Vascular etiology is the second most prevalent cause of cognitive impairment globally.Endothelin-1,which is produced and secreted by endothelial cells and astrocytes,is implicated in the pathogenesis of stroke.However...Vascular etiology is the second most prevalent cause of cognitive impairment globally.Endothelin-1,which is produced and secreted by endothelial cells and astrocytes,is implicated in the pathogenesis of stroke.However,the way in which changes in astrocytic endothelin-1 lead to poststroke cognitive deficits following transient middle cerebral artery occlusion is not well understood.Here,using mice in which astrocytic endothelin-1 was overexpressed,we found that the selective overexpression of endothelin-1 by astrocytic cells led to ischemic stroke-related dementia(1 hour of ischemia;7 days,28 days,or 3 months of reperfusion).We also revealed that astrocytic endothelin-1 overexpression contributed to the role of neural stem cell proliferation but impaired neurogenesis in the dentate gyrus of the hippocampus after middle cerebral artery occlusion.Comprehensive proteome profiles and western blot analysis confirmed that levels of glial fibrillary acidic protein and peroxiredoxin 6,which were differentially expressed in the brain,were significantly increased in mice with astrocytic endothelin-1 overexpression in comparison with wild-type mice 28 days after ischemic stroke.Moreover,the levels of the enriched differentially expressed proteins were closely related to lipid metabolism,as indicated by Kyoto Encyclopedia of Genes and Genomes pathway analysis.Liquid chromatography-mass spectrometry nontargeted metabolite profiling of brain tissues showed that astrocytic endothelin-1 overexpression altered lipid metabolism products such as glycerol phosphatidylcholine,sphingomyelin,and phosphatidic acid.Overall,this study demonstrates that astrocytic endothelin-1 overexpression can impair hippocampal neurogenesis and that it is correlated with lipid metabolism in poststroke cognitive dysfunction.展开更多
Objective Arsenic(As) and fluoride(F) are two of the most common elements contaminating groundwater resources. A growing number of studies have found that As and F can cause neurotoxicity in infants and children, lead...Objective Arsenic(As) and fluoride(F) are two of the most common elements contaminating groundwater resources. A growing number of studies have found that As and F can cause neurotoxicity in infants and children, leading to cognitive, learning, and memory impairments. However, early biomarkers of learning and memory impairment induced by As and/or F remain unclear. In the present study, the mechanisms by which As and/or F cause learning memory impairment are explored at the multi-omics level(microbiome and metabolome).Methods We stablished an SD rats model exposed to arsenic and/or fluoride from intrauterine to adult period.Results Arsenic and/fluoride exposed groups showed reduced neurobehavioral performance and lesions in the hippocampal CA1 region. 16S rRNA gene sequencing revealed that As and/or F exposure significantly altered the composition and diversity of the gut microbiome, featuring the Lachnospiraceae_NK4A136_group, Ruminococcus_1, Prevotellaceae_NK3B31_group, [Eubacterium]_xylanophilum_group. Metabolome analysis showed that As and/or F-induced learning and memory impairment may be related to tryptophan, lipoic acid, glutamate, gamma-aminobutyric acidergic(GABAergic) synapse, and arachidonic acid(AA) metabolism. The gut microbiota, metabolites, and learning memory indicators were significantly correlated.Conclusion Learning memory impairment triggered by As and/or F exposure may be mediated by different gut microbes and their associated metabolites.展开更多
Aim: To observe the rats’ learning and memory acquisition ability disturbance induced by BI-D1870. Methods: Male SD rats were randomly divided into control group, solvent control group and BI-D1870 group. The rats in...Aim: To observe the rats’ learning and memory acquisition ability disturbance induced by BI-D1870. Methods: Male SD rats were randomly divided into control group, solvent control group and BI-D1870 group. The rats in the control group were intraperitoneally injected with saline, while those in the solvent control group were intraperitoneally injected with DMSO + sulfobutyl-β-cyclodextrin solvent, and those in the BI-D1870 group were intraperitoneally injected with BI-D1870. All the rats’ appearance and behavior were daily observed, and body weight was recorded on the day 15, 30, 45, 60, 75 and 82 of BI-D1870 injected. Morris water maze was used to screen the rats’ learning and memory acquisition ability on the day 22 - 25, 52 - 55, and 82 - 85 of training by BI-D1870 treated. The successful rates of the rats’ memory impairment were respectively calculated for three times screening. Results: During the whole experiment, there was no obvious difference in appearance and fur color in all rats. The rats’ agitation began to appear on the day 10th of BI-D1870 given. The agitation rats’ number and rats’ body weight gradually increased along with BI-D1870 treated (P P Conclusion: Intraperitoneal injection of BI-D1870 can induce the rats’ learning and memory acquisition ability disorder.展开更多
Cerebral ischemia/reperfusion injury impairs learning and memory in patients.Studies have shown that synaptic function is involved in the formation and development of memory,and that DNA methylation plays a key role i...Cerebral ischemia/reperfusion injury impairs learning and memory in patients.Studies have shown that synaptic function is involved in the formation and development of memory,and that DNA methylation plays a key role in the regulation of learning and memory.To investigate the role of DNA hypomethylation in cerebral ischemia/reperfusion injury,in this study,we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery and then treated the rats with intraperitoneal 5-aza-2′-deoxycytidine,an inhibitor of DNA methylation.Our results showed that 5-aza-2′-deoxycytidine markedly improved the neurological function,and cognitive,social and spatial memory abilities,and dose-dependently increased the synaptic density and the expression of SYP and SHANK2 proteins in the hippocampus in a dose-dependent manner in rats with cerebral ischemia/reperfusion injury.The effects of 5-aza-2′-deoxycytidine were closely related to its reduction of genomic DNA methylation and DNA methylation at specific sites of the Syp and Shank2 genes in rats with cerebral ischemia/reperfusion injury.These findings suggest that inhibition of DNA methylation by 5-aza-2′-deoxycytidine promotes the recovery of learning and memory impairment in a rat model of cerebral ischemia/reperfusion injury.These results provide theoretical evidence for stroke treatment using epigenetic methods.展开更多
Microglia are the resident macrophages of the central nervous system.Microglia possess varied morphologies and functions.Under normal physiological conditions,microglia mainly exist in a resting state and constantly m...Microglia are the resident macrophages of the central nervous system.Microglia possess varied morphologies and functions.Under normal physiological conditions,microglia mainly exist in a resting state and constantly monitor their microenvironment and survey neuronal and synaptic activity.Through the C1 q,C3 and CR3"Eat Me"and CD47 and SIRPα"Don't Eat Me"complement pathways,as well as other pathways such as CX3 CR1 signaling,resting microglia regulate synaptic pruning,a process crucial for the promotion of synapse formation and the regulation of neuronal activity and synaptic plasticity.By mediating synaptic pruning,resting microglia play an important role in the regulation of experience-dependent plasticity in the barrel cortex and visual cortex after whisker removal or monocular deprivation,and also in the regulation of learning and memory,including the modulation of memory strength,forgetfulness,and memory quality.As a response to brain injury,infection or neuroinflammation,microglia become activated and increase in number.Activated microglia change to an amoeboid shape,migrate to sites of inflammation and secrete proteins such as cytokines,chemokines and reactive oxygen species.These molecules released by microglia can lead to synaptic plasticity and learning and memory deficits associated with aging,Alzheimer's disease,traumatic brain injury,HIV-associated neurocognitive disorder,and other neurological or mental disorders such as autism,depression and post-traumatic stress disorder.With a focus mainly on recently published literature,here we reviewed the studies investigating the role of resting microglia in synaptic plasticity and learning and memory,as well as how activated microglia modulate disease-related plasticity and learning and memory deficits.By summarizing the function of microglia in these processes,we aim to provide an overview of microglia regulation of synaptic plasticity and learning and memory,and to discuss the possibility of microglia manipulation as a therapeutic to ameliorate cognitive deficits associated with aging,Alzheimer's disease,traumatic brain injury,HIV-associated neurocognitive disorder,and mental disorders.展开更多
With key roles in essential brain functions ranging from the long-term potentiation(LTP) to synaptic plasticity,the N-methyl-D-aspartic acid receptor(NMDAR) can be considered as one of the fundamental glutamate recept...With key roles in essential brain functions ranging from the long-term potentiation(LTP) to synaptic plasticity,the N-methyl-D-aspartic acid receptor(NMDAR) can be considered as one of the fundamental glutamate receptors in the central nervous system.The role of NMDA R was first identified in synaptic plasticity and has been extensively studied.Some molecules,such as Ca^(2+),postsynaptic density 95(PSD-95),calcium/calmodulin-dependent protein kinase II(Ca MK II),protein kinase A(PKA),mitogen-activated protein kinase(MAPK) and cyclic adenosine monophosphate(c AMP) responsive element binding protein(CREB),are of special importance in learning and memory.This review mainly focused on the new research of key molecules connected with learning and memory,which played important roles in the NMDAR signaling pathway.展开更多
Damage to synaptic plasticity induced by neurotoxicity of amyloid-beta is regarded to be one of the pathological mechanisms of learning and memory disabilities in Alzheimer's disease patients.This study assumed th...Damage to synaptic plasticity induced by neurotoxicity of amyloid-beta is regarded to be one of the pathological mechanisms of learning and memory disabilities in Alzheimer's disease patients.This study assumed that the damage of amyloid-beta to learning and memory abilities was strongly associated with the changes in the Fyn/N-methyl-D-aspartate receptor 2B(NR2B) expression.An APP695V7171 transgenic mouse model of Alzheimer's disease was used and treatment with tetrahydroxy-stilbene glucoside was administered intragastrically.Results showed that intragastric administration of tetrahydroxy-stilbene glucoside improved the learning and memory abilities of the transgenic mice through increasing NR2 B receptors and Fyn expression.It also reversed parameters for synaptic interface structure of gray type I.These findings indicate that tetrahydroxy stilbene glucoside has protective effects on the brain,and has prospects for its clinical application to improve the learning and memory abilities and treat Alzheimer's disease.展开更多
BACKGROUND: Transplantation of fetal cell suspension or blocks of fetal tissue can ameliorate the nerve function after the injury or disease in the central nervous system, and it has been used to treat neurodegenerati...BACKGROUND: Transplantation of fetal cell suspension or blocks of fetal tissue can ameliorate the nerve function after the injury or disease in the central nervous system, and it has been used to treat neurodegenerative disorders induced by Parkinson disease. OBJECTIVE: To observe the effects of the transplantation of neuron-like cells derived from bone marrow stromal cells (rMSCs) into the brain in restoring the dysfunctions of muscle strength and balance as well as learning and memory in rat models of cerebral infarction. DESIGN: A randomized controlled experiment. SETTING: Department of Pathophysiology, Zhongshan Medical College of Sun Yat-sen University. MATERIALS: Twenty-four male SD rats (3-4 weeks of age, weighing 200-220 g) were used (Certification number:2001A027). METHODS: The experiments were carried out in Zhongshan Medical College of Sun Yat-sen University between December 2003 and December 2004. ① Twenty-four male SD rats randomized into three groups with 8 rats in each: experimental group, control group and sham-operated group. Rats in the experiment al group and control group were induced into models of middle cerebral artery occlusion. After in vitro cultured, purified and identified with digestion, the Fischer344 rMSCs were induced to differentiate by tanshinone ⅡA, which was locally injected into the striate cortex (18 area) of rats in the experimental group, and the rats in the control group were injected by L-DMEM basic culture media (without serum) of the same volume to the corresponding brain area. In the sham-operated group, only muscle and vessel of neck were separated. ② At 2 and 8 weeks after the transplantation, the rats were given the screen test, prehensile-traction test, balance beam test and Morris water-maze test. ③ The survival and distribution of the induced cells in corresponding brain area were observed with Nissl stained with toluidine blue and hematoxylin and eosin (HE) staining in the groups. MAIN OUTCOME MEASURES: ① Results of the behavioral tests (time of the Morris water-maze test screen test, prehensile-traction test, balance beam test); ② Survival and distribution of the induced cells. RESULTS: All the 24 rats were involved in the analysis of results. ① Two weeks after transplantation, rats with neuron-like cells grafts in the experimental group had significant improvement on their general muscle strength than those in the control group [screen test: (9.4±1.7), (4.7±1.0) s, P < 0.01]; forelimb muscle strength [prehensile-traction test: (7.6±1.4), (5.2±1.2) s, P < 0.01], ability to keep balance [balance beam test: (7.9±0.74), (6.1±0.91) s, P < 0.01] and abilities of learning and memory [latency to find the platform: (35.8±5.9), (117.5±11.6) s, P < 0.01; distance: (623.1±43.4), (1 902.3±98.6) cm, P < 0.01] as compared with those in the control group. The functional performances in the experimental group at 8 weeks were better than those at two weeks, which were still obviously different from those in the sham-operated group (P < 0.05). ② The HE and Nissl stained brain tissue section showed that there was nerve cell proliferation at the infarcted cortex in the experiment group, the density was higher than that in the control group, plenty of aggregative or scattered cells could be observed at the site where needle was inserted for transplantation, the cells migrated directively towards the area around them, the cerebral vascular walls were wrapped by plenty of cells; In the control group, most of the cortices were destroyed, karyopyknosis and necrosis of neurons were observed, normal nervous tissue structure disappeared induced by edema, only some nerve fibers and glial cells remained. CONCLUSION: The rMSCs transplantation can obviously enhance the motor function and the abilities of learning and memory in rat models of cerebral infarction.展开更多
