Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypot...Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypothalamic tract,which projects to the suprachiasmatic nucleus.Notably,Alzheimer’s disease hallmarks,including amyloid-β,are present in the retinas of Alzheimer’s disease patients,followed/associated by structural and functional disturbances.However,the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in Alzheimer’s disease is not fully understood,although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.展开更多
The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centere...The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease neuropathology.The examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer’s disease progression.The entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the hippocampus.Notably,ANK1 hypermethylation,a protein implicated in neurofibrillary tangle formation,was recurrently identified in the entorhinal cortex.Further,the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3,RHBDF2,and MCF2L,potentially influencing neuroinflammatory processes.The complex role of BIN1 in late-onset Alzheimer’s disease is underscored by its association with altered methylation patterns.Despite the disparities across studies,these findings highlight the intricate interplay between epigenetic modifications and Alzheimer’s disease pathology.Future research efforts should address methodological variations,incorporate diverse cohorts,and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer’s disease progression.展开更多
Ketamine,a multimodal dissociative anesthetic,produces powerful analgesia at subanesthetic doses in traumatically injured patients.As ketamine does not induce respiratory depression or hemodynamic instability,the Comm...Ketamine,a multimodal dissociative anesthetic,produces powerful analgesia at subanesthetic doses in traumatically injured patients.As ketamine does not induce respiratory depression or hemodynamic instability,the Committee on Tactical Combat Casualty Care for the US military recommends the use of subanesthetic doses of ketamine for acute pain management(Butler et al.,2014).Additionally,ketamine may have immunomodulatory effects after injury at subanesthetic doses,mediating the balance of pro-and anti-inflammatory processes(Loix et al.,2011;De Kock et al.,2013).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
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
The ears are air-filled structures that are directly impacted during blast exposure.In addition to hearing loss and tinnitus,blast victims often complain of vertigo,dizziness and unsteady posture,suggesting that blast...The ears are air-filled structures that are directly impacted during blast exposure.In addition to hearing loss and tinnitus,blast victims often complain of vertigo,dizziness and unsteady posture,suggesting that blast exposure induces damage to the vestibular end organs in the inner ear.However,the underlying mechanisms remain to be elucidated.In this report,single vestibular afferent activity and the vestibuloocular reflex(VOR)were investigated before and after exposure to blast shock waves(~20 PSI)delivered into the left external ear canals of anesthetized rats.Single vestibular afferent activity was recorded from the superior branch of the left vestibular nerves of the blast-treated and control rats one day after blast exposure.Blast exposure reduced the spontaneous discharge rates of the otolith and canal afferents.Blast exposure also reduced the sensitivity of irregular canal afferents to sinusoidal head rotation at 0.5e2Hz.Blast exposure,however,resulted in few changes in the VOR responses to sinusoidal head rotation and translation.To the best of our knowledge,this is the first study that reports blast exposure-induced damage to vestibular afferents in an animal model.These results provide insights that may be helpful in developing biomarkers for early diagnosis of blast-induced vestibular deficits in military and civilian populations.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
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
Traumatic brain injury(TBI)remains one of the leading causes of disability and death in infants and children.Studies have demonstrated that the youngest age group(especially≤4 years old)exhibit worse functional o...Traumatic brain injury(TBI)remains one of the leading causes of disability and death in infants and children.Studies have demonstrated that the youngest age group(especially≤4 years old)exhibit worse functional outcome following moderate to severe TBI compared to older children or adults(Anderson et al.,2005;Emami et al.,2017).These data suggest that age-at-injury may be an important determinant of outcome,展开更多
Great advances in retinal ganglion cells survival(RGCs),optic nerve preservation and regeneration have been made in the past 15years.Nowadays,we know that RGCs are capable of regenerating the full length of the opti...Great advances in retinal ganglion cells survival(RGCs),optic nerve preservation and regeneration have been made in the past 15years.Nowadays,we know that RGCs are capable of regenerating the full length of the optic nerve,cross the chiasm,enter the brain and reinnervate visual targets.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
