Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hip...Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hippocampal neurogenesis.Neurogenesis in the hippocampal dentate gyrus is likely to persist throughout life but declines with aging,especially in Alzheimer’s disease.Recent evidence indicated that RNA-binding protein 8A(Rbm8a)promotes the proliferation of neural progenitor cells,with lower expression levels observed in Alzheimer’s disease patients compared with healthy people.This study investigated the hypothesis that Rbm8a overexpression may enhance neurogenesis by promoting the proliferation of neural progenitor cells to improve memory impairment in Alzheimer’s disease.Therefore,Rbm8a overexpression was induced in the dentate gyrus of 5×FAD mice to validate this hypothesis.Elevated Rbm8a levels in the dentate gyrus triggered neurogenesis and abated pathological phenotypes(such as plaque formation,gliosis reaction,and dystrophic neurites),leading to ameliorated memory performance in 5×FAD mice.RNA sequencing data further substantiated these findings,showing the enrichment of differentially expressed genes involved in biological processes including neurogenesis,cell proliferation,and amyloid protein formation.In conclusion,overexpressing Rbm8a in the dentate gyrus of 5×FAD mouse brains improved cognitive function by ameliorating amyloid-beta-associated pathological phenotypes and enhancing neurogenesis.展开更多
The dentate gyrus subregion of the mammalian hippocampus is an adult neural stem cell niche and site of lifelong neurogenesis.Hypotheses regarding the role of adult-born neuron synaptic integration in hippocampal circ...The dentate gyrus subregion of the mammalian hippocampus is an adult neural stem cell niche and site of lifelong neurogenesis.Hypotheses regarding the role of adult-born neuron synaptic integration in hippocampal circuit function are framed by robust estimations of adultborn versus pre/perinatally-born neuron number.In contrast,the non-neurogenic functions of adult neural stem cells and their immediate progeny,such as secretion of bioactive growth factors and expression of extracellular matrix-modifying proteins,lack similar framing due to few estimates of their number versus other prominent secretory cells.Here,we apply immunohistochemical methods to estimate cell density of neural stem/progenitor cells versus other major classes of glial and endothelial cell types that are potentially secretory in the dentate gyrus of adult mice.Of the cell types quantified,we found that GFAP^(+)SOX2^(+)stellate astrocytes were the most numerous,followed by CD31^(+)endothelia,GFAP-SOX2^(+)intermediate progenitors,Olig2^(+)oligodendrocytes,Iba1+microglia,and GFAP^(+)SOX2^(+)radial glia-like neural stem cells.We did not observe any significant sex differences in density of any cell population.Notably,neural stem/progenitor cells were present at a similar density as several cell types known to have potent functional roles via their secretome.These findings may be useful for refining hypotheses regarding the contributions of these cell types to regulating hippocampal function and their potential therapeutic uses.All experimental protocols were approved by the Ohio State University Institutional Animal Care and Use Committee(protocol#2016A00000068)on July 14,2016.展开更多
BACKGROUND: Some studies suggest that the long-term potentiation (LTP) of synaptic transmission may be the basis for the neural synaptic plasticity of hippocampus, but can be evoked by various factors including electr...BACKGROUND: Some studies suggest that the long-term potentiation (LTP) of synaptic transmission may be the basis for the neural synaptic plasticity of hippocampus, but can be evoked by various factors including electroacupuncture. OBJECTIVE: To observe the effect of electroacupuncture on the activities of basic synaptic transmission in dentate gyrus of hippocampus and the changes of high frequency stimulation (HFS) induced activity of synaptic transmission in cerebral ischemic injured rats. DESIGN: A randomized control trial. SETTING: Shenzhen Hospital of Traditional Chinese Medicine affiliated to Guangzhou University of Traditional Chinese Medicine. MATERIALS: Sixty healthy male Wistar rats, weighing 150-250 g, were provided by the Experimental Animal Center of Guangzhou University of Traditional Chinese Medicine. The experiment began after adaptation of environment for 1 week under standard experimental environment. The main experimental instruments included the programming electrical acupuncture apparatus (PCEA, product of the Institute of Acupuncture and Meridians, Anhui College of Traditional Chinese Medicine) and multichannel physiologic recorder (RM-86, Nihon Konden). METHODS: The experiment was carried out in Guangzhou University of Traditional Chinese Medicine between July 2003 and July 2004. ① Embedding of brain electrodes: In reference of the Pellegrino’s rat brain atlas, the bipolar electrode stimulator was embedded into the perforant path (PP) anterior to the entorhinal area with location coordinates of AP 7.5 mm, L 4.2 mm and H 3.0 mm, that is, 7.5 mm posterior to the anterior fontanelle, 4.2 mm laterally on the right side and 3.0 mm under the subcortex. The subcortex recorder electrode coordinates are AP 3.8 mm, L 2.5 mm and H 3.5 mm, located in the granular cell layer of the unilateral dentate gyrus (DG) of hippocampus, at the site of which an opening with the diameter of 1.5 mm was drilled for the purpose of embedding of the stimulating and recording electrodes, and at the site by mild adjusting the positions of these electrodes where maximal population spike (PS) was recorded, fastened the electrodes at last. ② The 60 rats were randomized into two major groups, namely, fundamental stimulation (FS) group (basic group) and high frequency stimulation (HFS) group. Each group was further divided into three subgroups respectively: Sham-operated subgroup (n=10): only exposed bilateral common carotid arteries without blocking their blood flow; Cerebral ischemia model subgroup (n=10): exposing bilateral common carotid arteries and blocking their blood flow; Ischemia plus electroacupuncture subgroup (n=10): blocked blood flow of bilateral common carotid arteries and received electroacupuncture. The electroacupuncture acupoints were the points of Du meridian, including Baihui (GV20), Dazhui (GV14), and points of Ren meridian, including Qihai (CV6) and Guanyuan (CV4). ③ Process of electroacupuncture: All the rats underwent testing stimulation (1/30 Hz frequency and 0.1 ms breadth) at 30 minutes before modeling, PS values were recorded as the indexes of the excitation of DG granular cell population, and the data were input to computer for data analysis. During the experiment, the intensity of stimulation was kept stable by adopting 1/2 the value of stimulation intensity that could induce maximal PS amplitude. In the basic group, PS were recorded for 120 minutes after modeling, and among the rats in the electroacupuncture group, PS was recorded at 10 minutes before and 60 minutes after blocking blood flow in the carotid artery during continuous electrical acupuncture. In the HFS group, HFS was given immediately after modeling, PS were recorded for 180 minutes at 10 minutes after HFS was given in the sham-operated group and model group, rats in the electroacupuncture group were treated with electroacupuncture for 60 minutes at 30 minutes after HFS was given, and PS was recorded for 180 minutes after 10 minutes. LTP was triggered by HFS and PS values were determined and recorded through measuring stimulations respectively 0, 10, 30, 60, 120 and 180 minutes after the evokes. ④ Methods for expressing the level of synaptic transmission: Each testing stimulus provoked one PS, and 10 successive amplitude values (V/mV) were averaged relevant to a certain time cut. The averaged PS of 6 time cuts at 30 minutes before modeling was made as basal synaptic transmission level as control. Synaptic transmission at each time cut was expressed as: p=(Vdifferent time cut/Vbasal)×100%. MAIN OUTCOME MEASURES: The differences of synaptic transmission level were compared among the subgroups in the basic group after models also among the subgroups in the HFS group after HFS. RESULTS: All the 60 rats were involved in the analysis of results. ① Comparison of synaptic transmission level at different time cut after modeling and the effect of electroacupuncture in the subgroups of the basic group: The synaptic transmission level in the sham-operated subgroup had no significant change within 120 minutes (P > 0.05). The synaptic transmission levels at 10, 30 and 60 minutes in the model subgroup were obviously lower than those in the sham-operated group [(60±7)%, (90±3)%, (93±4)%; (100±5)%, (102±6)%, (105±7)%, P < 0.05-0.01]. With the prolongation of time for ischemia/reperfusion, the synaptic transmission level gradually ascended to the normal level, and those at 90 and 120 minutes were close to those in the sham-operated group (P > 0.05). In the subgroup of electroacupuncture, the synaptic transmission levels at 10, 30, 60, 90 and 120 minutes were obviously higher than those in the model subgroup [(93±5)%, (106±10)%, (123±16)%, (145±20)%, (168±25)%; (96±7)%, (98±8)%, P < 0.05-0.01]. ② Comparison of synaptic transmission level at different time cut after HFS and the effect of electroacupuncture in the groups: In the sham-operated group, the synaptic transmission level after HFS increased significantly, and maintained without decrease within 180 minutes. In the model group, the synaptic transmission level at 0, 10, 30, 60, 120 and 180 minutes after HFS were obviously lower than those in the sham-operated group [(60±7)%, (95±9)%, (138±11)%, (141±13)%, (140±13)%, (138±15)%; (100±6)%, (182±21)%, (179 ±18)%, (177±18)%, (175±23)%, (178±24)%, P < 0.01]. The synaptic transmission level at 60, 120 and 180 minutes after HFS in the electroacupuncture group were close to those in the sham-operated group (P > 0.05), those at 120 and 180 minutes after HFS in the electroacupuncture group were obviously higher than those in the model group [(171±22)%, (181±25)%, P < 0.05-0.01]. CONCLUSION: Electroacupuncture could enhance the basic activity of synaptic transmission in the dentate gyrus of hippocampus in cerebral ischemic injury in rats. Electroacupuncture has obvious LTP effect on the activity of synaptic transmission induced by HFS.展开更多