BACKGROUND: Tetramethylpyrazine (TMP) presents the effect of anti-platelet aggregation, reduces arterial resistance, increases cerebral blood flow, and improves microcirculation. OBJECTIVE: To observe the effects of T...BACKGROUND: Tetramethylpyrazine (TMP) presents the effect of anti-platelet aggregation, reduces arterial resistance, increases cerebral blood flow, and improves microcirculation. OBJECTIVE: To observe the effects of TMP on the learning and memory abilities and the number of neurons in cortex and hippocampus after focal cerebral ischemia in rats DESIGN: A randomized controlled trial. SETTING: Department of Human Anatomy and Histological Embryology, School of Medicine, Xi’an Jiaotong University. MATERIALS: Fifty adult male Sprague-Dawley rats, weighing 250-300 g were supplied by the Experimental Animal Center, School of Medicine, Xi’an Jiaotong University. TMP was purchased from Wuxi Seventh Pharmaceutical Co.Ltd (Lot Number: 2004051106, Specification: 2 mL/piece). METHODS: The experiments were carried out in School of Medicine of Xi’an Jiaotong University from June 2004 to May 2005. The 50 rats were randomly divided into five groups according to the random number table method: sham-operated group, cerebral ischemia control group, low-dose TMP group, middle-dose TMP group and high-dose TMP group, 10 rats in each group. Rats in the TMP groups were immediately treated with intraperitoneal injection of TMP of 40, 80 and 120 mg/kg respectively, and those in the sham-operated group and cerebral ischemia control group were injected intraperitoneally by isovolume saline, once a day for 14 days successively. On the 15th day, the spatial learning and memory abilities of the rats were assessed with the Morris water maze test, and then the changes of neuron numbers in cortex and hippocampus were observed by Nissl staining of brain sections. MAIN OUTCOME MEASURES: The results of Morris water maze test and the changes of neuron numbers in cortex and hippocampus by Nissl staining of brain sections were observed. RESULTS: Finally 39 rats were involved in the analysis of results, and the other 11 died of excessive anesthesia or failure in model establishment. ① The rats in the cerebral ischemia control group manifested obvious spatial cognitive deficits in the place navigation trial and spatial probe trial. The mean values of escape latency in the sham-operated group, low, middle and high-dose TMP groups were obviously shorter than that in the cerebral ischemia control group [(23.92±2.21), (41.84±3.74), (39.50±3.80), (31.38±3.72), (61.60±3.61) s, P < 0.05-0.01]. In the spatial probe trial, significant differences in the percentage of time spending in the former platform quadrant and frequency of crossing the former platform site in the sham-operated group, lose, middle and high-dose TMP groups were obviously higher or more than those in the cerebral ischemia control group [(36.27±3.42) %, (35.84±2.54)%, (38.43±3.08)%, (36.51±1.96)%, (22.24±3.46)%; (11±1), (10±1), (8±1), (8±1), (4±1) times, P < 0.01]. ② In the morphological observation, the numbers of neurons in ipsilateral (left) parietal cortex in the sham-operated group, low, middle and high-dose TMP groups were obviously more than that in the cerebral ischemia control group [(98±8), (65±5), (53±6), (57±6), (37±6)/0.625 mm2, P < 0.01], but the number of neurons in left hippocampus had no obvious differences among the groups (P > 0.05). CONCLUSION: TMP can improve obviously the spatial learning and memory function after permanent focal cerebral ischemia in rats, and the neuroprotective role of the drug in cortex may be involved in its mechanism.展开更多
Background:Studies have revealed the protective effect of DL-3-n-butylphthalide(NBP)against diseases associated with ischemic hypoxia.However,the role of NBP in animals with hypobaric hypoxia has not been elucidated.T...Background:Studies have revealed the protective effect of DL-3-n-butylphthalide(NBP)against diseases associated with ischemic hypoxia.However,the role of NBP in animals with hypobaric hypoxia has not been elucidated.This study investigated the effects of NBP on rodents with acute and chronic hypobaric hypoxia.Methods:Sprague-Dwaley rats and Kunming mice administered with NBP(0,60,120,and 240 mg/kg for rats and 0,90,180,and 360 mg/kg for mice)were placed in a hypobaric hypoxia chamber at 10,000 m and the survival percentages at 30 min were determined.Then,the time and distance to exhaustion of drug-treated rodents were evaluated during treadmill running and motor-driven wheel-track treadmill experiments,conducted at 5800 m for 3 days or 20 days,to evaluate changes in physical functions.The frequency of active escapes and duration of active escapes were also determined for rats in a shuttle-box experiment,conducted at 5800 m for 6 days or 27 days,to evaluate changes in learning and memory function.ATP levels were measured in the gastrocnemius muscle and malonaldehyde(MDA),superoxide dismutase(SOD),hydrogen peroxide(H_(2)O_(2)),glutathione peroxidase(GSH-Px),and lactate were detected in sera of rats,and routine blood tests were also performed.Results:Survival analysis at 10,000 m indicated NBP could improve hypoxia tolerance ability.The time and distance to exhaustion for mice(NBP,90 mg/kg)and time to exhaustion for rats(NBP,120 and 240 mg/kg)significantly increased under conditions of acute hypoxia compared with control group.NBP treatment also significantly increased the time to exhaustion for rats when exposed to chronic hypoxia.Moreover,240 mg/kg NBP significantly increased the frequency of active escapes under conditions of acute hypoxia.Furthermore,the levels of MDA and H_(2)O_(2) decreased but those of SOD and GSH-Px in the sera of rats increased under conditions of acute and chronic hypoxia.Additionally,ATP levels in the gastrocnemius muscle significantly increased,while lactate levels in sera significantly decreased.Conclusion:NBP improved physical and learning and memory functions in rodents exposed to acute or chronic hypobaric hypoxia by increasing their anti-oxidative capacity and energy supply.展开更多
BACKGROUD: Ethanol can influence neural development and the ability of learning and memory, but its mechanism of the neural toxicity is not clear till now. Endogenous nitric oxide (NO) as a gaseous messenger is proved...BACKGROUD: Ethanol can influence neural development and the ability of learning and memory, but its mechanism of the neural toxicity is not clear till now. Endogenous nitric oxide (NO) as a gaseous messenger is proved to play an important role in the formation of synaptic plasticity, transference of neuronal information and the neural development, but excessive nitro oxide can result in neurotoxicity. OBJECTIVE: To observe the effects of acute alcoholism on the learning and memory ability and the content of neuronal nitric oxide synthase (nNOS) in brain tissue of rats. DESIGN: A randomized controlled animal experiment. SETTING: Department of Physiology, Xinxiang Medical College. MATERIALS: Eighteen male clean-degree SD rats of 18-22 weeks were raised adaptively for 2 days, and then randomly divided into control group (n = 8) and experimental group (n = 10). The nNOS immunohistochemical reagent was provided by Beijing Zhongshan Golden Bridge Biotechnology Co.,Ltd. Y-maze was produced by Suixi Zhenghua Apparatus Plant. METHODS: The experiment was carried out in the laboratory of the Department of Physiology, Xinxiang Medical College from June to October in 2005. ① Rats in the experimental group were intraperitoneally injected with ethanol (2.5 g/kg) which was dissolved in normal saline (20%). The loss of righting reflex and ataxia within 5 minutes indicated the successful model. Whereas rats in the control group were given saline of the same volume. ② Examinations of learning and memory ability: The Y-maze tests for learning and memory ability were performed at 6 hours after the models establishment. The rats were put into the Y-maze separately. The test was performed in a quiet and dark room. There was a lamp at the end of each of three pathways in Y-maze and the base of maze had electric net. All the lamps of the three pathways were turned on for 3 minutes and then turned off. One lamp was turned on randomly, and the other two delayed automatically. In 5 seconds after alternation, pulsating electric current presented in the base of unsafe area to stimulate rat’s feet to run to the safe area. The lighting lasted for 15 seconds as one test. Running from unsafe area to safe area at one time in 10 seconds was justified as successful. Such test was repeated for 10 times for each rat and the successful frequency was recorded. The qualified standard of maze test was that the rat arrived in the safe area 9 times during 10 experiments. The number of trainings for the qualified standard was used to represent the result of spatial learning. ③ Determination of the content of nNOS in brain tissue: After the Y-maze test, the rats were anaesthetized, and blood was let from the incision on right auricle, transcardially perfused via the left ventricle with about 200 mL saline, then fixed by perfusion of 40 g/L paraformaldehyde. Hippocampal CA1 region, corpus striatum and cerebellum were taken to prepare serial freezing coronal sections. The nNOS contents in the brain regions were determined with the immunohistochemical methods to reflect the changes of nitric oxide in brain tissue. MAIN OUTCOME MEASURES: The changes of learning and memory ability and the changes of the nNOS contents in the brain tissue of rats with acute alcoholism were observed. RESULTS: One rat in the experimental group was excluded due to its slow reaction to electric stimulation in the Y-maze test, and the other 17 rats were involved in the analysis of results. ① The training times to reach qualifying standards of Y-maze in the experimental group was more than that in the control group [(34.33 ±13.04), (27.50±8.79) times, P < 0.05]. ② Forms and numbers of nNOS positive neurons in brain tissue: It could be observed under light microscope that in the hippocampal CA1 region, there were fewer nNOS positive neurons, which were lightly stained, and the processes were not clear enough; But the numbers of the positive neurons which were deeply stained as buffy were obviously increased in the experimental group, the cell body and cytoplasm of process were evenly stained, but the nucleus was not stained. The nNOS positive neurons in corpus striatum had similar forms and size in the experimental group and control group. The form of the nNOS positive neurons in cerebellum were similar between the two groups. The numbers of nNOS positive neurons in hippocampal CA1 region and corpus striatum in the experimental group [(18.22±7.47), (11.38±5.00) cells/high power field] were obviously higher than those in the control group [(10.15±4.24), (6.15±3.69) cells/high power field. The number of nNOS positive neurons in cerebellum had no significant difference between the two groups [(49.56±18.84), (44.43±15.42) cells/high power field, P > 0.05]. CONCLUSION: Acute alcoholism may impair learning and memory ability, and nitric oxide may be involved in mediating the neurotoxic role of ethanol.展开更多