Quantitative real-time reverse transcription-polymerase chain reaction (qPCR) is widely used to investigate transcriptional changes following experimental manipulations to the nervous system. Despite the widespread ...Quantitative real-time reverse transcription-polymerase chain reaction (qPCR) is widely used to investigate transcriptional changes following experimental manipulations to the nervous system. Despite the widespread utilization of qPCR, the interpretation of results is marred by the lack of a suitable reference gene due to the dynamic nature of endogenous transcription. To address this inherent deficiency, we investigated the use of an exogenous spike-in mRNA, luciferase, as an internal reference gene for the 2ct normalization method. To induce dynamic transcription, we systemically administered capsaicin, a neurotoxJn selective for C-type sensory neurons expressing the TRPV-1 receptor, to adult male Sprague-Dawley rats. We later isolated nodose ganglia for qPCR analysis with the reference being either exogenous luciferase mRNA or the commonly used endogenous reference 13-111 tubulin. The exogenous luciferase mRNA reference clearly demonstrated the dynamic expression of the endogenous reference. Furthermore, variability of the endogenous reference would lead to misinterpretation of other genes of interest. In conclusion, traditional reference genes are often unstable under physiologically normal situations, and certainly unstable following the damage to the nervous system. The use of exogenous spike-in reference provides a consistent and easily implemented alternative for the analysis of qPCR data.展开更多
Multiple sclerosis (MS) currently affects ~2.5 million people worldwide. MS is typically diagnosed in young adults and is usually not fatal, meaning people live long lives with MS. Affected individuals usually suffer ...Multiple sclerosis (MS) currently affects ~2.5 million people worldwide. MS is typically diagnosed in young adults and is usually not fatal, meaning people live long lives with MS. Affected individuals usually suffer from progressive physical and/or cognitive disability, often including fatigue (89.6%), depression (53.9%), memory loss (49.0%), motor or sensory dysfunction (76.4%, 70.4%) and urinary incontinence (50.8%).展开更多
The mechanisms that regulate neural stem cell(NSC)lineage progression and maintain NSCs within diffe rent domains of the adult neural stem cell niche,the subventricular zone are not well defined.Quiescent NSCs are arr...The mechanisms that regulate neural stem cell(NSC)lineage progression and maintain NSCs within diffe rent domains of the adult neural stem cell niche,the subventricular zone are not well defined.Quiescent NSCs are arranged at the apical ventricular wall,while mitotically activated NSCs are found in the basal,vascular region of the subventricular zone.Here,we found that ADAM 10(a disintegrin and metalloproteinase 10)is essential in NSC association with the ventricular wall,and via this adhesion to the apical domain,ADAM10 regulates the switch from quiescent and undiffe rentiated NSC to an actively prolife rative and differentiating cell state.Processing of JAMC(junctional adhesion molecule C)by ADAM 10 increases Rap1 GAP activity.This molecular machinery promotes NSC transit from the apical to the basal compartment and subsequent lineage progression.Understanding the molecular mechanisms responsible for regulating the proper positioning of NSCs within the subventricular zone niche and lineage progression of NSCs could provide new targets for drug development to enhance the regenerative prope rties of neural tissue.展开更多
Stimulation of the vagus nerve has been previously reported to promote neural plasticity and neurogenesis in the brain. Several studies also revealed plastic changes in the spinal cord after injuries to somatosensory ...Stimulation of the vagus nerve has been previously reported to promote neural plasticity and neurogenesis in the brain. Several studies also revealed plastic changes in the spinal cord after injuries to somatosensory nerves originating from both the brachial and lumbo-sacral plexuses. However, the neurogenic responses of the brain to the injury of the viscerosensory innervation are not as yet well understood. In the present study, we investigated whether cells in the dentate gyrus of the hippocampus respond to a chemical and physical damage to the vagus nerve in the adult rat. Intraperitoneal capsaicin administration was used to damage non-myelinated vagal afferents while subdiaphragmatic vagotomy was used to damage both the myelinated and non-myelinated vagal afferents. The 5-bromo-2-deoxyuridine (BrdU) incorporation together with cell-specific markers was used to study neural proliferation in subgranular zone, granule cell layer, molecular layer and hilus of the dentate gyrus. Microglia activation was determined by quantifying changes in the intensity of fluorescent staining with a primary antibody against ionizing calcium adapter-binding molecule 1. Results revealed that vagotomy decreased BrdU incorporation in the hilus 15 days after injury compared to the capsaicin group. Capsaicin administration decreased BrdU incorporation in the granular cell layer 60 days after the treatment. Capsaicin decreased the number of doublecortin-expressing cells in the dentate gyrus, whereas vagotomy did not alter the expression of doublecortin in the hippocampus. Both the capsaicin- and the vagotomy-induced damage to the vagus nerve decreased microglia activation in the hippocampus at 15 days after the injury. At 30 days post injury, capsaicin-treated and vagotomized rats revealed significantly more activated microglia. Our findings show that damage to the subdiaphragmatic vagus in adult rats is followed by microglia activation and long-lasting changes in the dentate gyrus, leading to alteration of neurogenesis.展开更多