BACKGROUND: Many researches have indicated that the imbalances of various amino acid transmitters and neurotransmitters in brain are involved in the formation of alcohol withdrawal, especially that glutamic acid is on...BACKGROUND: Many researches have indicated that the imbalances of various amino acid transmitters and neurotransmitters in brain are involved in the formation of alcohol withdrawal, especially that glutamic acid is one of the important transmitters for alcohol tolerance in central nervous system. OBJECTIVE: To observe the changes of excitatory amino acids in hippocampal dentate gyrus in rats with long-term alcohol drinking after withdrawal under consciousness, and investigate the therapeutic effect of topiramate on alcohol withdrawal. DESIGN: A randomized control animal experiment. SETTING: Department of Neurology, Affiliated Hospital of Yanbian University. MATERIALS: Thirty male Wistar rats of 4 months old, weighing 300-350 g, were purchased from the Experimental Animal Department, Medical College of Yanbian University. Topiramate was produced by Swish Cilag Company, and the batch number was 02CS063. METHODS: The experiments were carried out in the Department of Physiology, Medical College of Yanbian University from August 2005 to February 2006. ① The rats were divided randomly into three groups: control group (n=10), alcohol group (n=10) and topiramate-treated group (n=10). Rats in the alcohol group and topiramate-treated group were given intragastric perfusion of 500 g/L alcohol (10 mL/kg), once a day for 4 weeks successively, and then those in the topiramate-treated group were treated with 80 mg/kg topiramate at 24 hours after the last perfusion of alcohol, once a day for 3 days successively. Rats in the control group were intragastricly given isovolume saline. ② The withdrawal symptoms were assessed at 6, 30, 48 and 72 hours after the last perfusion of alcohol by using the withdrawal rating scale set by Erden et al, which had four observational indexes of stereotyped behaviors, agitation, tail stiffness and abnormal posture, each index was scored by 5 points, the higher the score, the more obvious the symptoms. ③ The contents of aspartic acid and glutamic acid in hippocampal dentate gyrus were detected with microdialysis technique and high-performance liquid chromatograpy (HPLC) respectively at 6, 30, 48 and 72 hours after the last perfusion of alcohol in the three groups. MAIN OUTCOME MEASURES: ① Scoring results of alcohol withdrawal symptoms; ② Changes of the contents of aspartic acid and glutamic acid in hippocampal dentate gyrus at the alcohol withdrawal symptoms, and the effects of topiramate. RESULTS: Seven rats were excluded due to inaccurate localization and natural death, and 23 rats were involved in the analysis of results. ① In the alcohol group, the scores of alcohol withdrawal symptoms at 30 and 48 hours after the last perfusion of alcohol were obviously higher than those in the control group (10.50±0.96, 14.17±1.25; 3.50±0.92, 3.16±0.31; P < 0.01). In the topiramate-treated group, the scores at 30 hours after the last perfusion of alcohol (6.06±0.82, 3.50±0.92, P < 0.05), and the withdrawal scores at 48 and 72 hours were close to those in the control group (4.57±0.58, 3.30±0.71; 3.16±0.31, 3.66±0.67; P > 0.05). ② Changes of the contents of glutamic acid in hippocampal dentate gyrus: In the alcohol group, the content of glutamic acid at 48 hours after the last perfusion of alcohol was significantly increased as compared with that at 6 hours [(143.32±11.42)%, (99.12±0.69)%; P < 0.05], and that at 72 hours was close to that at 6 hours [(78.50±16.40)%, (99.12±0.69)%; P > 0.05]. The contents of glutamic acid had no obvious differences at 6, 30, 48 and 72 hours after the last perfusion of alcohol in the topiramate-treated group [(100.30±0.37)%, (118.91±10.40)%, (99.55±12.81)%, (99.08±11.42)%; P > 0.05]. The content of glutamic acid at 48 hours after the last perfusion of alcohol in the topiramate-treated group was obviously lower than that in the alcohol group (P < 0.05), and those at 30 and 72 hours were close (P > 0.05). ③ Changes of the contents of aspartic acid in hippocampal dentate gyrus: In the alcohol group, the contents of aspartic acid at 30 and 48 hours after the last perfusion of alcohol were significantly increased as compared with that at 6 hours [(126.60±8.67)%, (129.17±10.40)%, (99.25±0.87)%; P < 0.05], and that at 72 hours was close to that at 6 hours [(89.87±9.93)%, (99.25±0.87)%; P > 0.05]. The contents of aspartic acid had no obvious differences at 6, 30, 48 and 72 hours after the last perfusion of alcohol in the topiramate-treated group [(100.27±0.32)%, (120.81±12.63)%, (98.91±7.83)%, (85.92±8.07)%; P > 0.05]. The content of aspartic acid at 48 hours after the last perfusion of alcohol in the topiramate-treated group was obviously lower than that in the alcohol group (P < 0.05), and those at 30 and 72 hours were close (P > 0.05). CONCLUSION: ① The occurrences of alcohol withdrawal symptoms are correlated with the increased contents of excitatory amino acids in hippocampal dentate gyrus in rats. ② Topiramate can alleviate the alcohol withdrawal symptoms, which may be correlated with the decreased contents of excitatory amino acids in hippocampal dentate gyrus in rats.展开更多
N-methyl-D-aspartate receptor hypofunction is the basis of pathophysiology in schizophrenia. Blocking the N-methyl-D-aspartate receptor impairs learning and memory abilities and induces pathological changes in the bra...N-methyl-D-aspartate receptor hypofunction is the basis of pathophysiology in schizophrenia. Blocking the N-methyl-D-aspartate receptor impairs learning and memory abilities and induces pathological changes in the brain. Previous studies have paid little attention to the role of the N-methyl-D-aspartate receptor subunit 1 (NR1) in neurogenesis in the hippocampus of schizophrenia. A mouse model of schizophrenia was established by intraperitoneal injection of 0.6 mg/kg MK-801, once a day, for 14 days. In N-methyl-D-aspartate-treated mice, N-methyl-D-aspartate was administered by intracerebroventricular injection in schizophrenia mice on day 15. The number of NR1-, Ki67- or BrdU-immunoreactive cells in the dentate gyrus was measured by immunofluorescence staining. Our data showed the number of NR1-immunoreactive cells increased along with the decreasing numbers of BrdU- and Ki67-immunoreactive cells in the schizophrenia groups compared with the control group. N-methyl-D-aspartate could reverse the above changes. These results indicated that NR1 can regulate neurogenesis in the hippocampal dentate gyrus of schizophrenia mice, supporting NR1 as a promising therapeutic target in the treatment of schizophrenia. This study was approved by the Experimental Animal Ethics Committee of the Ningxia Medical University, China (approval No. 2014-014) on March 6, 2014.展开更多
Stromal cell-derived factor-1 and its receptor CXCR4 are essential regulators of the neurogenesis that occurs in the adult hippocampal dentate gyrus.However,the effects of CXCR7,a new atypical receptor of stromal cell...Stromal cell-derived factor-1 and its receptor CXCR4 are essential regulators of the neurogenesis that occurs in the adult hippocampal dentate gyrus.However,the effects of CXCR7,a new atypical receptor of stromal cell-derived factor-1,on hippocampal neurogenesis after a stroke remain largely unknown.Our study is the first to investigate the effect of a CXCR7-neutralizing antibody on neurogenesis in the dentate gyrus and the associated recovery of cognitive function of rats in the chronic stage of cerebral ischemia.The rats were randomly divided into sham,sham+anti-CXCR7,ischemia and ischemia+anti-CXCR7 groups.Endothelin-1 was injected in the ipsilateral motor cortex and striatum to induce focal cerebral ischemia.Sham group rats were injected with saline instead of endothelin-1 via intracranial injection.Both sham and ischemic rats were treated with intraventricular infusions of CXCR7-neutralizing antibodies for 6 days 1 week after surgery.Immunofluorescence staining with doublecortin,a marker for neuronal precursors,was performed to assess the neurogenesis in the dentate gyrus.We found that anti-CXCR7 antibody infusion enhanced the proliferation and dendritic development of doublecortin-labeled cells in the dentate gyrus in both ischemic and sham-operated rats.Spatial learning and memory functions were assessed by Morris water maze tests 30-32 days after ischemia.CXCR7-neutralizing antibody treatment significantly reduced the escape latency of the spatial navigation trial and increased the time spent in the target quadrant of spatial probe trial in animals that received ischemic insult,but not in sham operated rats.These results suggest that CXCR7-neutralizing antibody enhances the neurogenesis in the dentate gyrus and improves the cognitive function after cerebral ischemia in rats.All animal experimental protocols and procedures were approved by the Institutional Animal Care and Use Committee of China Medical University(CMU16089 R)on December 8,2016.展开更多