BACKGROUND: Central adrenergic nerve and 5-serotonergic nerve can influence central cholinergic nerve on learning and memory and make easy for study; however, ginsenoside of stem and leaf (GSL) can improve functions o...BACKGROUND: Central adrenergic nerve and 5-serotonergic nerve can influence central cholinergic nerve on learning and memory and make easy for study; however, ginsenoside of stem and leaf (GSL) can improve functions of central adrenergic nerve; moreover, 5-serotonergic nerve and the combination with choline can produce synergistic effect and enhance learning and memory ability so as to improve learning and memory disorder of patients with Alzheimer disease (AD). OBJECTIVE: To observe the effects of GSL combining with choline on learning and memory of AD model rats.DESIGN: Randomized grouping design and controlled animal study.SETTING: Department of Pharmacology, Taishan Medical College. MATERIALS: The experiment was carried out in the Pharmacological Department of Medical College of Jilin University from October 1996 to January 1997. Forty healthy male Wistar rats of clean grade were randomly divided into 5 groups, including sham-injury group, model group, GSL group, choline group and combination group, with 8 rats in each group. Main medications: GSL with the volume more than 92.8% was provided by Department of Chemistry, Norman Bethune Medical College of Jilin University. Panaxatriol, the main component, was detected with thin layer scanning technique and regarded as the index of GSL quality [(55±1)%, CV = 2%, n = 5]. Choline was provided by the Third Shanghai Laboratory Factory. METHODS: 150 nmol quinolinic acid was used to damage bilateral Meynert basal nuclei of adult rats so as to establish AD models. Rats in GSL, choline and combination groups were intragastric administrated with 400 mg/kg GSL, 200 mg/kg choline (20 mL/kg), and both respectively last for 17 days starting from two days before operation. Rats in sham-injury group and model group were perfused with the same volume of distilled water once in each morning for the same days. ① Passive avoidance step-down test: Five minutes later, rats jumped up safe platform when they were shocked with 36 V alternating current. If rats jumped down from the platform and the feet touched railings, the response was wrong. Numbers of wrong response were recorded within 3 minutes, and then the test was redone after 24 hours. ② Morris water-maze spatial localization task: Swimming from jumping-off to platform directly was regarded as right response. Additionally, 4 successively right responses were regarded as the standard. Each rat was trained 10 times a day with 120 s per time for 3 successive days. The interval was 30 s. Three days later, numbers of right response were recorded. The training times were increased to 30 for unlearned rats. ③ Measurement of activity of choilne acetylase in cerebral cortex: Rats were sacrificed at 17 days after operation to obtain cerebral cortex to measure activity of choilne acetylase with radiochemistry technique. ④ Synergistic effect: It was expressed as Q value: Q value = factual incorporative effect/anticipant incorporative effect; Q ≥ 1 was regarded as synergistic effect. Anticipant incorporative effect = (EA+EB-EA·EB), EA and EB were single timing effect, respectively in GSL group and choline group. E (step-down test and Morris water maze test) = (x in model group - factual value in medicine groups)/x in model group; E (activity of choilne acetylase) = (factual value in medicine groups -x in model group)/x in model group. MAIN OUTCOME MEASURES: ① Passive avoidance step-down test and Morris water-maze spatial localization task in the study of learning and memory; ② activity of choilne acetylase. RESULTS: All 40 rats were involved in the final analysis. ① Passive avoidance response: At learning phase on first day and retesting phase on the next day, numbers of wrong responses within 3 minutes were more in model group than sham operation group, and there was significant difference [(5.88±1.46), (2.25±0.87) times; (2.63±1.06), (0.50±0.53) times; P < 0.01]; numbers of wrong responses within 3 minutes were less in combination group than model group, and there was significant difference [learning phase: (1.12±0.83), (5.88±1.46) times; retesting phase: (0.38±0.74), (2.63±1.06) times, P < 0.01]; moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.07 and 1.59, respectively and it showed synergistic effect. ② Spatial localization task: Training times were more in model group than sham operation group, and there was significant difference [(2.9±2.5), (12.6±3.5) times; P < 0.01]. Training times were less in combination group than model group, and there was significant difference [(11.8±2.4), (27.9±2.5) times, P < 0.01]; moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.07 and it showed synergistic effect. ③ Activity of choilne acetylase: Activity was lower in model group than sham operation group, and there was significant difference [(30.56±8.33), (61.11±8.33) nkat/g; P < 0.01]. Activity was higher in combination group than model group and there was significant difference [(50.00±8.33), (30.56±8.33) nkat/g, P < 0.01]; moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.5 and it showed synergistic effect. CONCLUSION: GSL in combination with choline can synergically improve the disorder of learning and memory of AD model rats. Its mechanism may be involved in enhancing the function of central cholinergic system.展开更多
OBJECTIVE Microglia M1/M2 po⁃larization play pro-inflammatory and anti-inflam⁃matory roles,respectively,which is involved in memory decline.There is a close relationship between impaired baroreflex function and memory...OBJECTIVE Microglia M1/M2 po⁃larization play pro-inflammatory and anti-inflam⁃matory roles,respectively,which is involved in memory decline.There is a close relationship between impaired baroreflex function and memory impairment.The present study was designed to investigate whether arterial baroreflex deficiency induced by sinoaortic denervation(SAD)affected inflammation through modulation of M1/M2 polar⁃ization leading to the aggravation of learning and memory disorders in rats.METHODS Adult male SD rats were divided into four groups:the sham control,the SAD,the sham+scopolamine,the SAD+scopolamine.In another experiment,there were also four groups:the sham control,the SAD,the SAD+scopolamine and the SAD+scopolamine+ketanserin.All rats were examined for various behaviors using Morris water maze test,new object recognition test,and light dark shuttle test and Y maze test 4 weeks after sham or SAD surgery.CD16,CD206,IL-10,IL-6,IL-1βand TNF-αfrom hippocampus using Western blotting,immunofluorescence and turbidimetry.RESULTS Compared with the sham+scopol⁃amine,the SAD+scopolamine rats showed the reduced crossing times in Morris water maze test,the longer residence time in dark box during light dark shuttle test,and the decreased alterna⁃tion ratio in Y maze test.The level of CD206,IL-10,T-AOC and GSH was decreased,whereas CD16,IL-6,TNF-α,MDA was increased in the hippocampus of SAD+scopolamine rats.Addi⁃tionally,all the above changes were improved in the SAD+scopolamine+ketanserin rats when compared with the SAD+scopolamine.CONCLU⁃SION Arterial baroreflex dysfunction aggravates learning and memory disorders in rats,which may be related to the polarization of microglia.展开更多
BACKGROUND: Calcitonin gene-related peptide (CGRP) and nerve growth actor (NGF) cam improve spatial learning and memory abilities of rats with cerebral ischemia/reperfusion; however, the effect of combination of them ...BACKGROUND: Calcitonin gene-related peptide (CGRP) and nerve growth actor (NGF) cam improve spatial learning and memory abilities of rats with cerebral ischemia/reperfusion; however, the effect of combination of them on relieving learning and memory injury following cerebral ischemia/reperfusion should be further studied. OBJECTIVE: To study the effects of exogenous CGRP and NGF on learning and memory abilities of rats with focal cerebral ischemia/reperfusion. DESIGN: Randomized controlled animal study. SETTING: Department of Neurosurgery, the Second Hospital of Xiamen; Department of Neurosurgery, the Second Affiliated Hospital of China Medical University; Department of Neurobiology, Basic Medical College of China Medical University. MATERIALS: A total of 30 healthy male SD rats, aged 8 weeks, of clean grade, weighing 250-300 g, were provided by Experimental Animal Department of China Medical University. All rats were randomly divided into sham-operation group, ischemia/reperfusion group and treatment group with 10 in each group. The main reagents were detailed as the follows: 100 g/L chloral hydrate, 0.5 mL CGRP (2 mg/L, Sigma Company, USA), and NGF (1× 106 U/L, 0.5 mL, Siweite Company, Dalian). METHODS: The experiment was carried out in the Department of Neurobiology, Basic Medical College of China Medical University from February to July 2005. Rat models of middle cerebral artery occlusion were established by method of occlusion, 2 hours after that rats were anesthetized and the thread was slightly drawn out for 10 mm under direct staring to perform reperfusion. Rats in the ischemia/reperfusion group received intraperitoneal injection of 1 mL saline via the abdomen at two hours later, while rats in the treatment group at 2 hours later received intraperitoneal injection of 2 mg/L CGRP (0.5 mL) and 1×106 U/L NGF (0.5 mL) once a day for 10 successive days. First administration was accomplished within 15 minutes after ischemia/reperfusion. Rats in the sham-operation group were separated of the vessels without occlusion or administration. The neural function was evaluated with Zea Longa 5-grade scale. Animals with the score of one, two and three points received Morris water-maze test to measure searching time on platform (omitting platform-escaping latency). Meanwhile, leaning and memory abilities of animals were reflected through testing times of passing through platform per minute. MAIN OUTCOME MEASURES: Experimental results of omitting platform-escaping latency and spatial probe. RESULTS: Three and two rats in the ischemia/reperfusion group and treatment group respectively were not in accordance with the criteria in the process, and the rest were involved in the final analysis. ① Comparisons of platform-escaping latency during Morris water-maze test in all the three groups: Ten days after modeling, the platform-escaping latency in the ischemia/reperfusion group was obviously longer than that in sham-operation group (P < 0.01), and was significantly shorter than that in the treatment group (P < 0.01). ② Comparisons of times of passing through platform in all the three groups: Times of passing through platform were remarkably less in the ischemia/reperfusion group than those in the sham-operation group [(1.79±0.39), (4.30±0.73) times/minute, P < 0.01], and those were markedly more in the treatment group than the ischemia/reperfusion group [(3.16±1.03), (1.79±0.39) times/minute, P < 0.01]. CONCLUSION: CGRP and NGF are capable of ameliorating the abilities of spatial learning and memory in MCAO rats, which indicates that CGRP and NGF can protect ischemic neurons.展开更多
OBJECTIVE To observe the effects of betaine on learning memory in SHR rats through behavioral experiments,and then to investigate the mechanisms of betaine to improve the cognitive impairment caused by hyperten⁃sion.M...OBJECTIVE To observe the effects of betaine on learning memory in SHR rats through behavioral experiments,and then to investigate the mechanisms of betaine to improve the cognitive impairment caused by hyperten⁃sion.METHODS 4-month-old male SHR rats were randomly divided into 4 groups,including betaine 10,30 and 100 mg·kg-1 groups and SHR group,and administered by gavage,10 mL·kg-1 once a day for 4 weeks.The control group was WKY rats,and the same amount of saline was given by gavage.The learning and memory behaviors of the rats were analyzed and evaluated through behavioral testing.RESULTS The results of Morris water maze showed that persistent hypertension decreased the time in the target quadrant and the number of platform crossing of the rats,and the intervention with different con⁃centrations of betaine increased the time in the target quadrant and the number of platform crossing of SHR in a dose-dependent manner.Then,persistent hypertension increased the escape latency of rats,and betaine inhibited this change.The results of new object recognition showed that the recognition index of SHR group decreased,and the recognition index of SHR rats increased with different concentrations of betaine intervention in a dose-dependent manner.The Y-maze results showed that persistent hypertension decreased the alternation in rats,and the alternation in SHR rats increased after the intervention with different concentrations of betaine,and in a dose-dependent manner.CON⁃CLUSION Persistent hypertension can cause learning memory impairment in rats.Betaine intervention has an ameliorative effect on the reduction of learning memory ability in rats caused by hypertension.展开更多
This study aimed to elucidate whether midazolam affected the learning and memory of rats through the extracellular signal-regulated kinase(ERK)/cyclic adenosine monophosphate response element-binding(CREB)signaling pa...This study aimed to elucidate whether midazolam affected the learning and memory of rats through the extracellular signal-regulated kinase(ERK)/cyclic adenosine monophosphate response element-binding(CREB)signaling pathway and hippocampal oxidative damage.Overall 120 Wistar rats were randomly assigned to four groups,including one control and three midazolam-exposed groups(20,60 and 150 mg•kg^(-1)).After an intraperitoneal injection of midazolam/physiological saline for both 1 h(n=15)and 24 h(n=15),10 rats(five came from 1 h,and the remaining five came from 24 h)were randomly selected from each group for the Morris water maze test.The hippocampus tissue samples were harvested for the assessment of superoxide dismutase(SOD)and catalase(CAT)activities as well as glutathione peroxidase(GPx),malonyl dialdehyde(MDA),nitric oxide(NO)and inducible nitric oxide synthase(iNOS)levels.The remaining 80 rats were euthanized,and the hippocampal tissue was isolated.The expressions of ERK1,ERK2 and CREB mRNA were tested using RT-qPCR.The protein expressions of p-ERK1/2 and p-CREB were tested using Western blotting.The Morris water maze tests indicated that midazolam-treated rats have weaker learning and memory ability compared to the control rats.Midazolam increased MDA,NO,iNOS and CAT,and decreased GPx and SOD activities compared to the control group.The expression levels of ERK1/2 and CREB in the hippocampus of rats in the midazolam treatment groups were significantly lower compared to the control group at 1 h after intraperitoneal injection of midazolam,and in a dose-dependent relationship but returning it to normal levels at 24 h after midazolam intraperitoneal injection.Therefore,it was concluded that the learning and memory impairment of midazolam might be associated with the down-regulation of the ERK/CREB signaling pathway and oxidative damage in rat hippocampus.展开更多