Neurological disorders are amongst the most widely studied human aliments.Yet,they are also one of the most poorly understood.Although most of these disorders are polygenic,genotype still plays an important role in th...Neurological disorders are amongst the most widely studied human aliments.Yet,they are also one of the most poorly understood.Although most of these disorders are polygenic,genotype still plays an important role in their etiologies.For example,in schizophrenia and autism spectrum disorders,there is a 40-60%concordance rate in monozygotic twins,with 60-90%heritability(Burmeister et al.,2008).However,the mechanisms by which multiple genes and their genomic variations influence the phenotypes of the disorders remain to be understood. The complexities of the disorders are tur- ther compounded by the individual rarity of the genomic variations and their variable penetrance (Cook and Scherer, 2008). Thus, conventional disease modeling, such as gene knockout in cells or in animals, to attain the desired disease genotype may not be the most suitable platform for tackling most neurological disorders.展开更多
The purpose of this study was to determine if the substituted pyrimidine, CXB-909 (formerly known as KP544) which has been shown to amplify the effects of nerve growth factor in elevating choline-acetyltransferase act...The purpose of this study was to determine if the substituted pyrimidine, CXB-909 (formerly known as KP544) which has been shown to amplify the effects of nerve growth factor in elevating choline-acetyltransferase activity in vitro, could attenuate memory deficits in the mu-p-75 saporin injected mouse model of Alzheimer’s disease (AD). Seventy-one, seven-week old C57/BL6 mice received daily oral intubation of 10, 15, or 20 mg/kg CXB-909, or vehicle (0.5% methylcellulose solution), which continued for 32 days. At postnatal week nine, mice received bilateral intra-cerebroventricular injections of mu-p-75 saporin, or sterile phosphate buffered saline. Seven days after surgery, mice were trained for two days, on a cued-platform version of the Morris water maze task, and then tested on a four-day hidden-platform version, followed by a one-day probe version of this task. Mice injected with mu-p-75 saporin, had increased latency to find the hidden-platform compared to sham mice. Furthermore, mice treated with CXB-909 at the 10, and 15 mg/kg doses, significantly reduced their latency to reach the hidden-platform, compared to vehicle-treated mice given mu-p-75 saporin. These results suggest that CXB-909 can attenuate memory deficits in the mu-p-75 saporin injected mouse model of AD.展开更多
BACKGROUND The coronavirus disease 2019(COVID-19)pandemic is an unprecedented challenge for public health and has caused the loss of millions of lives worldwide.Hospital workers play a key role in averting the collaps...BACKGROUND The coronavirus disease 2019(COVID-19)pandemic is an unprecedented challenge for public health and has caused the loss of millions of lives worldwide.Hospital workers play a key role in averting the collapse of the health system,but the mental health of many has deteriorated during the pandemic.Few studies have been devoted to identifying the needs of workers on frontline duty.AIM To investigate dimensions of common emotional symptoms and associated predictors among Brazilian workers in a COVID-19 reference hospital.METHODS This is an observational study of the mental health of professionals in a COVID-19 hospital in the city of São Paulo.We invited all hospital employees to respond to an online survey between July and August 2020,during the first peak of the pandemic.Data of 1000 participants who completed the survey were analyzed(83.9%were women and 34.3%were aged 30 to 40).Hospital workers selfreported the presence of symptoms of depression,anxiety,trauma-related stress,and burnout through the Patient Health Questionnaire-9,the Generalized Anxiety Disorder-7,the Impact of Event Scale-Revised and the Mini-Z Burnout Assessment respectively.Responses were assembled and subjected to exploratory factor analysis to reveal workers’core emotional distress.Multiple linear regression models were subsequently carried out to estimate the likelihood of dimensions of distress using questions on personal motivation,threatening events,and institutional support.RESULTS Around one in three participants in our sample scored above the threshold of depression,anxiety,post-traumatic stress disorder,and burnout.The factor analysis revealed a three-factor structure that explained 58%of the total data variance.Core distressing emotional domains were avoidance and re-experience,depression-anxiety,and sleep changes.Regression analysis revealed that institutional support was a significant protective factor for each of these dimensions(βrange=-0.41 to-0.20,P<0.001).However,participants’personal motivation to work in healthcare service was not associated with these emotional domains.Moreover,the likelihood of presenting the avoidance and re-experience dimension was associated with having a family member or close friend be hospitalized or die due to COVID-19 and having faced an ethical conflict.CONCLUSION Distressing emotional domains among hospital workers were avoidance and re-experience,depression and anxiety,and sleep changes.Improving working conditions through institutional support could protect hospital workers'mental health during devastating public health crises.展开更多
文摘Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypothalamic tract,which projects to the suprachiasmatic nucleus.Notably,Alzheimer’s disease hallmarks,including amyloid-β,are present in the retinas of Alzheimer’s disease patients,followed/associated by structural and functional disturbances.However,the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in Alzheimer’s disease is not fully understood,although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.