This study investigated the effects of progesterone(P4) on the production and survival of neurons in the hippocampal dentate gyrus of adult male mice.The administration of P4(4 mg/kg) for 3 consecutive days beginning ...This study investigated the effects of progesterone(P4) on the production and survival of neurons in the hippocampal dentate gyrus of adult male mice.The administration of P4(4 mg/kg) for 3 consecutive days beginning on the 0-2 nd day after the first BrdU-injection(BrdU-D0-2) produced an approximately twofold increase in the number of 28-and 56-day-old BrdU(+) cells in comparison to the controls,whereas it did not alter the number of 24 /48-h-old BrdU(+) cells.P4 preferentially promoted the survival of newborn neurons when administered at BrdU-D5-7,but not at BrdU-D10-12 and BrdU-D15-17.Androstenedione(Ad),testosterone(TE),or estradiol(E2) at the same-dose of P4,when administered at BrdU-D0-2,could not replicate the effect of P4,while the inhibition of 5 alpha-reductase by finasteride did not affect the P4-action,indicating that the P4-effect is exerted by P4 itself but not by its metabolites.On the other hand,the P4R antagonist RU486 partially suppressed the P4-effect,while inhibitors for Src,MEK,or PI3K totally suppressed the P4-effect.Finally,the P4-enhanced survival of newborn neurons was accompanied by a potentiation of spatial learning and memory,which was P4R-dependent.These findings suggest that P4 enhances the survival of newborn neurons through P4R and /or the Src-ERK and PI3K pathways independent of its influence on cell proliferation,which is well correlated with the potentiated spatial cognitive function of P4-treated animals.展开更多
Tooth loss has been shown to affect learning and memory in mice and increases the risk of Alzheimer's disease. The dentate gyrus is strongly associated with cognitive function. This study hypothesized that tooth l...Tooth loss has been shown to affect learning and memory in mice and increases the risk of Alzheimer's disease. The dentate gyrus is strongly associated with cognitive function. This study hypothesized that tooth loss affects neurons in the dentate gyrus. Adult male mice were randomly assigned to either the tooth loss group or normal control group. In the tooth loss group, the left maxillary and mandibular molars were extracted. Normal control mice did not receive any intervention. Immunofluorescence staining revealed that the density and absorbance of doublecortin- and neuronal nuclear antigen-positive cells were lower in the tooth loss group than in the normal control group. These data suggest that tooth loss may inhibit neurogenesis in the dentate gyrus of adult mice.展开更多
Jujuboside A( JuA) is a main component of Jujubogenin extracted from the seeds of Ziziphus.The authors have not seen report on JuA's direct effect on the neruons of the central nervous system.This study aimed to a...Jujuboside A( JuA) is a main component of Jujubogenin extracted from the seeds of Ziziphus.The authors have not seen report on JuA's direct effect on the neruons of the central nervous system.This study aimed to assess the effect of JuA on paried-pulse responses of dentate gyrus granule cells in urethaneanasesthetized rats,used intracerebroventricular(i.c.v.) JuA to mimic in vitro tath conditions in vivo.Pariedpulse stimuli with 80ms interpulse interval were used to stimulate the perforant pathway.Evoked responses first responses,the slopoes of excitatory postsynaptic potential(EPSP1) and the amplitudes of population spike (PS1) decreased significantly after administration of JuA while the PS1 latencies increased significantly.In the second responses.the EPSP2 slops and PS2 latencies were changed similarly to those of the first ones.but PS2 amplitudes increased.The results showed that JuA may have some inhibitory effect on the granule cell excitability mediated by presynaptic mechanism but may have little effect on the excitability mediated by postsynaptic mechanism since the second evoked N-methyl-D-aspartic mediating paired-pulse facilitation is a postsynaptic mechanism.展开更多
Objective To explore the possible mechanisms that cause the dentate gyrus (DG) neurons to play different roles in information coding. Methods In vivo extracellular single unit recording was performed on 22 waking fema...Objective To explore the possible mechanisms that cause the dentate gyrus (DG) neurons to play different roles in information coding. Methods In vivo extracellular single unit recording was performed on 22 waking female guinea pigs, which were positioned in a sound-attenuated recording chamber without any muscular relaxants. The spontaneous firing patterns of the DG neurons were detected and compared. Results There were two different electrophysiological populations in the DG of guinea pigs, principal cells (PCs) and fast spiking interneurons (INs). Of the PCs, 1.3% discharged regularly, 48.1% irregularly and 50.6% in bursts; in contrast, of the INs units, 64.1% discharged regularly, 2.6% irregularly and 33.3% in bursts. The spontaneous firing patterns of PCs were significantly different from those of INs (P<0.01). In addition, the differences of several interspike interval (ISI) parameters also have been observed: (1) the ISI coefficients of variation of PCs (3.39±3.56) were significantly higher than those of INs (1.08±0.46) (P<0.01); (2) the ISI asymmetric indexes of PCs (0.047±0.059) were significantly lower than those of INs (0.569±0.238) (P<0.01). Conclusion In the DG, the spontaneous firing patterns of PCs were significantly different from those of INs. The former were prone to fire in bursts, the latter were prone to fire regularly. The different roles in information coding between PCs and INs might be caused by their different firing patterns.展开更多
Previous studies reported that some plants,including butternut squash,exert positive effects on the brain.However,few studies have examined the effects of butternut squash on learning,memory,and neurogenesis.This stud...Previous studies reported that some plants,including butternut squash,exert positive effects on the brain.However,few studies have examined the effects of butternut squash on learning,memory,and neurogenesis.This study studied the effects of butternut squash extract on spatial learning and cell proliferation in the dentate gyrus of healthy male rats.Thirty-five male Wistar rats were intrap-eritoneally injected with 0,50,100,200 and 400 mg/kg butternut squash extract once daily for 2 months.After the last administration,rat's spatial memory was studied using the Morris water maze.Finally,rats were sacrificed and hippocampal sections were prepared for light microscopy and bromodeoxyuridine immunohistochemistry studies.The results revealed that escape latency and swim distance decreased in all treatment groups compared with the control rats,and that the number of bromodeoxyuridine-positive cells in the dentate gyrus was significantly increased in the treatment groups compared with the controls.These findings suggest that butternut squash extract improves the learning and memory abilities of male rats,and increases the proliferation of dentate gyrus cells.展开更多
Objective To explore the effects of exercise on dentate gyrus (DG) neurogenesis and the ability of learning and memory in hippocampus-lesioned adult rats. Methods Hippocampus lesion was produced by intrahippocampal mi...Objective To explore the effects of exercise on dentate gyrus (DG) neurogenesis and the ability of learning and memory in hippocampus-lesioned adult rats. Methods Hippocampus lesion was produced by intrahippocampal microinjection of kainic acid (KA). Bromodeoxyuridine (BrdU) was used to label dividing cells. Y maze test was used to evaluate the ability of learning and memory. Exercise was conducted in the form of forced running in a motor-driven running wheel. The speed of wheel revolution was regulated at 3 kinds of intensity: lightly running, moderately running, or heavily running. Results Hippocampus lesion could increase the number of BrdU-labeled DG cells, moderately running after lesion could further enhance the number of BrdU-labeled cells and decrease the error number (EN) in Y maze test, while neither lightly running, nor heavily running had such effects. There was a negative correlation between the number of DG BrdU-labeled cells and the EN in the Y maze test after running. Conclusion Moderate exercise could enhance the DG neurogenesis and ameliorate the ability of learning and memory in hippocampus-lesioned rats.展开更多
Traumatic brain injury can cause loss of neuronal tissue, remote symptomatic epilepsy, and cognitive deficits. However, the mechanisms underlying the effects of traumatic brain injury are not yet clear. Hippocampal ex...Traumatic brain injury can cause loss of neuronal tissue, remote symptomatic epilepsy, and cognitive deficits. However, the mechanisms underlying the effects of traumatic brain injury are not yet clear. Hippocampal excitability is strongly correlated with cognitive dysfunction and remote symptomatic epilepsy. In this study, we examined the relationship between traumatic brain injury-induced neuronal loss and subsequent hippocampal regional excitability. We used hydraulic percussion to generate a rat model of traumatic brain injury. At 7 days after injury, the mean modified neurological severity score was 9.5, suggesting that the neurological function of the rats was remarkably impaired. Electrophysiology and immunocytochemical staining revealed increases in the slope of excitatory postsynaptic potentials and long-term depression(indicating weakened long-term inhibition), and the numbers of cholecystokinin and parvalbumin immunoreactive cells were clearly reduced in the rat hippocampal dentate gyrus. These results indicate that interneuronal loss and changes in excitability occurred in the hippocampal dentate gyrus. Thus, traumatic brain injury-induced loss of interneurons appears to be associated with reduced long-term depression in the hippocampal dentate gyrus.展开更多