[Objectives]To evaluate the effects of Tongdu Tiaoshen Acupuncture method on improving learning and memory function and hippocampal nerve regeneration and repair after stroke.[Methods]Animal models of cognitive impair...[Objectives]To evaluate the effects of Tongdu Tiaoshen Acupuncture method on improving learning and memory function and hippocampal nerve regeneration and repair after stroke.[Methods]Animal models of cognitive impairment in the recovery phase of cerebral infarction in rats were prepared,and rats were randomly divided into control group,model group,donepezil group,and acupuncture group.Morris water maze experiment was carried out to evaluate learning and memory ability.Nissl staining,BrdU and DCX immunofluorescence staining were used to observe the number and morphological structure of neuronal pyramidal and granular cells in the dentate gyrus(DG)area of the hippocampus,as well as the proliferation and differentiation of neural progenitor cells.TUNEL method was used to detect cell apoptosis.[Results]Before intervention,the scores and ELP of the model group,donepezil group and acupuncture group were significantly higher than those of the blank group(P<0.05);after the intervention,the neurological scores and ELP of the blank group and the model group were not significantly different from those before the intervention(P<0.05);the donepezil group and acupuncture group were significantly reduced,there was no difference between the donepezil group and acupuncture group(P>0.05),but it was still significantly higher than the blank group(P<0.05).The results of BrdU and DCX immunofluorescence staining showed that there were only a few BrdU positive cells and DCX protein in the hippocampal DG area of mice in the blank group,and the positive cells in the model group were significantly increased(P<0.05);donepezil group and acupuncture group showed significant increase compared with the model group(P<0.05);compared with the blank group,the number of neurons in the hippocampal DG area of each group was significantly reduced(P<0.01),and the neuronal apoptosis index was significantly increased(P<0.01);compared with the blank group,the number of neurons in the hippocampal DG area of each group was significantly reduced(P<0.01),and the neuronal apoptosis index was significantly increased(P<0.01).The number of neurons in the hippocampal DG area of rats in the acupuncture group and donepezil group was significantly increased(P<0.01),and the neuronal apoptosis index was significantly decreased(P<0.01).[Conclusions]Tongdu Tiaoshen Acupuncture method can improve the learning and memory function of stroke model rats by promoting the regeneration and repair of hippocampal nerve in rats with cerebral infarction.展开更多
OBJECTIVE To investigate the influence of gingerol on the improvement of learning and memory impairment of rat model of Alzheimer disease induced by β-amyloid peptide fragment 25-35(Aβ_(25-35)) and to analysis the p...OBJECTIVE To investigate the influence of gingerol on the improvement of learning and memory impairment of rat model of Alzheimer disease induced by β-amyloid peptide fragment 25-35(Aβ_(25-35)) and to analysis the possible mechanism. METHODS SD rats were randomly divided into 5groups: blank control group,model group,sham-operated group,low dose drug group(gingerol emulsion,10 mg·kg^(-1)·d^(-1)),high dose drug group(gingerol emulsion,50 mg·kg^(-1)·d^(-1)). Model group and two drug groups were injected Aβ_(25-35)(5 μL) in lateral cerebral ventricle. Sham-operated group were injected the same amount of sterile PBS solution. For blank control group without any treatment. When all the rats refresh themselves and had post-operated activities,two drug groups were gavaged with different concentration of gingerol emulsion,Meanwhile,sham-operated group were gavaged with sterile physiological saline,the remaining two groups without any treatment. After three weeks,we make use of Y labyrinth to test the ability of space learning and memory of rats. Finally,rats were sacrificed to collect blood by abdominal aortic method. The content of acetylcholine(ACh),SOD and MDA were detected in serum. RESULTS(1) Compared with blank control group,the ability of learning and memory of model group rats were weakened,the error times increased in Y labyrinth experiment. In addition,the content of ACh and the activity of SOD significantly decreased,the content of MDA increased(P<0.05).(2) On the contrary,the rats gavaged with gingerol emusion have less error times in Y labyrinth experiment compared with model group. the content of Ach and the activity of SOD significantly increased,the content of MDA decreased(P<0.05). However,two different gingerol emusion concentration groups have no significantly difference. CONCLUSION The ability of learning and memory of rats gavaged with gingerol emusion were significantly improved compared with Aβ_(25-35) induced rats without any treatment.Its mechanism may be related to antioxidant and neurotransmitter.展开更多
BACKGROUND: Generally speaking, anesthesia is often used in gravid body and it has been already proved that many kind of medicine can result in malformation. OBJECTIVE: To explore embryonic skeleton development and ne...BACKGROUND: Generally speaking, anesthesia is often used in gravid body and it has been already proved that many kind of medicine can result in malformation. OBJECTIVE: To explore embryonic skeleton development and neonatal learning and memory of rats anesthetized with pentobarbital sodium in gravid rats. DESIGN: A randomized control trial. SETTING: Laboratory Animal Center of Xuzhou Medical College. MATERIALS: A total of 80 adult female SD rats, of clean grade and weighing 220-240 g, were selected in this study. The main reagents were detailed as follows: pentobarbital sodium (Shanghai Xingzhi Chemical Plant, batch number: 921019); MG-2 maze test apparatus (Zhangjiagang Biomedical Instrument Factory); somatotype microscope (Beijing Taike Instrument Co., Ltd.). METHODS: ① A total of 160 SD rats of half males and females were selected in this study. All rats were copulated. The day that the plug was checked out in the vagina next day was looked as the first day of pregnancy. Gravid rats were divided randomly into four groups, including early anesthesia group, second anesthesia group, late anesthesia group and control group with 20 in each group. Rats in the early anesthesia group were injected with 25 mg/kg soluble pentobarbitone on the 7th day of pregnancy for once; rats in the second anesthesia group were anesthetized with 25 mg/kg soluble pentobarbitone on the 7th and the 14th days of pregnancy for once; rats in the late anesthesia group were anesthetized with 25 mg/kg soluble pentobarbitone on the 14th day of pregnancy for once; rats in the control group did not treat with anything. The time of anesthetizing was controlled in 3 to 4 hours and ether was absorbed while the time was not enough. ② Half of each group was sacrificed on day 20th of pregnancy and the fetus was taken out to be stained with alizarin red S. After stained, the fetal skeleton was examined. The learning and memorizing of one-month rats that were given birth by the rest gravid rats were tested through electric mare method. Determine their study ability according to their correct rate of 90% or above of arrival at the safe area in 20 s. After they finally learned to arrive at the safe area correctly, test them once more in 24 hours and record the correct rate of 15 times. MAIN OUTCOME MEASURES: The rate of malformation in fetus and ability of learning and memory in one-month rats. RESULTS: A total of 80 female rats were anesthetized in this experiment. Totally 490 immature rats were tested with maze testing machine and 196 fetuses were stained with alizarin red S to observe the development of their skeleton. However, one of the 80 female rats was led to death because of overdose. ① Malformation experiment: Learning ability of second anesthesia group was evidently different from the control group while the other two groups were not in the electric mare method. The fetal skeleton malformation rate of three experimental groups was 87.0%, 60.9% and 17.9%, respectively, while it was 5.6% in the control group. ② Electric mare method: Times of rats which arrived at the safe regions were respectively 49.0±31.0, 68.0±35.0, 47.0±31.0 and 44.0±21.0 in early anesthesia group, second anesthesia group, late anesthesia group and control group; and then, there was significant difference between the second anesthesia group and the control group (P < 0.05). Exact rates of memory of rats were respectively (64.36±14.35)%, (62.15±18.33)%, (54.19±12.28)% and (68.24±15.91)% in early anesthesia group, second anesthesia group, late anesthesia group and control group; and then, there were no significant differences as compared with the control group (P > 0.05). CONCLUSION: The influence of anesthesia with pentobarbital sodium is obvious in fetal skeleton development and learning and memory ability.展开更多
Oxidative stress is involved in the pathogenesis of vascular dementia. Studies have shown that lycopene can significantly inhibit oxidative stress;therefore, we hypothesized that lycopene can reduce the level of oxida...Oxidative stress is involved in the pathogenesis of vascular dementia. Studies have shown that lycopene can significantly inhibit oxidative stress;therefore, we hypothesized that lycopene can reduce the level of oxidative stress in vascular dementia. A vascular dementia model was established by permanent bilateral ligation of common carotid arteries. The dosage groups were treated with lycopene(50, 100 and 200 mg/kg) every other day for 2 months. Rats without bilateral carotid artery ligation were prepared as a sham group. To test the ability of learning and memory, the Morris water maze was used to detect the average escape latency and the change of search strategy. Hematoxylin-eosin staining was used to observe changes of hippocampal neurons. The levels of oxidative stress factors, superoxide dismutase and malondialdehyde, were measured in the hippocampus by biochemical detection. The levels of reactive oxygen species in the hippocampus were observed by dihydroethidium staining. The distribution and expression of oxidative stress related protein, neuron-restrictive silencer factor, in hippocampal neurons were detected by immunofluorescence histochemistry and western blot assays. After 2 months of drug administration,(1) in the model group, the average escape latency was longer than that of the sham group, and the proportion of straight and tend tactics was lower than that of the sham group, and the hippocampal neurons were irregularly arranged and the cytoplasm was hyperchromatic.(2) The levels of reactive oxygen species and malondialdehyde in the hippocampus of the model group rats were increased, and the activity of superoxide dismutase was decreased.(3) Lycopene(50, 100 and 200 mg/kg) intervention improved the above changes, and the lycopene 100 mg/kg group showed the most significant improvement effect.(4) Neuron-restrictive silencer factor expression in the hippocampus was lower in the sham group and the lycopene 100 mg/kg group than in the model group.(5) The above data indicate that lycopene 100 mg/kg could protect against the learning-memory ability impairment of vascular dementia rats. The protective mechanism was achieved by inhibiting oxidative stress in the hippocampus. The experiment was approved by the Animal Ethics Committee of Fujian Medical University, China(approval No. 2014-025) in June 2014.展开更多
基金financially supported by the National Natural Science Foundation of China,No.81303115,81774042 (both to XC)the Pearl River S&T Nova Program of Guangzhou,No.201806010025 (to XC)+3 种基金the Specialty Program of Guangdong Province Hospital of Chinese Medicine of China,No.YN2018ZD07 (to XC)the Natural Science Foundatior of Guangdong Province of China,No.2023A1515012174 (to JL)the Science and Technology Program of Guangzhou of China,No.20210201 0268 (to XC),20210201 0339 (to JS)Guangdong Provincial Key Laboratory of Research on Emergency in TCM,Nos.2018-75,2019-140 (to JS)
文摘Vascular etiology is the second most prevalent cause of cognitive impairment globally.Endothelin-1,which is produced and secreted by endothelial cells and astrocytes,is implicated in the pathogenesis of stroke.However,the way in which changes in astrocytic endothelin-1 lead to poststroke cognitive deficits following transient middle cerebral artery occlusion is not well understood.Here,using mice in which astrocytic endothelin-1 was overexpressed,we found that the selective overexpression of endothelin-1 by astrocytic cells led to ischemic stroke-related dementia(1 hour of ischemia;7 days,28 days,or 3 months of reperfusion).We also revealed that astrocytic endothelin-1 overexpression contributed to the role of neural stem cell proliferation but impaired neurogenesis in the dentate gyrus of the hippocampus after middle cerebral artery occlusion.Comprehensive proteome profiles and western blot analysis confirmed that levels of glial fibrillary acidic protein and peroxiredoxin 6,which were differentially expressed in the brain,were significantly increased in mice with astrocytic endothelin-1 overexpression in comparison with wild-type mice 28 days after ischemic stroke.Moreover,the levels of the enriched differentially expressed proteins were closely related to lipid metabolism,as indicated by Kyoto Encyclopedia of Genes and Genomes pathway analysis.Liquid chromatography-mass spectrometry nontargeted metabolite profiling of brain tissues showed that astrocytic endothelin-1 overexpression altered lipid metabolism products such as glycerol phosphatidylcholine,sphingomyelin,and phosphatidic acid.Overall,this study demonstrates that astrocytic endothelin-1 overexpression can impair hippocampal neurogenesis and that it is correlated with lipid metabolism in poststroke cognitive dysfunction.