文摘The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease neuropathology.The examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer’s disease progression.The entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the hippocampus.Notably,ANK1 hypermethylation,a protein implicated in neurofibrillary tangle formation,was recurrently identified in the entorhinal cortex.Further,the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3,RHBDF2,and MCF2L,potentially influencing neuroinflammatory processes.The complex role of BIN1 in late-onset Alzheimer’s disease is underscored by its association with altered methylation patterns.Despite the disparities across studies,these findings highlight the intricate interplay between epigenetic modifications and Alzheimer’s disease pathology.Future research efforts should address methodological variations,incorporate diverse cohorts,and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer’s disease progression.
文摘Ketamine,a multimodal dissociative anesthetic,produces powerful analgesia at subanesthetic doses in traumatically injured patients.As ketamine does not induce respiratory depression or hemodynamic instability,the Committee on Tactical Combat Casualty Care for the US military recommends the use of subanesthetic doses of ketamine for acute pain management(Butler et al.,2014).Additionally,ketamine may have immunomodulatory effects after injury at subanesthetic doses,mediating the balance of pro-and anti-inflammatory processes(Loix et al.,2011;De Kock et al.,2013).
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.
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.
文摘The ears are air-filled structures that are directly impacted during blast exposure.In addition to hearing loss and tinnitus,blast victims often complain of vertigo,dizziness and unsteady posture,suggesting that blast exposure induces damage to the vestibular end organs in the inner ear.However,the underlying mechanisms remain to be elucidated.In this report,single vestibular afferent activity and the vestibuloocular reflex(VOR)were investigated before and after exposure to blast shock waves(~20 PSI)delivered into the left external ear canals of anesthetized rats.Single vestibular afferent activity was recorded from the superior branch of the left vestibular nerves of the blast-treated and control rats one day after blast exposure.Blast exposure reduced the spontaneous discharge rates of the otolith and canal afferents.Blast exposure also reduced the sensitivity of irregular canal afferents to sinusoidal head rotation at 0.5e2Hz.Blast exposure,however,resulted in few changes in the VOR responses to sinusoidal head rotation and translation.To the best of our knowledge,this is the first study that reports blast exposure-induced damage to vestibular afferents in an animal model.These results provide insights that may be helpful in developing biomarkers for early diagnosis of blast-induced vestibular deficits in military and civilian populations.
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 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).
文摘Traumatic brain injury(TBI)remains one of the leading causes of disability and death in infants and children.Studies have demonstrated that the youngest age group(especially≤4 years old)exhibit worse functional outcome following moderate to severe TBI compared to older children or adults(Anderson et al.,2005;Emami et al.,2017).These data suggest that age-at-injury may be an important determinant of outcome,
文摘Great advances in retinal ganglion cells survival(RGCs),optic nerve preservation and regeneration have been made in the past 15years.Nowadays,we know that RGCs are capable of regenerating the full length of the optic nerve,cross the chiasm,enter the brain and reinnervate visual targets.
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.