Bumetanide has been shown to lessen cerebral edema and reduce the infarct area in the acute stage of cerebral ischemia. Few studies focus on the effects of bumetanide on neuroprotection and neurogenesis in the chronic...Bumetanide has been shown to lessen cerebral edema and reduce the infarct area in the acute stage of cerebral ischemia. Few studies focus on the effects of bumetanide on neuroprotection and neurogenesis in the chronic stage of cerebral ischemia. We established a rat model of cerebral ischemia by injecting endothelin-1 in the left cortical motor area and left corpus striatum. Seven days later, bumetanide 200 μg/kg/day was injected into the lateral ventricle for 21 consecutive days with a mini-osmotic pump. Results demonstrated that the number of neuroblasts cells and the total length of dendrites increased, escape latency reduced, and the number of platform crossings increased in the rat hippocampal dentate gyrus in the chronic stage of cerebral ischemia. These findings suggest that bumetanide promoted neural precursor cell regeneration, dendritic development and the recovery of cognitive function, and protected brain tissue in the chronic stage of ischemia.展开更多
Brain injuries often result in the promotion of cell proliferation in the hippocampal dentate gyrus(DG),but the number of newborn cells declines with time.However,the cause of this decline remains poorly understood.El...Brain injuries often result in the promotion of cell proliferation in the hippocampal dentate gyrus(DG),but the number of newborn cells declines with time.However,the cause of this decline remains poorly understood.Elucidation of the fate of these newborn cells will further the understanding of the pathological process and treatment of brain injury.In the present study,the number of newborn cells was quantitatively analyzed using an unbiased stereological method following hippocampal lesion by kainic acid,in combination with detection of apoptosis and autophagy.Results revealed that hippocampal lesion resulted in a significantly increased number of 5-bromo-2-deoxyuridine(BrdU)-positive cells in the DG,which subsequently decreased with time.BrdU/cleaved caspase-3 double-labeled cells were detected in the granular cell layer and hilus of DG.However,expressions of LC3-II,Beclin 1,and p53 were upregulated,and pro-caspase-3 and Bcl-2 were downregulated.Results indicated that hippocampal lesion in adult rats resulted in significant cell proliferation in the DG,which subsequently reduced with time.In addition,results suggested that apoptosis and autophagic processes could regulate cell proliferation in the DG following hippocampal lesion.展开更多
In this study, we investigated the effects of streptozotocin-induced type 1 diabetes on antioxidant-like protein-1 immunoreactivity, protein carbonyl levels, and malondialdehyde formation, a marker for lipid peroxidat...In this study, we investigated the effects of streptozotocin-induced type 1 diabetes on antioxidant-like protein-1 immunoreactivity, protein carbonyl levels, and malondialdehyde formation, a marker for lipid peroxidation, in the hippocampus. For this study, streptozotocin(75 mg/kg) was intraperitoneally injected into adult rats to induce type 1 diabetes. The three experimental parameters were determined at 2, 3, 4 weeks after streptozotocin treatment. Fasting blood glucose levels significantly increased by 20.7–21.9 m M after streptozotocin treatment. The number of antioxidant-like protein-1 immunoreactive neurons significantly decreased in the hippocampal CA1 region, but not the dentate gyrus, 3 weeks after streptozotocin treatment compared to the control group. Malondialdehyde and protein carbonyl levels, which are modified by oxidative stress, significantly increased with a peak at 3 weeks after malondialdehyde treatment, and then decreased 4 weeks after malondialdehyde treatment. These results suggest that neurons in the hippocampal CA1 region, but not the dentate gyrus, are susceptible to oxidative stress 3 weeks after malondialdehyde treatment.展开更多
BACKGROUND: Previous experiments have confirmed bone morphogenetic proteins (BMPs) upregulate cholinergic expression in neurons isolated from the embryonic rat hippocampus and cerebral cortex. Therefore, BMPs could be...BACKGROUND: Previous experiments have confirmed bone morphogenetic proteins (BMPs) upregulate cholinergic expression in neurons isolated from the embryonic rat hippocampus and cerebral cortex. Therefore, BMPs could be useful for treating Alzheimer's disease and other neurodegenerative diseases. OBJECTIVE: BMP-4 was infused into the hippocampal dentate gyrus of fornix-fimbria transected rats to test the effects of BMP-4 on cholinergic expression in dentate gyrus neurons, and to observe changes in spatial memory behavior. DESIGN: A randomized controlled animal experiment. SETTING: Department of Neurosurgery and Laboratory for Cell Biology, Institute of Geriatrics, General Hospital of Chinese PLA. MATERIALS: Twenty-seven healthy adult male Sprague Dawley (SD) rats, weighing 250-300 g, were provided by the Laboratory Animal Center of the General Hospital of Chinese PLA. Reagents: BMP-4 (B-2680, Sigma Company) and choline acetyl transferase (ChAT) antibody (AB5042, Chemicon Company) were used in this study. Equipments: a rat stereotaxic instrument (type: SN-2N, Narushige Group, Japan) and Image-prog-plus image analysis software (Media Cybernetics company, USA) were used in this study. The protocol was carried out in accordance with ethical guidelines for the use and care of animals. METHODS: This experiment was performed in the Institute of Geriatrics, General Hospital of Chinese PLA between July 2004 and March 2005. Rats were randomly divided into 4 groups: Alzheimer's disease group (n = 7), normal control group (n = 5), BMP-4-Alzheimer's disease group (n = 8), and model group (n = 7). In the Alzheimer's disease group, the left hippocampal fornix-fimbria of rats was transected to mimic Alzheimer's disease symptoms. In the BMP-4-Alzheimer's disease group, 1 μL BMP-4 (10 mg/L) was perfused into the left dentate gyrus with a microinjector at 1 μL/min. In the model group, 1 μL saline was perfused into the same position by the same method. Twenty-eight days after injection, Morris water maze test was performed in all rats to test spatial memory. Time-to-platform and swim-path length were recorded. Immunohistochemical staining of cholinergic neurons was performed on brain sections containing dentate gyrus. The area covered by ChAT-positive cells was analyzed using an Image-prog-plus image analysis software. MAIN OUTCOME MEASURES: Area covered by ChAT-positive cells in the dentate gyrus. Time-to-platform and swim path-length. RESULTS: Twenty-seven rats were included in the final analysis. In the Alzheimer's disease group, the area covered by ChAT-positive cells was significantly smaller compared with the normal control group (F = 76.03, P < 0.01). The area covered by ChAT-positive cells was significantly larger in the BMP-4- Alzheimer's disease group than in the model group (F = 35.17, P < 0.05), but significantly smaller than in the normal control group (F = 40.17, P < 0.05). Time-to-platform and swim-path length were significantly longer in the Alzheimer's disease group than in the normal control group (F =24.62 and 631.58, respectively, both P < 0.05). Time-to-platform and swim-path length were significantly shorter in the BMP4-Alzheimer's disease group compared with the model group (F = 22.06 and 606.89, respectively P < 0.05). CONCLUSION: Injection of BMP-4 into the dentate gyrus of Alzheimer's disease model rats alleviates central cholinergic system injury and concomitantly improves spatial memory.展开更多
Long-term administration of scopolamine, a muscarinic receptor antagonist, can inhibit the survival of newly generated cells, but its effect on the proliferation, differentiation and migration of nerve cells in the ad...Long-term administration of scopolamine, a muscarinic receptor antagonist, can inhibit the survival of newly generated cells, but its effect on the proliferation, differentiation and migration of nerve cells in the adult mouse hippocampal dentate gyrus remain poorly understood. In this study, we used immunohistochemistry and western blot methods to weekly detect the biological behaviors of nerve cells in the hippocampal dentate gyrus of adult mice that received intraperitoneal administration of scopolamine for 4 weeks. Expression of neuronal nuclear antigen(Neu N; a neuronal marker) and Fluoro-Jade B(a marker for the localization of neuronal degeneration) was also detected. After scopolamine treatment, mouse hippocampal neurons did not die, and Ki-67(a marker for proliferating cells)-immunoreactive cells were reduced in number and reac hed the lowest level at 4 weeks. Doublecortin(DCX; a marker for newly generated neurons)-immunoreactive cells were gradually shortened in length and reduced in number with time. After scopolamine treatment for 4 weeks, nearly all of the 5-bromo-2′-deoxyuridine(Brd U)-labeled newly generated cells were located in the subgranular zone of the dentate gyrus, but they did not migrate into the granule cell layer. Few mature Brd U/Neu N double-labeled cells were seen in the subgranular zone of the dentate gyrus. These findings suggest that long-term administration of scopolamine interferes with the proliferation, differentiation and migration of nerve cells in the adult mouse hippocampal dentate gyrus, but it does not induce cell death.展开更多