基金supported by National Natural Science Foundation of China [No. 81773405 to Y.Q. and No. 82173644to X.Y.]Shanxi Natural Science Foundation of China [No.202203021211246 and No. 202103021224242]。
文摘Objective Arsenic(As) and fluoride(F) are two of the most common elements contaminating groundwater resources. A growing number of studies have found that As and F can cause neurotoxicity in infants and children, leading to cognitive, learning, and memory impairments. However, early biomarkers of learning and memory impairment induced by As and/or F remain unclear. In the present study, the mechanisms by which As and/or F cause learning memory impairment are explored at the multi-omics level(microbiome and metabolome).Methods We stablished an SD rats model exposed to arsenic and/or fluoride from intrauterine to adult period.Results Arsenic and/fluoride exposed groups showed reduced neurobehavioral performance and lesions in the hippocampal CA1 region. 16S rRNA gene sequencing revealed that As and/or F exposure significantly altered the composition and diversity of the gut microbiome, featuring the Lachnospiraceae_NK4A136_group, Ruminococcus_1, Prevotellaceae_NK3B31_group, [Eubacterium]_xylanophilum_group. Metabolome analysis showed that As and/or F-induced learning and memory impairment may be related to tryptophan, lipoic acid, glutamate, gamma-aminobutyric acidergic(GABAergic) synapse, and arachidonic acid(AA) metabolism. The gut microbiota, metabolites, and learning memory indicators were significantly correlated.Conclusion Learning memory impairment triggered by As and/or F exposure may be mediated by different gut microbes and their associated metabolites.
文摘Aim: To observe the rats’ learning and memory acquisition ability disturbance induced by BI-D1870. Methods: Male SD rats were randomly divided into control group, solvent control group and BI-D1870 group. The rats in the control group were intraperitoneally injected with saline, while those in the solvent control group were intraperitoneally injected with DMSO + sulfobutyl-β-cyclodextrin solvent, and those in the BI-D1870 group were intraperitoneally injected with BI-D1870. All the rats’ appearance and behavior were daily observed, and body weight was recorded on the day 15, 30, 45, 60, 75 and 82 of BI-D1870 injected. Morris water maze was used to screen the rats’ learning and memory acquisition ability on the day 22 - 25, 52 - 55, and 82 - 85 of training by BI-D1870 treated. The successful rates of the rats’ memory impairment were respectively calculated for three times screening. Results: During the whole experiment, there was no obvious difference in appearance and fur color in all rats. The rats’ agitation began to appear on the day 10th of BI-D1870 given. The agitation rats’ number and rats’ body weight gradually increased along with BI-D1870 treated (P P Conclusion: Intraperitoneal injection of BI-D1870 can induce the rats’ learning and memory acquisition ability disorder.
基金supported by the National Natural Science Foundation of China,No.82101567Doctoral Start-up Foundation of Liaoning Province,No.2021-BS-111345 Talent Project of Shengjing Hospital of China Medical University,No.M0673(all to XYF)。
文摘Cerebral ischemia/reperfusion injury impairs learning and memory in patients.Studies have shown that synaptic function is involved in the formation and development of memory,and that DNA methylation plays a key role in the regulation of learning and memory.To investigate the role of DNA hypomethylation in cerebral ischemia/reperfusion injury,in this study,we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery and then treated the rats with intraperitoneal 5-aza-2′-deoxycytidine,an inhibitor of DNA methylation.Our results showed that 5-aza-2′-deoxycytidine markedly improved the neurological function,and cognitive,social and spatial memory abilities,and dose-dependently increased the synaptic density and the expression of SYP and SHANK2 proteins in the hippocampus in a dose-dependent manner in rats with cerebral ischemia/reperfusion injury.The effects of 5-aza-2′-deoxycytidine were closely related to its reduction of genomic DNA methylation and DNA methylation at specific sites of the Syp and Shank2 genes in rats with cerebral ischemia/reperfusion injury.These findings suggest that inhibition of DNA methylation by 5-aza-2′-deoxycytidine promotes the recovery of learning and memory impairment in a rat model of cerebral ischemia/reperfusion injury.These results provide theoretical evidence for stroke treatment using epigenetic methods.
文摘Microglia are the resident macrophages of the central nervous system.Microglia possess varied morphologies and functions.Under normal physiological conditions,microglia mainly exist in a resting state and constantly monitor their microenvironment and survey neuronal and synaptic activity.Through the C1 q,C3 and CR3"Eat Me"and CD47 and SIRPα"Don't Eat Me"complement pathways,as well as other pathways such as CX3 CR1 signaling,resting microglia regulate synaptic pruning,a process crucial for the promotion of synapse formation and the regulation of neuronal activity and synaptic plasticity.By mediating synaptic pruning,resting microglia play an important role in the regulation of experience-dependent plasticity in the barrel cortex and visual cortex after whisker removal or monocular deprivation,and also in the regulation of learning and memory,including the modulation of memory strength,forgetfulness,and memory quality.As a response to brain injury,infection or neuroinflammation,microglia become activated and increase in number.Activated microglia change to an amoeboid shape,migrate to sites of inflammation and secrete proteins such as cytokines,chemokines and reactive oxygen species.These molecules released by microglia can lead to synaptic plasticity and learning and memory deficits associated with aging,Alzheimer's disease,traumatic brain injury,HIV-associated neurocognitive disorder,and other neurological or mental disorders such as autism,depression and post-traumatic stress disorder.With a focus mainly on recently published literature,here we reviewed the studies investigating the role of resting microglia in synaptic plasticity and learning and memory,as well as how activated microglia modulate disease-related plasticity and learning and memory deficits.By summarizing the function of microglia in these processes,we aim to provide an overview of microglia regulation of synaptic plasticity and learning and memory,and to discuss the possibility of microglia manipulation as a therapeutic to ameliorate cognitive deficits associated with aging,Alzheimer's disease,traumatic brain injury,HIV-associated neurocognitive disorder,and mental disorders.
基金supported by the National Natural Science Foundation of China(61401497)
文摘With key roles in essential brain functions ranging from the long-term potentiation(LTP) to synaptic plasticity,the N-methyl-D-aspartic acid receptor(NMDAR) can be considered as one of the fundamental glutamate receptors in the central nervous system.The role of NMDA R was first identified in synaptic plasticity and has been extensively studied.Some molecules,such as Ca^(2+),postsynaptic density 95(PSD-95),calcium/calmodulin-dependent protein kinase II(Ca MK II),protein kinase A(PKA),mitogen-activated protein kinase(MAPK) and cyclic adenosine monophosphate(c AMP) responsive element binding protein(CREB),are of special importance in learning and memory.This review mainly focused on the new research of key molecules connected with learning and memory,which played important roles in the NMDAR signaling pathway.
基金supported by the National Natural Science Foundation of China,No.81303097,81373794
文摘Damage to synaptic plasticity induced by neurotoxicity of amyloid-beta is regarded to be one of the pathological mechanisms of learning and memory disabilities in Alzheimer's disease patients.This study assumed that the damage of amyloid-beta to learning and memory abilities was strongly associated with the changes in the Fyn/N-methyl-D-aspartate receptor 2B(NR2B) expression.An APP695V7171 transgenic mouse model of Alzheimer's disease was used and treatment with tetrahydroxy-stilbene glucoside was administered intragastrically.Results showed that intragastric administration of tetrahydroxy-stilbene glucoside improved the learning and memory abilities of the transgenic mice through increasing NR2 B receptors and Fyn expression.It also reversed parameters for synaptic interface structure of gray type I.These findings indicate that tetrahydroxy stilbene glucoside has protective effects on the brain,and has prospects for its clinical application to improve the learning and memory abilities and treat Alzheimer's disease.