基金This project was supported by the Washington State University Start-up Funds, George W. Bagby Research Fund
文摘Quantitative real-time reverse transcription-polymerase chain reaction (qPCR) is widely used to investigate transcriptional changes following experimental manipulations to the nervous system. Despite the widespread utilization of qPCR, the interpretation of results is marred by the lack of a suitable reference gene due to the dynamic nature of endogenous transcription. To address this inherent deficiency, we investigated the use of an exogenous spike-in mRNA, luciferase, as an internal reference gene for the 2ct normalization method. To induce dynamic transcription, we systemically administered capsaicin, a neurotoxJn selective for C-type sensory neurons expressing the TRPV-1 receptor, to adult male Sprague-Dawley rats. We later isolated nodose ganglia for qPCR analysis with the reference being either exogenous luciferase mRNA or the commonly used endogenous reference 13-111 tubulin. The exogenous luciferase mRNA reference clearly demonstrated the dynamic expression of the endogenous reference. Furthermore, variability of the endogenous reference would lead to misinterpretation of other genes of interest. In conclusion, traditional reference genes are often unstable under physiologically normal situations, and certainly unstable following the damage to the nervous system. The use of exogenous spike-in reference provides a consistent and easily implemented alternative for the analysis of qPCR data.
文摘Multiple sclerosis (MS) currently affects ~2.5 million people worldwide. MS is typically diagnosed in young adults and is usually not fatal, meaning people live long lives with MS. Affected individuals usually suffer from progressive physical and/or cognitive disability, often including fatigue (89.6%), depression (53.9%), memory loss (49.0%), motor or sensory dysfunction (76.4%, 70.4%) and urinary incontinence (50.8%).
基金National Institutes of Health(NIH)Grants R01 RMH099384(to AA)and T32GM008444(to NM)。
文摘The mechanisms that regulate neural stem cell(NSC)lineage progression and maintain NSCs within diffe rent domains of the adult neural stem cell niche,the subventricular zone are not well defined.Quiescent NSCs are arranged at the apical ventricular wall,while mitotically activated NSCs are found in the basal,vascular region of the subventricular zone.Here,we found that ADAM 10(a disintegrin and metalloproteinase 10)is essential in NSC association with the ventricular wall,and via this adhesion to the apical domain,ADAM10 regulates the switch from quiescent and undiffe rentiated NSC to an actively prolife rative and differentiating cell state.Processing of JAMC(junctional adhesion molecule C)by ADAM 10 increases Rap1 GAP activity.This molecular machinery promotes NSC transit from the apical to the basal compartment and subsequent lineage progression.Understanding the molecular mechanisms responsible for regulating the proper positioning of NSCs within the subventricular zone niche and lineage progression of NSCs could provide new targets for drug development to enhance the regenerative prope rties of neural tissue.
基金Washington State University Start-up Funds, George W. Bagby Research Fund and Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR)
文摘Stimulation of the vagus nerve has been previously reported to promote neural plasticity and neurogenesis in the brain. Several studies also revealed plastic changes in the spinal cord after injuries to somatosensory nerves originating from both the brachial and lumbo-sacral plexuses. However, the neurogenic responses of the brain to the injury of the viscerosensory innervation are not as yet well understood. In the present study, we investigated whether cells in the dentate gyrus of the hippocampus respond to a chemical and physical damage to the vagus nerve in the adult rat. Intraperitoneal capsaicin administration was used to damage non-myelinated vagal afferents while subdiaphragmatic vagotomy was used to damage both the myelinated and non-myelinated vagal afferents. The 5-bromo-2-deoxyuridine (BrdU) incorporation together with cell-specific markers was used to study neural proliferation in subgranular zone, granule cell layer, molecular layer and hilus of the dentate gyrus. Microglia activation was determined by quantifying changes in the intensity of fluorescent staining with a primary antibody against ionizing calcium adapter-binding molecule 1. Results revealed that vagotomy decreased BrdU incorporation in the hilus 15 days after injury compared to the capsaicin group. Capsaicin administration decreased BrdU incorporation in the granular cell layer 60 days after the treatment. Capsaicin decreased the number of doublecortin-expressing cells in the dentate gyrus, whereas vagotomy did not alter the expression of doublecortin in the hippocampus. Both the capsaicin- and the vagotomy-induced damage to the vagus nerve decreased microglia activation in the hippocampus at 15 days after the injury. At 30 days post injury, capsaicin-treated and vagotomized rats revealed significantly more activated microglia. Our findings show that damage to the subdiaphragmatic vagus in adult rats is followed by microglia activation and long-lasting changes in the dentate gyrus, leading to alteration of neurogenesis.