Increasing evidence suggests that heat shock factor 1 exerts endogenous protective effects on working memory under conditions of chronic psychological stress.However,the precise underlying mechanisms remain poorly und...Increasing evidence suggests that heat shock factor 1 exerts endogenous protective effects on working memory under conditions of chronic psychological stress.However,the precise underlying mechanisms remain poorly understood.This study examined the protective factors affecting working memory in heat shock transcription factor 1 gene knockout mice.The results indicated that the number of correct T maze alternations decreased following mild chronic psychological stress in knockout mice.This change was accompanied by a decrease in neurogenesis and an increase in neuronal apoptosis in the hippocampal dentate gyrus.The number of correct T maze alternations was positively correlated with neurogenesis in hippocampal dentate gyrus,and negatively correlated with neuronal apoptosis.In wild type mice,no significant difference was detected in the number of correct T maze alternations or neuronal apoptosis in hippocampal dentate gyrus.These results indicate that the heat shock factor 1 gene has an endogenous protective role in working memory during mild chronic psychological stress associated with dentate gyrus neuronal apoptosis.Moreover,dentate gyrus neurogenesis appears to participate in the protective mechanism.展开更多
We investigated the effects of ethanol extracted Scutellaria baicalensis(EESB) on spatial memory function and neurogenesis in the hippocampal dentate gyrus.Adult Sprague-Dawley rats were orally administered 50,100,or ...We investigated the effects of ethanol extracted Scutellaria baicalensis(EESB) on spatial memory function and neurogenesis in the hippocampal dentate gyrus.Adult Sprague-Dawley rats were orally administered 50,100,or 200 mg/kg of EESB for 6 successive days.The radial-arm maze test showed that 200 mg/kg of EESB improved the spatial memory of adult rats.Confocal microscopy results showed that 100 mg/kg of EESB increased the number of bromodeoxyuridine(BrdU)-and neuron-specific nuclear protein-positive cells in the granular cell layer,and that 100 and 200 mg/kg of EESB increased the number of BrdU-/neuron-specific nuclear protein-positive cells in the sub-granular zone.200 mg/kg of EESB increased the number of BrdU-/glial fibrillary acid protein-positive cells in the subgranular zone.These findings indicate that EESB can effectively promote neurogenesis in the hippocampal dentate gyrus and improve spatial memory function.展开更多
基金supported by the National Natural Science Foundation of China,No.91849104(to YW)。
文摘Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hippocampal neurogenesis.Neurogenesis in the hippocampal dentate gyrus is likely to persist throughout life but declines with aging,especially in Alzheimer’s disease.Recent evidence indicated that RNA-binding protein 8A(Rbm8a)promotes the proliferation of neural progenitor cells,with lower expression levels observed in Alzheimer’s disease patients compared with healthy people.This study investigated the hypothesis that Rbm8a overexpression may enhance neurogenesis by promoting the proliferation of neural progenitor cells to improve memory impairment in Alzheimer’s disease.Therefore,Rbm8a overexpression was induced in the dentate gyrus of 5×FAD mice to validate this hypothesis.Elevated Rbm8a levels in the dentate gyrus triggered neurogenesis and abated pathological phenotypes(such as plaque formation,gliosis reaction,and dystrophic neurites),leading to ameliorated memory performance in 5×FAD mice.RNA sequencing data further substantiated these findings,showing the enrichment of differentially expressed genes involved in biological processes including neurogenesis,cell proliferation,and amyloid protein formation.In conclusion,overexpressing Rbm8a in the dentate gyrus of 5×FAD mouse brains improved cognitive function by ameliorating amyloid-beta-associated pathological phenotypes and enhancing neurogenesis.
基金a R00 Pathway to Independence Award from NIH/NINDS(R00NS089938to EDK).
文摘The dentate gyrus subregion of the mammalian hippocampus is an adult neural stem cell niche and site of lifelong neurogenesis.Hypotheses regarding the role of adult-born neuron synaptic integration in hippocampal circuit function are framed by robust estimations of adultborn versus pre/perinatally-born neuron number.In contrast,the non-neurogenic functions of adult neural stem cells and their immediate progeny,such as secretion of bioactive growth factors and expression of extracellular matrix-modifying proteins,lack similar framing due to few estimates of their number versus other prominent secretory cells.Here,we apply immunohistochemical methods to estimate cell density of neural stem/progenitor cells versus other major classes of glial and endothelial cell types that are potentially secretory in the dentate gyrus of adult mice.Of the cell types quantified,we found that GFAP^(+)SOX2^(+)stellate astrocytes were the most numerous,followed by CD31^(+)endothelia,GFAP-SOX2^(+)intermediate progenitors,Olig2^(+)oligodendrocytes,Iba1+microglia,and GFAP^(+)SOX2^(+)radial glia-like neural stem cells.We did not observe any significant sex differences in density of any cell population.Notably,neural stem/progenitor cells were present at a similar density as several cell types known to have potent functional roles via their secretome.These findings may be useful for refining hypotheses regarding the contributions of these cell types to regulating hippocampal function and their potential therapeutic uses.All experimental protocols were approved by the Ohio State University Institutional Animal Care and Use Committee(protocol#2016A00000068)on July 14,2016.
文摘BACKGROUND: Some studies suggest that the long-term potentiation (LTP) of synaptic transmission may be the basis for the neural synaptic plasticity of hippocampus, but can be evoked by various factors including electroacupuncture. OBJECTIVE: To observe the effect of electroacupuncture on the activities of basic synaptic transmission in dentate gyrus of hippocampus and the changes of high frequency stimulation (HFS) induced activity of synaptic transmission in cerebral ischemic injured rats. DESIGN: A randomized control trial. SETTING: Shenzhen Hospital of Traditional Chinese Medicine affiliated to Guangzhou University of Traditional Chinese Medicine. MATERIALS: Sixty healthy male Wistar rats, weighing 150-250 g, were provided by the Experimental Animal Center of Guangzhou University of Traditional Chinese Medicine. The experiment began after adaptation of environment for 1 week under standard experimental environment. The main experimental instruments included the programming electrical acupuncture apparatus (PCEA, product of the Institute of Acupuncture and Meridians, Anhui College of Traditional Chinese Medicine) and multichannel physiologic recorder (RM-86, Nihon Konden). METHODS: The experiment was carried out in Guangzhou University of Traditional Chinese Medicine between July 2003 and July 2004. ① Embedding of brain electrodes: In reference of the Pellegrino’s rat brain atlas, the bipolar electrode stimulator was embedded into the perforant path (PP) anterior to the entorhinal area with location coordinates of AP 7.5 mm, L 4.2 mm and H 3.0 mm, that is, 7.5 mm posterior to the anterior fontanelle, 4.2 mm laterally on the right side and 3.0 mm under the subcortex. The subcortex recorder electrode coordinates are AP 3.8 mm, L 2.5 mm and H 3.5 mm, located in the granular cell layer of the unilateral dentate gyrus (DG) of hippocampus, at the site of which an opening with the diameter of 1.5 mm was drilled for the purpose of embedding of the stimulating and recording electrodes, and at the site by mild adjusting the positions of these electrodes where maximal population spike (PS) was recorded, fastened the electrodes at last. ② The 60 rats were randomized into two major groups, namely, fundamental stimulation (FS) group (basic group) and high frequency stimulation (HFS) group. Each group was further divided into three subgroups respectively: Sham-operated subgroup (n=10): only exposed bilateral common carotid arteries without blocking their blood flow; Cerebral ischemia model subgroup (n=10): exposing bilateral common carotid arteries and blocking their blood flow; Ischemia plus electroacupuncture subgroup (n=10): blocked blood flow of bilateral common carotid arteries and received electroacupuncture. The electroacupuncture acupoints were the points of Du meridian, including Baihui (GV20), Dazhui (GV14), and points of Ren meridian, including Qihai (CV6) and Guanyuan (CV4). ③ Process of electroacupuncture: All the rats underwent testing stimulation (1/30 Hz frequency and 0.1 ms breadth) at 30 minutes before modeling, PS values were recorded as the indexes of the excitation of DG granular cell population, and the data were input to computer for data analysis. During the experiment, the intensity of stimulation was kept stable by adopting 1/2 the value of stimulation intensity that could induce maximal PS amplitude. In the basic group, PS were recorded for 120 minutes after modeling, and among the rats in the electroacupuncture group, PS was recorded at 10 minutes before and 60 minutes after blocking blood flow in the carotid artery during continuous electrical acupuncture. In the HFS group, HFS was given immediately after modeling, PS were recorded for 180 minutes at 10 minutes after HFS was given in the sham-operated group and model group, rats in the electroacupuncture