基金the National Natural Science Foundation of China, No. 03030307 the Great Special Fund of Guangdong Province, No. 2004A30201002
文摘BACKGROUND: Transplantation of fetal cell suspension or blocks of fetal tissue can ameliorate the nerve function after the injury or disease in the central nervous system, and it has been used to treat neurodegenerative disorders induced by Parkinson disease. OBJECTIVE: To observe the effects of the transplantation of neuron-like cells derived from bone marrow stromal cells (rMSCs) into the brain in restoring the dysfunctions of muscle strength and balance as well as learning and memory in rat models of cerebral infarction. DESIGN: A randomized controlled experiment. SETTING: Department of Pathophysiology, Zhongshan Medical College of Sun Yat-sen University. MATERIALS: Twenty-four male SD rats (3-4 weeks of age, weighing 200-220 g) were used (Certification number:2001A027). METHODS: The experiments were carried out in Zhongshan Medical College of Sun Yat-sen University between December 2003 and December 2004. ① Twenty-four male SD rats randomized into three groups with 8 rats in each: experimental group, control group and sham-operated group. Rats in the experiment al group and control group were induced into models of middle cerebral artery occlusion. After in vitro cultured, purified and identified with digestion, the Fischer344 rMSCs were induced to differentiate by tanshinone ⅡA, which was locally injected into the striate cortex (18 area) of rats in the experimental group, and the rats in the control group were injected by L-DMEM basic culture media (without serum) of the same volume to the corresponding brain area. In the sham-operated group, only muscle and vessel of neck were separated. ② At 2 and 8 weeks after the transplantation, the rats were given the screen test, prehensile-traction test, balance beam test and Morris water-maze test. ③ The survival and distribution of the induced cells in corresponding brain area were observed with Nissl stained with toluidine blue and hematoxylin and eosin (HE) staining in the groups. MAIN OUTCOME MEASURES: ① Results of the behavioral tests (time of the Morris water-maze test screen test, prehensile-traction test, balance beam test); ② Survival and distribution of the induced cells. RESULTS: All the 24 rats were involved in the analysis of results. ① Two weeks after transplantation, rats with neuron-like cells grafts in the experimental group had significant improvement on their general muscle strength than those in the control group [screen test: (9.4±1.7), (4.7±1.0) s, P < 0.01]; forelimb muscle strength [prehensile-traction test: (7.6±1.4), (5.2±1.2) s, P < 0.01], ability to keep balance [balance beam test: (7.9±0.74), (6.1±0.91) s, P < 0.01] and abilities of learning and memory [latency to find the platform: (35.8±5.9), (117.5±11.6) s, P < 0.01; distance: (623.1±43.4), (1 902.3±98.6) cm, P < 0.01] as compared with those in the control group. The functional performances in the experimental group at 8 weeks were better than those at two weeks, which were still obviously different from those in the sham-operated group (P < 0.05). ② The HE and Nissl stained brain tissue section showed that there was nerve cell proliferation at the infarcted cortex in the experiment group, the density was higher than that in the control group, plenty of aggregative or scattered cells could be observed at the site where needle was inserted for transplantation, the cells migrated directively towards the area around them, the cerebral vascular walls were wrapped by plenty of cells; In the control group, most of the cortices were destroyed, karyopyknosis and necrosis of neurons were observed, normal nervous tissue structure disappeared induced by edema, only some nerve fibers and glial cells remained. CONCLUSION: The rMSCs transplantation can obviously enhance the motor function and the abilities of learning and memory in rat models of cerebral infarction.
基金the National Natural Science Foundation of China, No. 30170300 30300109
文摘BACKGROUND: Tetramethylpyrazine (TMP) presents the effect of anti-platelet aggregation, reduces arterial resistance, increases cerebral blood flow, and improves microcirculation. OBJECTIVE: To observe the effects of TMP on the learning and memory abilities and the number of neurons in cortex and hippocampus after focal cerebral ischemia in rats DESIGN: A randomized controlled trial. SETTING: Department of Human Anatomy and Histological Embryology, School of Medicine, Xi’an Jiaotong University. MATERIALS: Fifty adult male Sprague-Dawley rats, weighing 250-300 g were supplied by the Experimental Animal Center, School of Medicine, Xi’an Jiaotong University. TMP was purchased from Wuxi Seventh Pharmaceutical Co.Ltd (Lot Number: 2004051106, Specification: 2 mL/piece). METHODS: The experiments were carried out in School of Medicine of Xi’an Jiaotong University from June 2004 to May 2005. The 50 rats were randomly divided into five groups according to the random number table method: sham-operated group, cerebral ischemia control group, low-dose TMP group, middle-dose TMP group and high-dose TMP group, 10 rats in each group. Rats in the TMP groups were immediately treated with intraperitoneal injection of TMP of 40, 80 and 120 mg/kg respectively, and those in the sham-operated group and cerebral ischemia control group were injected intraperitoneally by isovolume saline, once a day for 14 days successively. On the 15th day, the spatial learning and memory abilities of the rats were assessed with the Morris water maze test, and then the changes of neuron numbers in cortex and hippocampus were observed by Nissl staining of brain sections. MAIN OUTCOME MEASURES: The results of Morris water maze test and the changes of neuron numbers in cortex and hippocampus by Nissl staining of brain sections were observed. RESULTS: Finally 39 rats were involved in the analysis of results, and the other 11 died of excessive anesthesia or failure in model establishment. ① The rats in the cerebral ischemia control group manifested obvious spatial cognitive deficits in the place navigation trial and spatial probe trial. The mean values of escape latency in the sham-operated group, low, middle and high-dose TMP groups were obviously shorter than that in the cerebral ischemia control group [(23.92±2.21), (41.84±3.74), (39.50±3.80), (31.38±3.72), (61.60±3.61) s, P < 0.05-0.01]. In the spatial probe trial, significant differences in the percentage of time spending in the former platform quadrant and frequency of crossing the former platform site in the sham-operated group, lose, middle and high-dose TMP groups were obviously higher or more than those in the cerebral ischemia control group [(36.27±3.42) %, (35.84±2.54)%, (38.43±3.08)%, (36.51±1.96)%, (22.24±3.46)%; (11±1), (10±1), (8±1), (8±1), (4±1) times, P < 0.01]. ② In the morphological observation, the numbers of neurons in ipsilateral (left) parietal cortex in the sham-operated group, low, middle and high-dose TMP groups were obviously more than that in the cerebral ischemia control group [(98±8), (65±5), (53±6), (57±6), (37±6)/0.625 mm2, P < 0.01], but the number of neurons in left hippocampus had no obvious differences among the groups (P > 0.05). CONCLUSION: TMP can improve obviously the spatial learning and memory function after permanent focal cerebral ischemia in rats, and the neuroprotective role of the drug in cortex may be involved in its mechanism.
基金supported by grants from the National Science and Technology Major Project(2014ZX09J14102-05B and 2018ZX09J18109)。
文摘Background:Studies have revealed the protective effect of DL-3-n-butylphthalide(NBP)against diseases associated with ischemic hypoxia.However,the role of NBP in animals with hypobaric hypoxia has not been elucidated.This study investigated the effects of NBP on rodents with acute and chronic hypobaric hypoxia.Methods:Sprague-Dwaley rats and Kunming mice administered with NBP(0,60,120,and 240 mg/kg for rats and 0,90,180,and 360 mg/kg for mice)were placed in a hypobaric hypoxia chamber at 10,000 m and the survival percentages at 30 min were determined.Then,the time and distance to exhaustion of drug-treated rodents were evaluated during treadmill running and motor-driven wheel-track treadmill experiments,conducted at 5800 m for 3 days or 20 days,to evaluate changes in physical functions.The frequency of active escapes and duration of active escapes were also determined for rats in a shuttle-box experiment,conducted at 5800 m for 6 days or 27 days,to evaluate changes in learning and memory function.ATP levels were measured in the gastrocnemius muscle and malonaldehyde(MDA),superoxide dismutase(SOD),hydrogen peroxide(H_(2)O_(2)),glutathione peroxidase(GSH-Px),and lactate were detected in sera of rats,and routine blood tests were also performed.Results:Survival analysis at 10,000 m indicated NBP could improve hypoxia tolerance ability.The time and distance to exhaustion for mice(NBP,90 mg/kg)and time to exhaustion for rats(NBP,120 and 240 mg/kg)significantly increased under conditions of acute hypoxia compared with control group.NBP treatment also significantly increased the time to exhaustion for rats when exposed to chronic hypoxia.Moreover,240 mg/kg NBP significantly increased the frequency of active escapes under conditions of acute hypoxia.Furthermore,the levels of MDA and H_(2)O_(2) decreased but those of SOD and GSH-Px in the sera of rats increased under conditions of acute and chronic hypoxia.Additionally,ATP levels in the gastrocnemius muscle significantly increased,while lactate levels in sera significantly decreased.Conclusion:NBP improved physical and learning and memory functions in rodents exposed to acute or chronic hypobaric hypoxia by increasing their anti-oxidative capacity and energy supply.
基金the Natural Sci-ence Foundation of HenanProvince, No. 984021100 agrant from Key Subject Fund ofXinxiang Medical College
文摘BACKGROUD: Ethanol can influence neural development and the ability of learning and memory, but its mechanism of the neural toxicity is not clear till now. Endogenous nitric oxide (NO) as a gaseous messenger is proved to play an important role in the formation of synaptic plasticity, transference of neuronal information and the neural development, but excessive nitro oxide can result in neurotoxicity. OBJECTIVE: To observe the effects of acute alcoholism on the learning and memory ability and the content of neuronal nitric oxide synthase (nNOS) in brain tissue of rats. DESIGN: A randomized controlled animal experiment. SETTING: Department of Physiology, Xinxiang Medical College. MATERIALS: Eighteen male clean-degree SD rats of 18-22 weeks were raised adaptively for 2 days, and then randomly divided into control group (n = 8) and experimental group (n = 10). The nNOS immunohistochemical reagent was provided by Beijing Zhongshan Golden Bridge Biotechnology Co.,Ltd. Y-maze was produced by Suixi Zhenghua Apparatus Plant. METHODS: The experiment was carried out in the laboratory of the Department of Physiology, Xinxiang Medical College from June to October in 2005. ① Rats in the experimental group were intraperitoneally injected with ethanol (2.5 g/kg) which was dissolved in normal saline (20%). The loss of righting reflex and ataxia within 5 minutes indicated the successful model. Whereas rats in the control group were given saline of the same volume. ② Examinations of learning and memory ability: The Y-maze tests for learning and memory ability were performed at 6 hours after the models establishment. The rats were put into the Y-maze separately. The test was performed in a quiet and dark room. There was a lamp at the end of each of three pathways in Y-maze and the base of maze had electric net. All the lamps of the three pathways were turned on for 3 minutes and then turned off. One lamp was turned on randomly, and the other two delayed automatically. In 5 seconds after alternation, pulsating electric current presented in the base of unsafe area to stimulate rat’s feet to run to the safe area. The lighting lasted for 15 seconds as one test. Running from unsafe area to safe area at one time in 10 seconds was justified as successful. Such test was repeated for 10 times for each rat and the successful frequency was recorded. The qualified standard of maze test was that the rat arrived in the safe area 9 times during 10 experiments. The number of trainings for the qualified standard was used to represent the result of spatial learning. ③ Determination of the content of nNOS in brain tissue: After the Y-maze test, the rats were anaesthetized, and blood was let from the incision on right auricle, transcardially perfused via the left ventricle with about 200 mL saline, then fixed by perfusion of 40 g/L paraformaldehyde. Hippocampal CA1 region, corpus striatum and cerebellum were taken to prepare serial freezing coronal sections. The nNOS contents in the brain regions were determined with the immunohistochemical methods to reflect the changes of nitric oxide in brain tissue. MAIN OUTCOME MEASURES: The changes of learning and memory ability and the changes of the nNOS contents in the brain tissue of rats with acute alcoholism were observed. RESULTS: One rat in the experimental group was excluded due to its slow reaction to electric stimulation in the Y-maze test, and the other 17 rats were involved in the analysis of results. ① The training times to reach qualifying standards of Y-maze in the experimental group was more than that in the control group [(34.33 ±13.04), (27.50±8.79) times, P < 0.05]. ② Forms and numbers of nNOS positive neurons in brain tissue: It could be observed under light microscope that in the hippocampal CA1 region, there were fewer nNOS positive neurons, which were lightly stained, and the processes were not clear enough; But the numbers of the positive neurons which were deeply stained as buffy were obviously increased in the experimental group, the cell body and cytoplasm of process were evenly stained, but the nucleus was not stained. The nNOS positive neurons in corpus striatum had similar forms and size in the experimental group and control group. The form of the nNOS positive neurons in cerebellum were similar between the two groups. The numbers of nNOS positive neurons in hippocampal CA1 region and corpus striatum in the experimental group [(18.22±7.47), (11.38±5.00) cells/high power field] were obviously higher than those in the control group [(10.15±4.24), (6.15±3.69) cells/high power field. The number of nNOS positive neurons in cerebellum had no significant difference between the two groups [(49.56±18.84), (44.43±15.42) cells/high power field, P > 0.05]. CONCLUSION: Acute alcoholism may impair learning and memory ability, and nitric oxide may be involved in mediating the neurotoxic role of ethanol.
