression,increased pHH3,and mitotic catastrophe after knockdown.In this study,we demonstrated that the knockdown of γ-syn within primary human cortical astrocytes using chimera RNAi leads to cell cycle disruption and apoptosis,indicating an essential role for γ-syn in regulating normal cell division in astrocytes.Therefore,disruption to γ-syn function would influence astrocytic proliferation,and could be an important contributor to neurological diseases.
文摘Acquired neurological injuries initiate a pathological cascade of secondary injury processes,including inflammation,which continue for days to weeks following injury.Injury-induced neuroinflammation acts as a host defense mechanism contributing to the neutralization of the insult（removing offending factors）and restoring structure and function of the brain（establish homeostasis）.The timing of these protective functions of the immune response is vital,since chronic inflammation
文摘Background:There is a growing interest to understand the neurobiological mechanisms that drive the positive associations of physical activity and fitness with measures of cognitive performance.To better understand those mechanisms,several studies have employed eye-based measures(e.g., eye movement measures such as saccades,pupillary measures such as pupil dilation,and vascular measures such as retinal vessel diameter)deemed to be proxies for specific neurobiological mechanisms.However,there is currently no systematic review providing a comprehensive overview of these studies in the field of exercise-cognition science.Thus,this review aimed to address that gap in the literature.Methods:To identify eligible studies,we searched 5 electronic databases on October 23,2022.Two researchers independently extracted data and assessed the risk of bias using a modified version of the Tool for the assEssment of Study qualiTy and reporting in EXercise(TESTEX scale,for interventional studies) and the critical appraisal tool from the Joanna Briggs Institute(for cross-sectional studies).Results:Our systematic review(n=35 studies) offers the following main findings:(a) there is insufficient evidence available to draw solid conclusions concerning gaze-fixation-based measures;(b) the evidence that pupillometric measures,which are a proxy for the noradrenergic system,can explain the positive effect of acute exercise and cardiorespiratory fitness on cognitive performance is mixed;(c) physical training-or fitness-related changes of the cerebrovascular system(operationalized via changes in retinal vasculature) are,in general,positively associated with cognitive performance improvements;(d) acute and chronic physical exercises show a positive effect based on an oculomotor-based measure function(operationalized via antisaccade tasks);and(e) the positive association between cardiorespiratory fitness and cognitive performance is partly mediated by the dopaminergic system(operationalized via spontaneous eye-blink rate).Conclusion:This systematic review offers confirmation that eye-based measures can provide valuable insigt into the neurobiological mechanisms that may drive positive associations between physical activity and fitness and measures of cognitive performance.However,due to the limited number of studies utilizing specific methods for obtaining eye-based measures(e.g.,pupillometry,retinal vessel analysis,spontaneous eye blink rate) or investigating a possible dose-response relationship,further research is necessary before more nuanced conclusions can be drawn.Given that eye-based measures are economical and non-invasive,we hope this review will foster the future application of eye-based measures in the field of exercise-cognition science.
文摘Spinal cord injury can lead to severe motor,sensory and autonomic dysfunction.Currently,there is no effective treatment for the injured spinalcord.The transplantation of Schwann cells,neural stem cells or progenitor cells,olfactory ensheathing cells,oligodendrocyte precursor cells and mesenchymal stem cells has been investigated as potential therapies for spinal cord injury.However,little is known about the mechanisms through which these individual cell types promote repair and functional improvements.The five most commonly proposed mechanisms include neuroprotection,immunomodulation,axon regeneration,neuronal relay formation and myelin regeneration.A better understanding of the mechanisms whereby these cells promote functional improvements,as well as an appreciation of the obstacles in implementing these therapies and effectively modeling spinal cord injury,will be important to make cell transplantation a viable clinical option and may lead to the development of more targeted therapies.
文摘Most conceptual and computational models assume that synaptic transmission is reliable, a simplification rarely substantiated by data. The functional consequences of the recruitment of high and low initial release probability synapses on the reliability and precision of their postsynaptic targets are studied in a multi-compartmental model of a hippocampal CA1 pyramidal cell. We show that changes in the firing rate of CA3 afferent inputs (rate remapping) are not reflected in the firing rate of the CA1 cell but in the reliability and precise timing of some of its action potentials, suggesting that a signature of remapping may be found in the precise spike timing of CA1. Our results suggest that about half of the action potentials produced by a CA1 cell can potentially carry reliable information in their precise timing with about 25 ms precision, a time scale on the order of the gamma cycle. We show further that reliable events were primarily elicited by CA3 synapses in a state of low probability of release. Overall, our results suggest that the non-uniform distribution of initial release probabilities observed experimentally achieves an optimum yielding simultaneously high precision and high reliability, and allows large populations of CA3 synapses to contribute to the production of reliable CA1 spiking events.
基金the National Key R&D Program of China(2019YFA0801900,2018YFA0800300)the National Natural Science Foundation of China(91749104 and 31971074)+2 种基金the Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee(18140901300)the Open Research Fund of the National Key Laboratory of Genetic Engineering(SKLGE1803)the Shanghai Pujiang Talent Project(18PJ1400700)to T.L.,and Dr.Tong is the holder of Cullen Chair in Molecular Medicine at McGovern Medical School of UTHealth.
文摘Obesity and aging are two important epidemic factors for metabolic syndrome and many other health issues,which contribute to devastating diseases such as cardiovascular diseases,stroke and cancers.The brain plays a central role in controlling metabolic physiology in that it integrates information from other metabolic organs,sends regulatory projections and orchestrates the whole-body function.Emerging studies suggest that brain dysfunction in sensing various internal cues or processing external cues may have profound effects on metabolic and other physiological functions.This review highlights brain dysfunction linked to genetic mutations,sex,brain inflammation,microbiota,stress as causes for whole-body pathophysiology,arguing brain dysfunction as a root cause for the epidemic of aging and obesity-related disorders.We also speculate key issues that need to be addressed on how to reveal relevant brain dysfunction that underlines the development of these disorders and diseases in order to develop new treatment strategies against these health problems.
基金This work was supported by Canadian Institutes of Health Research(CIHR)Operating Grant CCI-117952W.S.was the holder of the Tier 1 Canada Research Chair in Alzheimer's Disease+1 种基金S.Z.was the recipient of the Chinese Scholarship Council awardM.Z.is supported by UBC 4YF Scholarship.
文摘Presenilins(PSs)are the catalytic core of γ-secretase complex.However,the mechanism of FAD-associated PS mutations in AD pathogenesis still remains elusive.Here we review the general biology and mechanism of γ-secretase and focus on the catalytic components–presenilins and their biological functions and contributions to the AD pathogenesis.The functions of presenilins are divided into γ-secretase dependent and γ-secretase independent ones.The γ-secretase dependent functions of presenilins are exemplified by the sequential cleavages in the processing of APP and Notch;the γ-secretase independent functions of presenilins include stabilizing β-catenin in Wnt signaling pathway,regulating calcium homeostasis and their interaction with synaptic transmission.
文摘There has been a surge of diagnosis of autism spectrum disorders （ASD） over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.