group were treated with electroacupuncture for 60 minutes at 30 minutes after HFS was given, and PS was recorded for 180 minutes after 10 minutes. LTP was triggered by HFS and PS values were determined and recorded through measuring stimulations respectively 0, 10, 30, 60, 120 and 180 minutes after the evokes. ④ Methods for expressing the level of synaptic transmission: Each testing stimulus provoked one PS, and 10 successive amplitude values (V/mV) were averaged relevant to a certain time cut. The averaged PS of 6 time cuts at 30 minutes before modeling was made as basal synaptic transmission level as control. Synaptic transmission at each time cut was expressed as: p=(Vdifferent time cut/Vbasal)×100%. MAIN OUTCOME MEASURES: The differences of synaptic transmission level were compared among the subgroups in the basic group after models also among the subgroups in the HFS group after HFS. RESULTS: All the 60 rats were involved in the analysis of results. ① Comparison of synaptic transmission level at different time cut after modeling and the effect of electroacupuncture in the subgroups of the basic group: The synaptic transmission level in the sham-operated subgroup had no significant change within 120 minutes (P > 0.05). The synaptic transmission levels at 10, 30 and 60 minutes in the model subgroup were obviously lower than those in the sham-operated group [(60±7)%, (90±3)%, (93±4)%; (100±5)%, (102±6)%, (105±7)%, P < 0.05-0.01]. With the prolongation of time for ischemia/reperfusion, the synaptic transmission level gradually ascended to the normal level, and those at 90 and 120 minutes were close to those in the sham-operated group (P > 0.05). In the subgroup of electroacupuncture, the synaptic transmission levels at 10, 30, 60, 90 and 120 minutes were obviously higher than those in the model subgroup [(93±5)%, (106±10)%, (123±16)%, (145±20)%, (168±25)%; (96±7)%, (98±8)%, P < 0.05-0.01]. ② Comparison of synaptic transmission level at different time cut after HFS and the effect of electroacupuncture in the groups: In the sham-operated group, the synaptic transmission level after HFS increased significantly, and maintained without decrease within 180 minutes. In the model group, the synaptic transmission level at 0, 10, 30, 60, 120 and 180 minutes after HFS were obviously lower than those in the sham-operated group [(60±7)%, (95±9)%, (138±11)%, (141±13)%, (140±13)%, (138±15)%; (100±6)%, (182±21)%, (179 ±18)%, (177±18)%, (175±23)%, (178±24)%, P < 0.01]. The synaptic transmission level at 60, 120 and 180 minutes after HFS in the electroacupuncture group were close to those in the sham-operated group (P > 0.05), those at 120 and 180 minutes after HFS in the electroacupuncture group were obviously higher than those in the model group [(171±22)%, (181±25)%, P < 0.05-0.01]. CONCLUSION: Electroacupuncture could enhance the basic activity of synaptic transmission in the dentate gyrus of hippocampus in cerebral ischemic injury in rats. Electroacupuncture has obvious LTP effect on the activity of synaptic transmission induced by HFS.
文摘BACKGROUND: Many researches have indicated that the imbalances of various amino acid transmitters and neurotransmitters in brain are involved in the formation of alcohol withdrawal, especially that glutamic acid is one of the important transmitters for alcohol tolerance in central nervous system. OBJECTIVE: To observe the changes of excitatory amino acids in hippocampal dentate gyrus in rats with long-term alcohol drinking after withdrawal under consciousness, and investigate the therapeutic effect of topiramate on alcohol withdrawal. DESIGN: A randomized control animal experiment. SETTING: Department of Neurology, Affiliated Hospital of Yanbian University. MATERIALS: Thirty male Wistar rats of 4 months old, weighing 300-350 g, were purchased from the Experimental Animal Department, Medical College of Yanbian University. Topiramate was produced by Swish Cilag Company, and the batch number was 02CS063. METHODS: The experiments were carried out in the Department of Physiology, Medical College of Yanbian University from August 2005 to February 2006. ① The rats were divided randomly into three groups: control group (n=10), alcohol group (n=10) and topiramate-treated group (n=10). Rats in the alcohol group and topiramate-treated group were given intragastric perfusion of 500 g/L alcohol (10 mL/kg), once a day for 4 weeks successively, and then those in the topiramate-treated group were treated with 80 mg/kg topiramate at 24 hours after the last perfusion of alcohol, once a day for 3 days successively. Rats in the control group were intragastricly given isovolume saline. ② The withdrawal symptoms were assessed at 6, 30, 48 and 72 hours after the last perfusion of alcohol by using the withdrawal rating scale set by Erden et al, which had four observational indexes of stereotyped behaviors, agitation, tail stiffness and abnormal posture, each index was scored by 5 points, the higher the score, the more obvious the symptoms. ③ The contents of aspartic acid and glutamic acid in hippocampal dentate gyrus were detected with microdialysis technique and high-performance liquid chromatograpy (HPLC) respectively at 6, 30, 48 and 72 hours after the last perfusion of alcohol in the three groups. MAIN OUTCOME MEASURES: ① Scoring results of alcohol withdrawal symptoms; ② Changes of the contents of aspartic acid and glutamic acid in hippocampal dentate gyrus at the alcohol withdrawal symptoms, and the effects of topiramate. RESULTS: Seven rats were excluded due to inaccurate localization and natural death, and 23 rats were involved in the analysis of results. ① In the alcohol group, the scores of alcohol withdrawal symptoms at 30 and 48 hours after the last perfusion of alcohol were obviously higher than those in the control group (10.50±0.96, 14.17±1.25; 3.50±0.92, 3.16±0.31; P < 0.01). In the topiramate-treated group, the scores at 30 hours after the last perfusion of alcohol (6.06±0.82, 3.50±0.92, P < 0.05), and the withdrawal scores at 48 and 72 hours were close to those in the control group (4.57±0.58, 3.30±0.71; 3.16±0.31, 3.66±0.67; P > 0.05). ② Changes of the contents of glutamic acid in hippocampal dentate gyrus: In the alcohol group, the content of glutamic acid at 48 hours after the last perfusion of alcohol was significantly increased as compared with that at 6 hours [(143.32±11.42)%, (99.12±0.69)%; P < 0.05], and that at 72 hours was close to that at 6 hours [(78.50±16.40)%, (99.12±0.69)%; P > 0.05]. The contents of glutamic acid had no obvious differences at 6, 30, 48 and 72 hours after the last perfusion of alcohol in the topiramate-treated group [(100.30±0.37)%, (118.91±10.40)%, (99.55±12.81)%, (99.08±11.42)%; P > 0.05]. The content of glutamic acid at 48 hours after the last perfusion of alcohol in the topiramate-treated group was obviously lower than that in the alcohol group (P < 0.05), and those at 30 and 72 hours were close (P > 0.05). ③ Changes of the contents of aspartic acid in hippocampal dentate gyrus: In the alcohol group, the contents of aspartic acid at 30 and 48 hours after the last perfusion of alcohol were significantly increased as compared with that at 6 hours [(126.60±8.67)%, (129.17±10.40)%, (99.25±0.87)%; P < 0.05], and that at 72 hours was close to that at 6 hours [(89.87±9.93)%, (99.25±0.87)%; P > 0.05]. The contents of aspartic acid had no obvious differences at 6, 30, 48 and 72 hours after the last perfusion of alcohol in the topiramate-treated group [(100.27±0.32)%, (120.81±12.63)%, (98.91±7.83)%, (85.92±8.07)%; P > 0.05]. The content of aspartic acid at 48 hours after the last perfusion of alcohol in the topiramate-treated group was obviously lower than that in the alcohol group (P < 0.05), and those at 30 and 72 hours were close (P > 0.05). CONCLUSION: ① The occurrences of alcohol withdrawal symptoms are correlated with the increased contents of excitatory amino acids in hippocampal dentate gyrus in rats. ② Topiramate can alleviate the alcohol withdrawal symptoms, which may be correlated with the decreased contents of excitatory amino acids in hippocampal dentate gyrus in rats.
基金supported by the National Natural Science Foundation of China,No.81160169(to JL),81460214(to JL),31660270(to JD),31460255(to JD)the Natural Science Foundation of Ningxia Hui Autonomous Region of China,No.2018AAC02005(to JL)
文摘N-methyl-D-aspartate receptor hypofunction is the basis of pathophysiology in schizophrenia. Blocking the N-methyl-D-aspartate receptor impairs learning and memory abilities and induces pathological changes in the brain. Previous studies have paid little attention to the role of the N-methyl-D-aspartate receptor subunit 1 (NR1) in neurogenesis in the hippocampus of schizophrenia. A mouse model of schizophrenia was established by intraperitoneal injection of 0.6 mg/kg MK-801, once a day, for 14 days. In N-methyl-D-aspartate-treated mice, N-methyl-D-aspartate was administered by intracerebroventricular injection in schizophrenia mice on day 15. The number of NR1-, Ki67- or BrdU-immunoreactive cells in the dentate gyrus was measured by immunofluorescence staining. Our data showed the number of NR1-immunoreactive cells increased along with the decreasing numbers of BrdU- and Ki67-immunoreactive cells in the schizophrenia groups compared with the control group. N-methyl-D-aspartate could reverse the above changes. These results indicated that NR1 can regulate neurogenesis in the hippocampal dentate gyrus of schizophrenia mice, supporting NR1 as a promising therapeutic target in the treatment of schizophrenia. This study was approved by the Experimental Animal Ethics Committee of the Ningxia Medical University, China (approval No. 2014-014) on March 6, 2014.