文摘BACKGROUND: Central adrenergic nerve and 5-serotonergic nerve can influence central cholinergic nerve on learning and memory and make easy for study; however, ginsenoside of stem and leaf (GSL) can improve functions of central adrenergic nerve; moreover, 5-serotonergic nerve and the combination with choline can produce synergistic effect and enhance learning and memory ability so as to improve learning and memory disorder of patients with Alzheimer disease (AD). OBJECTIVE: To observe the effects of GSL combining with choline on learning and memory of AD model rats.DESIGN: Randomized grouping design and controlled animal study.SETTING: Department of Pharmacology, Taishan Medical College. MATERIALS: The experiment was carried out in the Pharmacological Department of Medical College of Jilin University from October 1996 to January 1997. Forty healthy male Wistar rats of clean grade were randomly divided into 5 groups, including sham-injury group, model group, GSL group, choline group and combination group, with 8 rats in each group. Main medications: GSL with the volume more than 92.8% was provided by Department of Chemistry, Norman Bethune Medical College of Jilin University. Panaxatriol, the main component, was detected with thin layer scanning technique and regarded as the index of GSL quality [(55±1)%, CV = 2%, n = 5]. Choline was provided by the Third Shanghai Laboratory Factory. METHODS: 150 nmol quinolinic acid was used to damage bilateral Meynert basal nuclei of adult rats so as to establish AD models. Rats in GSL, choline and combination groups were intragastric administrated with 400 mg/kg GSL, 200 mg/kg choline (20 mL/kg), and both respectively last for 17 days starting from two days before operation. Rats in sham-injury group and model group were perfused with the same volume of distilled water once in each morning for the same days. ① Passive avoidance step-down test: Five minutes later, rats jumped up safe platform when they were shocked with 36 V alternating current. If rats jumped down from the platform and the feet touched railings, the response was wrong. Numbers of wrong response were recorded within 3 minutes, and then the test was redone after 24 hours. ② Morris water-maze spatial localization task: Swimming from jumping-off to platform directly was regarded as right response. Additionally, 4 successively right responses were regarded as the standard. Each rat was trained 10 times a day with 120 s per time for 3 successive days. The interval was 30 s. Three days later, numbers of right response were recorded. The training times were increased to 30 for unlearned rats. ③ Measurement of activity of choilne acetylase in cerebral cortex: Rats were sacrificed at 17 days after operation to obtain cerebral cortex to measure activity of choilne acetylase with radiochemistry technique. ④ Synergistic effect: It was expressed as Q value: Q value = factual incorporative effect/anticipant incorporative effect; Q ≥ 1 was regarded as synergistic effect. Anticipant incorporative effect = (EA+EB-EA·EB), EA and EB were single timing effect, respectively in GSL group and choline group. E (step-down test and Morris water maze test) = (x in model group - factual value in medicine groups)/x in model group; E (activity of choilne acetylase) = (factual value in medicine groups -x in model group)/x in model group. MAIN OUTCOME MEASURES: ① Passive avoidance step-down test and Morris water-maze spatial localization task in the study of learning and memory; ② activity of choilne acetylase. RESULTS: All 40 rats were involved in the final analysis. ① Passive avoidance response: At learning phase on first day and retesting phase on the next day, numbers of wrong responses within 3 minutes were more in model group than sham operation group, and there was significant difference [(5.88±1.46), (2.25±0.87) times; (2.63±1.06), (0.50±0.53) times; P < 0.01]; numbers of wrong responses within 3 minutes were less in combination group than model group, and there was significant difference [learning phase: (1.12±0.83), (5.88±1.46) times; retesting phase: (0.38±0.74), (2.63±1.06) times, P < 0.01]; moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.07 and 1.59, respectively and it showed synergistic effect. ② Spatial localization task: Training times were more in model group than sham operation group, and there was significant difference [(2.9±2.5), (12.6±3.5) times; P < 0.01]. Training times were less in combination group than model group, and there was significant difference [(11.8±2.4), (27.9±2.5) times, P < 0.01]; moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.07 and it showed synergistic effect. ③ Activity of choilne acetylase: Activity was lower in model group than sham operation group, and there was significant difference [(30.56±8.33), (61.11±8.33) nkat/g; P < 0.01]. Activity was higher in combination group than model group and there was significant difference [(50.00±8.33), (30.56±8.33) nkat/g, P < 0.01]; moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.5 and it showed synergistic effect. CONCLUSION: GSL in combination with choline can synergically improve the disorder of learning and memory of AD model rats. Its mechanism may be involved in enhancing the function of central cholinergic system.
基金Natural Science Foundation of Shandong Province(ZR2017MH048)。
文摘OBJECTIVE Microglia M1/M2 po⁃larization play pro-inflammatory and anti-inflam⁃matory roles,respectively,which is involved in memory decline.There is a close relationship between impaired baroreflex function and memory impairment.The present study was designed to investigate whether arterial baroreflex deficiency induced by sinoaortic denervation(SAD)affected inflammation through modulation of M1/M2 polar⁃ization leading to the aggravation of learning and memory disorders in rats.METHODS Adult male SD rats were divided into four groups:the sham control,the SAD,the sham+scopolamine,the SAD+scopolamine.In another experiment,there were also four groups:the sham control,the SAD,the SAD+scopolamine and the SAD+scopolamine+ketanserin.All rats were examined for various behaviors using Morris water maze test,new object recognition test,and light dark shuttle test and Y maze test 4 weeks after sham or SAD surgery.CD16,CD206,IL-10,IL-6,IL-1βand TNF-αfrom hippocampus using Western blotting,immunofluorescence and turbidimetry.RESULTS Compared with the sham+scopol⁃amine,the SAD+scopolamine rats showed the reduced crossing times in Morris water maze test,the longer residence time in dark box during light dark shuttle test,and the decreased alterna⁃tion ratio in Y maze test.The level of CD206,IL-10,T-AOC and GSH was decreased,whereas CD16,IL-6,TNF-α,MDA was increased in the hippocampus of SAD+scopolamine rats.Addi⁃tionally,all the above changes were improved in the SAD+scopolamine+ketanserin rats when compared with the SAD+scopolamine.CONCLU⁃SION Arterial baroreflex dysfunction aggravates learning and memory disorders in rats,which may be related to the polarization of microglia.
文摘BACKGROUND: Calcitonin gene-related peptide (CGRP) and nerve growth actor (NGF) cam improve spatial learning and memory abilities of rats with cerebral ischemia/reperfusion; however, the effect of combination of them on relieving learning and memory injury following cerebral ischemia/reperfusion should be further studied. OBJECTIVE: To study the effects of exogenous CGRP and NGF on learning and memory abilities of rats with focal cerebral ischemia/reperfusion. DESIGN: Randomized controlled animal study. SETTING: Department of Neurosurgery, the Second Hospital of Xiamen; Department of Neurosurgery, the Second Affiliated Hospital of China Medical University; Department of Neurobiology, Basic Medical College of China Medical University. MATERIALS: A total of 30 healthy male SD rats, aged 8 weeks, of clean grade, weighing 250-300 g, were provided by Experimental Animal Department of China Medical University. All rats were randomly divided into sham-operation group, ischemia/reperfusion group and treatment group with 10 in each group. The main reagents were detailed as the follows: 100 g/L chloral hydrate, 0.5 mL CGRP (2 mg/L, Sigma Company, USA), and NGF (1× 106 U/L, 0.5 mL, Siweite Company, Dalian). METHODS: The experiment was carried out in the Department of Neurobiology, Basic Medical College of China Medical University from February to July 2005. Rat models of middle cerebral artery occlusion were established by method of occlusion, 2 hours after that rats were anesthetized and the thread was slightly drawn out for 10 mm under direct staring to perform reperfusion. Rats in the ischemia/reperfusion group received intraperitoneal injection of 1 mL saline via the abdomen at two hours later, while rats in the treatment group at 2 hours later received intraperitoneal injection of 2 mg/L CGRP (0.5 mL) and 1×106 U/L NGF (0.5 mL) once a day for 10 successive days. First administration was accomplished within 15 minutes after ischemia/reperfusion. Rats in the sham-operation group were separated of the vessels without occlusion or administration. The neural function was evaluated with Zea Longa 5-grade scale. Animals with the score of one, two and three points received Morris water-maze test to measure searching time on platform (omitting platform-escaping latency). Meanwhile, leaning and memory abilities of animals were reflected through testing times of passing through platform per minute. MAIN OUTCOME MEASURES: Experimental results of omitting platform-escaping latency and spatial probe. RESULTS: Three and two rats in the ischemia/reperfusion group and treatment group respectively were not in accordance with the criteria in the process, and the rest were involved in the final analysis. ① Comparisons of platform-escaping latency during Morris water-maze test in all the three groups: Ten days after modeling, the platform-escaping latency in the ischemia/reperfusion group was obviously longer than that in sham-operation group (P < 0.01), and was significantly shorter than that in the treatment group (P < 0.01). ② Comparisons of times of passing through platform in all the three groups: Times of passing through platform were remarkably less in the ischemia/reperfusion group than those in the sham-operation group [(1.79±0.39), (4.30±0.73) times/minute, P < 0.01], and those were markedly more in the treatment group than the ischemia/reperfusion group [(3.16±1.03), (1.79±0.39) times/minute, P < 0.01]. CONCLUSION: CGRP and NGF are capable of ameliorating the abilities of spatial learning and memory in MCAO rats, which indicates that CGRP and NGF can protect ischemic neurons.
基金National Natural Science Foundation of China(81400182)and Natural Science Foundation of Shandong Province(BS2014YY045)。
文摘OBJECTIVE To observe the effects of betaine on learning memory in SHR rats through behavioral experiments,and then to investigate the mechanisms of betaine to improve the cognitive impairment caused by hyperten⁃sion.METHODS 4-month-old male SHR rats were randomly divided into 4 groups,including betaine 10,30 and 100 mg·kg-1 groups and SHR group,and administered by gavage,10 mL·kg-1 once a day for 4 weeks.The control group was WKY rats,and the same amount of saline was given by gavage.The learning and memory behaviors of the rats were analyzed and evaluated through behavioral testing.RESULTS The results of Morris water maze showed that persistent hypertension decreased the time in the target quadrant and the number of platform crossing of the rats,and the intervention with different con⁃centrations of betaine increased the time in the target quadrant and the number of platform crossing of SHR in a dose-dependent manner.Then,persistent hypertension increased the escape latency of rats,and betaine inhibited this change.The results of new object recognition showed that the recognition index of SHR group decreased,and the recognition index of SHR rats increased with different concentrations of betaine intervention in a dose-dependent manner.The Y-maze results showed that persistent hypertension decreased the alternation in rats,and the alternation in SHR rats increased after the intervention with different concentrations of betaine,and in a dose-dependent manner.CON⁃CLUSION Persistent hypertension can cause learning memory impairment in rats.Betaine intervention has an ameliorative effect on the reduction of learning memory ability in rats caused by hypertension.