文摘Neurological disorders are amongst the most widely studied human aliments.Yet,they are also one of the most poorly understood.Although most of these disorders are polygenic,genotype still plays an important role in their etiologies.For example,in schizophrenia and autism spectrum disorders,there is a 40-60%concordance rate in monozygotic twins,with 60-90%heritability(Burmeister et al.,2008).However,the mechanisms by which multiple genes and their genomic variations influence the phenotypes of the disorders remain to be understood. The complexities of the disorders are tur- ther compounded by the individual rarity of the genomic variations and their variable penetrance (Cook and Scherer, 2008). Thus, conventional disease modeling, such as gene knockout in cells or in animals, to attain the desired disease genotype may not be the most suitable platform for tackling most neurological disorders.
文摘The purpose of this study was to determine if the substituted pyrimidine, CXB-909 (formerly known as KP544) which has been shown to amplify the effects of nerve growth factor in elevating choline-acetyltransferase activity in vitro, could attenuate memory deficits in the mu-p-75 saporin injected mouse model of Alzheimer’s disease (AD). Seventy-one, seven-week old C57/BL6 mice received daily oral intubation of 10, 15, or 20 mg/kg CXB-909, or vehicle (0.5% methylcellulose solution), which continued for 32 days. At postnatal week nine, mice received bilateral intra-cerebroventricular injections of mu-p-75 saporin, or sterile phosphate buffered saline. Seven days after surgery, mice were trained for two days, on a cued-platform version of the Morris water maze task, and then tested on a four-day hidden-platform version, followed by a one-day probe version of this task. Mice injected with mu-p-75 saporin, had increased latency to find the hidden-platform compared to sham mice. Furthermore, mice treated with CXB-909 at the 10, and 15 mg/kg doses, significantly reduced their latency to reach the hidden-platform, compared to vehicle-treated mice given mu-p-75 saporin. These results suggest that CXB-909 can attenuate memory deficits in the mu-p-75 saporin injected mouse model of AD.
文摘BACKGROUND The coronavirus disease 2019(COVID-19)pandemic is an unprecedented challenge for public health and has caused the loss of millions of lives worldwide.Hospital workers play a key role in averting the collapse of the health system,but the mental health of many has deteriorated during the pandemic.Few studies have been devoted to identifying the needs of workers on frontline duty.AIM To investigate dimensions of common emotional symptoms and associated predictors among Brazilian workers in a COVID-19 reference hospital.METHODS This is an observational study of the mental health of professionals in a COVID-19 hospital in the city of São Paulo.We invited all hospital employees to respond to an online survey between July and August 2020,during the first peak of the pandemic.Data of 1000 participants who completed the survey were analyzed(83.9%were women and 34.3%were aged 30 to 40).Hospital workers selfreported the presence of symptoms of depression,anxiety,trauma-related stress,and burnout through the Patient Health Questionnaire-9,the Generalized Anxiety Disorder-7,the Impact of Event Scale-Revised and the Mini-Z Burnout Assessment respectively.Responses were assembled and subjected to exploratory factor analysis to reveal workers’core emotional distress.Multiple linear regression models were subsequently carried out to estimate the likelihood of dimensions of distress using questions on personal motivation,threatening events,and institutional support.RESULTS Around one in three participants in our sample scored above the threshold of depression,anxiety,post-traumatic stress disorder,and burnout.The factor analysis revealed a three-factor structure that explained 58%of the total data variance.Core distressing emotional domains were avoidance and re-experience,depression-anxiety,and sleep changes.Regression analysis revealed that institutional support was a significant protective factor for each of these dimensions(βrange=-0.41 to-0.20,P<0.001).However,participants’personal motivation to work in healthcare service was not associated with these emotional domains.Moreover,the likelihood of presenting the avoidance and re-experience dimension was associated with having a family member or close friend be hospitalized or die due to COVID-19 and having faced an ethical conflict.CONCLUSION Distressing emotional domains among hospital workers were avoidance and re-experience,depression and anxiety,and sleep changes.Improving working conditions through institutional support could protect hospital workers'mental health during devastating public health crises.