基金supported by the National Natural Science Foundation of China,No.81401002(to SSZ)
文摘Stromal cell-derived factor-1 and its receptor CXCR4 are essential regulators of the neurogenesis that occurs in the adult hippocampal dentate gyrus.However,the effects of CXCR7,a new atypical receptor of stromal cell-derived factor-1,on hippocampal neurogenesis after a stroke remain largely unknown.Our study is the first to investigate the effect of a CXCR7-neutralizing antibody on neurogenesis in the dentate gyrus and the associated recovery of cognitive function of rats in the chronic stage of cerebral ischemia.The rats were randomly divided into sham,sham+anti-CXCR7,ischemia and ischemia+anti-CXCR7 groups.Endothelin-1 was injected in the ipsilateral motor cortex and striatum to induce focal cerebral ischemia.Sham group rats were injected with saline instead of endothelin-1 via intracranial injection.Both sham and ischemic rats were treated with intraventricular infusions of CXCR7-neutralizing antibodies for 6 days 1 week after surgery.Immunofluorescence staining with doublecortin,a marker for neuronal precursors,was performed to assess the neurogenesis in the dentate gyrus.We found that anti-CXCR7 antibody infusion enhanced the proliferation and dendritic development of doublecortin-labeled cells in the dentate gyrus in both ischemic and sham-operated rats.Spatial learning and memory functions were assessed by Morris water maze tests 30-32 days after ischemia.CXCR7-neutralizing antibody treatment significantly reduced the escape latency of the spatial navigation trial and increased the time spent in the target quadrant of spatial probe trial in animals that received ischemic insult,but not in sham operated rats.These results suggest that CXCR7-neutralizing antibody enhances the neurogenesis in the dentate gyrus and improves the cognitive function after cerebral ischemia in rats.All animal experimental protocols and procedures were approved by the Institutional Animal Care and Use Committee of China Medical University(CMU16089 R)on December 8,2016.
文摘This study investigated the effects of progesterone(P4) on the production and survival of neurons in the hippocampal dentate gyrus of adult male mice.The administration of P4(4 mg/kg) for 3 consecutive days beginning on the 0-2 nd day after the first BrdU-injection(BrdU-D0-2) produced an approximately twofold increase in the number of 28-and 56-day-old BrdU(+) cells in comparison to the controls,whereas it did not alter the number of 24 /48-h-old BrdU(+) cells.P4 preferentially promoted the survival of newborn neurons when administered at BrdU-D5-7,but not at BrdU-D10-12 and BrdU-D15-17.Androstenedione(Ad),testosterone(TE),or estradiol(E2) at the same-dose of P4,when administered at BrdU-D0-2,could not replicate the effect of P4,while the inhibition of 5 alpha-reductase by finasteride did not affect the P4-action,indicating that the P4-effect is exerted by P4 itself but not by its metabolites.On the other hand,the P4R antagonist RU486 partially suppressed the P4-effect,while inhibitors for Src,MEK,or PI3K totally suppressed the P4-effect.Finally,the P4-enhanced survival of newborn neurons was accompanied by a potentiation of spatial learning and memory,which was P4R-dependent.These findings suggest that P4 enhances the survival of newborn neurons through P4R and /or the Src-ERK and PI3K pathways independent of its influence on cell proliferation,which is well correlated with the potentiated spatial cognitive function of P4-treated animals.
基金supported by the Science and Technology Key Project of Ministry of Education of China,No.106152the Scientific Research Project of Second Hospital of Lanzhou University of China,No.C1708
文摘Tooth loss has been shown to affect learning and memory in mice and increases the risk of Alzheimer's disease. The dentate gyrus is strongly associated with cognitive function. This study hypothesized that tooth loss affects neurons in the dentate gyrus. Adult male mice were randomly assigned to either the tooth loss group or normal control group. In the tooth loss group, the left maxillary and mandibular molars were extracted. Normal control mice did not receive any intervention. Immunofluorescence staining revealed that the density and absorbance of doublecortin- and neuronal nuclear antigen-positive cells were lower in the tooth loss group than in the normal control group. These data suggest that tooth loss may inhibit neurogenesis in the dentate gyrus of adult mice.
文摘Jujuboside A( JuA) is a main component of Jujubogenin extracted from the seeds of Ziziphus.The authors have not seen report on JuA's direct effect on the neruons of the central nervous system.This study aimed to assess the effect of JuA on paried-pulse responses of dentate gyrus granule cells in urethaneanasesthetized rats,used intracerebroventricular(i.c.v.) JuA to mimic in vitro tath conditions in vivo.Pariedpulse stimuli with 80ms interpulse interval were used to stimulate the perforant pathway.Evoked responses first responses,the slopoes of excitatory postsynaptic potential(EPSP1) and the amplitudes of population spike (PS1) decreased significantly after administration of JuA while the PS1 latencies increased significantly.In the second responses.the EPSP2 slops and PS2 latencies were changed similarly to those of the first ones.but PS2 amplitudes increased.The results showed that JuA may have some inhibitory effect on the granule cell excitability mediated by presynaptic mechanism but may have little effect on the excitability mediated by postsynaptic mechanism since the second evoked N-methyl-D-aspartic mediating paired-pulse facilitation is a postsynaptic mechanism.
文摘Objective To explore the possible mechanisms that cause the dentate gyrus (DG) neurons to play different roles in information coding. Methods In vivo extracellular single unit recording was performed on 22 waking female guinea pigs, which were positioned in a sound-attenuated recording chamber without any muscular relaxants. The spontaneous firing patterns of the DG neurons were detected and compared. Results There were two different electrophysiological populations in the DG of guinea pigs, principal cells (PCs) and fast spiking interneurons (INs). Of the PCs, 1.3% discharged regularly, 48.1% irregularly and 50.6% in bursts; in contrast, of the INs units, 64.1% discharged regularly, 2.6% irregularly and 33.3% in bursts. The spontaneous firing patterns of PCs were significantly different from those of INs (P<0.01). In addition, the differences of several interspike interval (ISI) parameters also have been observed: (1) the ISI coefficients of variation of PCs (3.39±3.56) were significantly higher than those of INs (1.08±0.46) (P<0.01); (2) the ISI asymmetric indexes of PCs (0.047±0.059) were significantly lower than those of INs (0.569±0.238) (P<0.01). Conclusion In the DG, the spontaneous firing patterns of PCs were significantly different from those of INs. The former were prone to fire in bursts, the latter were prone to fire regularly. The different roles in information coding between PCs and INs might be caused by their different firing patterns.
基金a grant from the Research Institute for Islamic and Complementary Medicine (RICM),Tehran University of Medical Sciences,No. p26/m/t/1088
文摘Previous studies reported that some plants,including butternut squash,exert positive effects on the brain.However,few studies have examined the effects of butternut squash on learning,memory,and neurogenesis.This study studied the effects of butternut squash extract on spatial learning and cell proliferation in the dentate gyrus of healthy male rats.Thirty-five male Wistar rats were intrap-eritoneally injected with 0,50,100,200 and 400 mg/kg butternut squash extract once daily for 2 months.After the last administration,rat's spatial memory was studied using the Morris water maze.Finally,rats were sacrificed and hippocampal sections were prepared for light microscopy and bromodeoxyuridine immunohistochemistry studies.The results revealed that escape latency and swim distance decreased in all treatment groups compared with the control rats,and that the number of bromodeoxyuridine-positive cells in the dentate gyrus was significantly increased in the treatment groups compared with the controls.These findings suggest that butternut squash extract improves the learning and memory abilities of male rats,and increases the proliferation of dentate gyrus cells.
文摘Objective To explore the effects of exercise on dentate gyrus (DG) neurogenesis and the ability of learning and memory in hippocampus-lesioned adult rats. Methods Hippocampus lesion was produced by intrahippocampal microinjection of kainic acid (KA). Bromodeoxyuridine (BrdU) was used to label dividing cells. Y maze test was used to evaluate the ability of learning and memory. Exercise was conducted in the form of forced running in a motor-driven running wheel. The speed of wheel revolution was regulated at 3 kinds of intensity: lightly running, moderately running, or heavily running. Results Hippocampus lesion could increase the number of BrdU-labeled DG cells, moderately running after lesion could further enhance the number of BrdU-labeled cells and decrease the error number (EN) in Y maze test, while neither lightly running, nor heavily running had such effects. There was a negative correlation between the number of DG BrdU-labeled cells and the EN in the Y maze test after running. Conclusion Moderate exercise could enhance the DG neurogenesis and ameliorate the ability of learning and memory in hippocampus-lesioned rats.