基金Supported by the National Natural Science Foundation of China(32273078)the Applied Technology Research and Development Plan of Heilongjiang Province(GX18B023)。
文摘This study aimed to elucidate whether midazolam affected the learning and memory of rats through the extracellular signal-regulated kinase(ERK)/cyclic adenosine monophosphate response element-binding(CREB)signaling pathway and hippocampal oxidative damage.Overall 120 Wistar rats were randomly assigned to four groups,including one control and three midazolam-exposed groups(20,60 and 150 mg•kg^(-1)).After an intraperitoneal injection of midazolam/physiological saline for both 1 h(n=15)and 24 h(n=15),10 rats(five came from 1 h,and the remaining five came from 24 h)were randomly selected from each group for the Morris water maze test.The hippocampus tissue samples were harvested for the assessment of superoxide dismutase(SOD)and catalase(CAT)activities as well as glutathione peroxidase(GPx),malonyl dialdehyde(MDA),nitric oxide(NO)and inducible nitric oxide synthase(iNOS)levels.The remaining 80 rats were euthanized,and the hippocampal tissue was isolated.The expressions of ERK1,ERK2 and CREB mRNA were tested using RT-qPCR.The protein expressions of p-ERK1/2 and p-CREB were tested using Western blotting.The Morris water maze tests indicated that midazolam-treated rats have weaker learning and memory ability compared to the control rats.Midazolam increased MDA,NO,iNOS and CAT,and decreased GPx and SOD activities compared to the control group.The expression levels of ERK1/2 and CREB in the hippocampus of rats in the midazolam treatment groups were significantly lower compared to the control group at 1 h after intraperitoneal injection of midazolam,and in a dose-dependent relationship but returning it to normal levels at 24 h after midazolam intraperitoneal injection.Therefore,it was concluded that the learning and memory impairment of midazolam might be associated with the down-regulation of the ERK/CREB signaling pathway and oxidative damage in rat hippocampus.
基金Research Project of Health Commission of Hubei Province(WJ2017F072):Study on Brain Function Imaging Mechanism of Scalp Acupuncture Treatment of Post-Stroke Depression.
文摘[Objectives]To evaluate the effects of Tongdu Tiaoshen Acupuncture method on improving learning and memory function and hippocampal nerve regeneration and repair after stroke.[Methods]Animal models of cognitive impairment in the recovery phase of cerebral infarction in rats were prepared,and rats were randomly divided into control group,model group,donepezil group,and acupuncture group.Morris water maze experiment was carried out to evaluate learning and memory ability.Nissl staining,BrdU and DCX immunofluorescence staining were used to observe the number and morphological structure of neuronal pyramidal and granular cells in the dentate gyrus(DG)area of the hippocampus,as well as the proliferation and differentiation of neural progenitor cells.TUNEL method was used to detect cell apoptosis.[Results]Before intervention,the scores and ELP of the model group,donepezil group and acupuncture group were significantly higher than those of the blank group(P<0.05);after the intervention,the neurological scores and ELP of the blank group and the model group were not significantly different from those before the intervention(P<0.05);the donepezil group and acupuncture group were significantly reduced,there was no difference between the donepezil group and acupuncture group(P>0.05),but it was still significantly higher than the blank group(P<0.05).The results of BrdU and DCX immunofluorescence staining showed that there were only a few BrdU positive cells and DCX protein in the hippocampal DG area of mice in the blank group,and the positive cells in the model group were significantly increased(P<0.05);donepezil group and acupuncture group showed significant increase compared with the model group(P<0.05);compared with the blank group,the number of neurons in the hippocampal DG area of each group was significantly reduced(P<0.01),and the neuronal apoptosis index was significantly increased(P<0.01);compared with the blank group,the number of neurons in the hippocampal DG area of each group was significantly reduced(P<0.01),and the neuronal apoptosis index was significantly increased(P<0.01).The number of neurons in the hippocampal DG area of rats in the acupuncture group and donepezil group was significantly increased(P<0.01),and the neuronal apoptosis index was significantly decreased(P<0.01).[Conclusions]Tongdu Tiaoshen Acupuncture method can improve the learning and memory function of stroke model rats by promoting the regeneration and repair of hippocampal nerve in rats with cerebral infarction.
基金The project supported by National College Students'Innovative and Entrepreneurial Training Project(201510439078)Science and Technology Development Plan of Tai'an City(201540707)
文摘OBJECTIVE To investigate the influence of gingerol on the improvement of learning and memory impairment of rat model of Alzheimer disease induced by β-amyloid peptide fragment 25-35(Aβ_(25-35)) and to analysis the possible mechanism. METHODS SD rats were randomly divided into 5groups: blank control group,model group,sham-operated group,low dose drug group(gingerol emulsion,10 mg·kg^(-1)·d^(-1)),high dose drug group(gingerol emulsion,50 mg·kg^(-1)·d^(-1)). Model group and two drug groups were injected Aβ_(25-35)(5 μL) in lateral cerebral ventricle. Sham-operated group were injected the same amount of sterile PBS solution. For blank control group without any treatment. When all the rats refresh themselves and had post-operated activities,two drug groups were gavaged with different concentration of gingerol emulsion,Meanwhile,sham-operated group were gavaged with sterile physiological saline,the remaining two groups without any treatment. After three weeks,we make use of Y labyrinth to test the ability of space learning and memory of rats. Finally,rats were sacrificed to collect blood by abdominal aortic method. The content of acetylcholine(ACh),SOD and MDA were detected in serum. RESULTS(1) Compared with blank control group,the ability of learning and memory of model group rats were weakened,the error times increased in Y labyrinth experiment. In addition,the content of ACh and the activity of SOD significantly decreased,the content of MDA increased(P<0.05).(2) On the contrary,the rats gavaged with gingerol emusion have less error times in Y labyrinth experiment compared with model group. the content of Ach and the activity of SOD significantly increased,the content of MDA decreased(P<0.05). However,two different gingerol emusion concentration groups have no significantly difference. CONCLUSION The ability of learning and memory of rats gavaged with gingerol emusion were significantly improved compared with Aβ_(25-35) induced rats without any treatment.Its mechanism may be related to antioxidant and neurotransmitter.
文摘BACKGROUND: Generally speaking, anesthesia is often used in gravid body and it has been already proved that many kind of medicine can result in malformation. OBJECTIVE: To explore embryonic skeleton development and neonatal learning and memory of rats anesthetized with pentobarbital sodium in gravid rats. DESIGN: A randomized control trial. SETTING: Laboratory Animal Center of Xuzhou Medical College. MATERIALS: A total of 80 adult female SD rats, of clean grade and weighing 220-240 g, were selected in this study. The main reagents were detailed as follows: pentobarbital sodium (Shanghai Xingzhi Chemical Plant, batch number: 921019); MG-2 maze test apparatus (Zhangjiagang Biomedical Instrument Factory); somatotype microscope (Beijing Taike Instrument Co., Ltd.). METHODS: ① A total of 160 SD rats of half males and females were selected in this study. All rats were copulated. The day that the plug was checked out in the vagina next day was looked as the first day of pregnancy. Gravid rats were divided randomly into four groups, including early anesthesia group, second anesthesia group, late anesthesia group and control group with 20 in each group. Rats in the early anesthesia group were injected with 25 mg/kg soluble pentobarbitone on the 7th day of pregnancy for once; rats in the second anesthesia group were anesthetized with 25 mg/kg soluble pentobarbitone on the 7th and the 14th days of pregnancy for once; rats in the late anesthesia group were anesthetized with 25 mg/kg soluble pentobarbitone on the 14th day of pregnancy for once; rats in the control group did not treat with anything. The time of anesthetizing was controlled in 3 to 4 hours and ether was absorbed while the time was not enough. ② Half of each group was sacrificed on day 20th of pregnancy and the fetus was taken out to be stained with alizarin red S. After stained, the fetal skeleton was examined. The learning and memorizing of one-month rats that were given birth by the rest gravid rats were tested through electric mare method. Determine their study ability according to their correct rate of 90% or above of arrival at the safe area in 20 s. After they finally learned to arrive at the safe area correctly, test them once more in 24 hours and record the correct rate of 15 times. MAIN OUTCOME MEASURES: The rate of malformation in fetus and ability of learning and memory in one-month rats. RESULTS: A total of 80 female rats were anesthetized in this experiment. Totally 490 immature rats were tested with maze testing machine and 196 fetuses were stained with alizarin red S to observe the development of their skeleton. However, one of the 80 female rats was led to death because of overdose. ① Malformation experiment: Learning ability of second anesthesia group was evidently different from the control group while the other two groups were not in the electric mare method. The fetal skeleton malformation rate of three experimental groups was 87.0%, 60.9% and 17.9%, respectively, while it was 5.6% in the control group. ② Electric mare method: Times of rats which arrived at the safe regions were respectively 49.0±31.0, 68.0±35.0, 47.0±31.0 and 44.0±21.0 in early anesthesia group, second anesthesia group, late anesthesia group and control group; and then, there was significant difference between the second anesthesia group and the control group (P < 0.05). Exact rates of memory of rats were respectively (64.36±14.35)%, (62.15±18.33)%, (54.19±12.28)% and (68.24±15.91)% in early anesthesia group, second anesthesia group, late anesthesia group and control group; and then, there were no significant differences as compared with the control group (P > 0.05). CONCLUSION: The influence of anesthesia with pentobarbital sodium is obvious in fetal skeleton development and learning and memory ability.
基金financially supported by the National Innovation and Entrepreneurship Training Project of China in 2013,No.201310392009(to XZZ)the Innovation and Entrepreneurship Training Project of Fujian Province of China in 2014,No.201410392058(to XZZ)
文摘Oxidative stress is involved in the pathogenesis of vascular dementia. Studies have shown that lycopene can significantly inhibit oxidative stress;therefore, we hypothesized that lycopene can reduce the level of oxidative stress in vascular dementia. A vascular dementia model was established by permanent bilateral ligation of common carotid arteries. The dosage groups were treated with lycopene(50, 100 and 200 mg/kg) every other day for 2 months. Rats without bilateral carotid artery ligation were prepared as a sham group. To test the ability of learning and memory, the Morris water maze was used to detect the average escape latency and the change of search strategy. Hematoxylin-eosin staining was used to observe changes of hippocampal neurons. The levels of oxidative stress factors, superoxide dismutase and malondialdehyde, were measured in the hippocampus by biochemical detection. The levels of reactive oxygen species in the hippocampus were observed by dihydroethidium staining. The distribution and expression of oxidative stress related protein, neuron-restrictive silencer factor, in hippocampal neurons were detected by immunofluorescence histochemistry and western blot assays. After 2 months of drug administration,(1) in the model group, the average escape latency was longer than that of the sham group, and the proportion of straight and tend tactics was lower than that of the sham group, and the hippocampal neurons were irregularly arranged and the cytoplasm was hyperchromatic.(2) The levels of reactive oxygen species and malondialdehyde in the hippocampus of the model group rats were increased, and the activity of superoxide dismutase was decreased.(3) Lycopene(50, 100 and 200 mg/kg) intervention improved the above changes, and the lycopene 100 mg/kg group showed the most significant improvement effect.(4) Neuron-restrictive silencer factor expression in the hippocampus was lower in the sham group and the lycopene 100 mg/kg group than in the model group.(5) The above data indicate that lycopene 100 mg/kg could protect against the learning-memory ability impairment of vascular dementia rats. The protective mechanism was achieved by inhibiting oxidative stress in the hippocampus. The experiment was approved by the Animal Ethics Committee of Fujian Medical University, China(approval No. 2014-025) in June 2014.