基金supported by the National Natural Science Foundation of China,No.81330029,81501057the Natural Science Foundation of Tianjin of China,No.17JCQNJC12000the Tianjin Medical University General Hospital Funding in China,No.ZYYFY2016014
文摘Traumatic brain injury can cause loss of neuronal tissue, remote symptomatic epilepsy, and cognitive deficits. However, the mechanisms underlying the effects of traumatic brain injury are not yet clear. Hippocampal excitability is strongly correlated with cognitive dysfunction and remote symptomatic epilepsy. In this study, we examined the relationship between traumatic brain injury-induced neuronal loss and subsequent hippocampal regional excitability. We used hydraulic percussion to generate a rat model of traumatic brain injury. At 7 days after injury, the mean modified neurological severity score was 9.5, suggesting that the neurological function of the rats was remarkably impaired. Electrophysiology and immunocytochemical staining revealed increases in the slope of excitatory postsynaptic potentials and long-term depression(indicating weakened long-term inhibition), and the numbers of cholecystokinin and parvalbumin immunoreactive cells were clearly reduced in the rat hippocampal dentate gyrus. These results indicate that interneuronal loss and changes in excitability occurred in the hippocampal dentate gyrus. Thus, traumatic brain injury-induced loss of interneurons appears to be associated with reduced long-term depression in the hippocampal dentate gyrus.
文摘Bumetanide has been shown to lessen cerebral edema and reduce the infarct area in the acute stage of cerebral ischemia. Few studies focus on the effects of bumetanide on neuroprotection and neurogenesis in the chronic stage of cerebral ischemia. We established a rat model of cerebral ischemia by injecting endothelin-1 in the left cortical motor area and left corpus striatum. Seven days later, bumetanide 200 μg/kg/day was injected into the lateral ventricle for 21 consecutive days with a mini-osmotic pump. Results demonstrated that the number of neuroblasts cells and the total length of dendrites increased, escape latency reduced, and the number of platform crossings increased in the rat hippocampal dentate gyrus in the chronic stage of cerebral ischemia. These findings suggest that bumetanide promoted neural precursor cell regeneration, dendritic development and the recovery of cognitive function, and protected brain tissue in the chronic stage of ischemia.
基金the Sino-Japanese Inter-University Cooperative Research Fund,No. EE 134005Excellent Doctoral Dissertation Fund of Soochow University,No.23320822
文摘Brain injuries often result in the promotion of cell proliferation in the hippocampal dentate gyrus(DG),but the number of newborn cells declines with time.However,the cause of this decline remains poorly understood.Elucidation of the fate of these newborn cells will further the understanding of the pathological process and treatment of brain injury.In the present study,the number of newborn cells was quantitatively analyzed using an unbiased stereological method following hippocampal lesion by kainic acid,in combination with detection of apoptosis and autophagy.Results revealed that hippocampal lesion resulted in a significantly increased number of 5-bromo-2-deoxyuridine(BrdU)-positive cells in the DG,which subsequently decreased with time.BrdU/cleaved caspase-3 double-labeled cells were detected in the granular cell layer and hilus of DG.However,expressions of LC3-II,Beclin 1,and p53 were upregulated,and pro-caspase-3 and Bcl-2 were downregulated.Results indicated that hippocampal lesion in adult rats resulted in significant cell proliferation in the DG,which subsequently reduced with time.In addition,results suggested that apoptosis and autophagic processes could regulate cell proliferation in the DG following hippocampal lesion.
基金supported by a National Research Foundation of Korea Grant funded by the Korean Government(MEST)Republic of Korea,No.2010-0007712
文摘In this study, we investigated the effects of streptozotocin-induced type 1 diabetes on antioxidant-like protein-1 immunoreactivity, protein carbonyl levels, and malondialdehyde formation, a marker for lipid peroxidation, in the hippocampus. For this study, streptozotocin(75 mg/kg) was intraperitoneally injected into adult rats to induce type 1 diabetes. The three experimental parameters were determined at 2, 3, 4 weeks after streptozotocin treatment. Fasting blood glucose levels significantly increased by 20.7–21.9 m M after streptozotocin treatment. The number of antioxidant-like protein-1 immunoreactive neurons significantly decreased in the hippocampal CA1 region, but not the dentate gyrus, 3 weeks after streptozotocin treatment compared to the control group. Malondialdehyde and protein carbonyl levels, which are modified by oxidative stress, significantly increased with a peak at 3 weeks after malondialdehyde treatment, and then decreased 4 weeks after malondialdehyde treatment. These results suggest that neurons in the hippocampal CA1 region, but not the dentate gyrus, are susceptible to oxidative stress 3 weeks after malondialdehyde treatment.
文摘BACKGROUND: Previous experiments have confirmed bone morphogenetic proteins (BMPs) upregulate cholinergic expression in neurons isolated from the embryonic rat hippocampus and cerebral cortex. Therefore, BMPs could be useful for treating Alzheimer's disease and other neurodegenerative diseases. OBJECTIVE: BMP-4 was infused into the hippocampal dentate gyrus of fornix-fimbria transected rats to test the effects of BMP-4 on cholinergic expression in dentate gyrus neurons, and to observe changes in spatial memory behavior. DESIGN: A randomized controlled animal experiment. SETTING: Department of Neurosurgery and Laboratory for Cell Biology, Institute of Geriatrics, General Hospital of Chinese PLA. MATERIALS: Twenty-seven healthy adult male Sprague Dawley (SD) rats, weighing 250-300 g, were provided by the Laboratory Animal Center of the General Hospital of Chinese PLA. Reagents: BMP-4 (B-2680, Sigma Company) and choline acetyl transferase (ChAT) antibody (AB5042, Chemicon Company) were used in this study. Equipments: a rat stereotaxic instrument (type: SN-2N, Narushige Group, Japan) and Image-prog-plus image analysis software (Media Cybernetics company, USA) were used in this study. The protocol was carried out in accordance with ethical guidelines for the use and care of animals. METHODS: This experiment was performed in the Institute of Geriatrics, General Hospital of Chinese PLA between July 2004 and March 2005. Rats were randomly divided into 4 groups: Alzheimer's disease group (n = 7), normal control group (n = 5), BMP-4-Alzheimer's disease group (n = 8), and model group (n = 7). In the Alzheimer's disease group, the left hippocampal fornix-fimbria of rats was transected to mimic Alzheimer's disease symptoms. In the BMP-4-Alzheimer's disease group, 1 μL BMP-4 (10 mg/L) was perfused into the left dentate gyrus with a microinjector at 1 μL/min. In the model group, 1 μL saline was perfused into the same position by the same method. Twenty-eight days after injection, Morris water maze test was performed in all rats to test spatial memory. Time-to-platform and swim-path length were recorded. Immunohistochemical staining of cholinergic neurons was performed on brain sections containing dentate gyrus. The area covered by ChAT-positive cells was analyzed using an Image-prog-plus image analysis software. MAIN OUTCOME MEASURES: Area covered by ChAT-positive cells in the dentate gyrus. Time-to-platform and swim path-length. RESULTS: Twenty-seven rats were included in the final analysis. In the Alzheimer's disease group, the area covered by ChAT-positive cells was significantly smaller compared with the normal control group (F = 76.03, P < 0.01). The area covered by ChAT-positive cells was significantly larger in the BMP-4- Alzheimer's disease group than in the model group (F = 35.17, P < 0.05), but significantly smaller than in the normal control group (F = 40.17, P < 0.05). Time-to-platform and swim-path length were significantly longer in the Alzheimer's disease group than in the normal control group (F =24.62 and 631.58, respectively, both P < 0.05). Time-to-platform and swim-path length were significantly shorter in the BMP4-Alzheimer's disease group compared with the model group (F = 22.06 and 606.89, respectively P < 0.05). CONCLUSION: Injection of BMP-4 into the dentate gyrus of Alzheimer's disease model rats alleviates central cholinergic system injury and concomitantly improves spatial memory.
基金supported by the National Research Foundation of Korea(NRF)funded by the Ministry of Education,Science and Technology,No.2010-0010580+1 种基金Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT and future Planning,No.NRF-2013R1A2A2A01068190
文摘Long-term administration of scopolamine, a muscarinic receptor antagonist, can inhibit the survival of newly generated cells, but its effect on the proliferation, differentiation and migration of nerve cells in the adult mouse hippocampal dentate gyrus remain poorly understood. In this study, we used immunohistochemistry and western blot methods to weekly detect the biological behaviors of nerve cells in the hippocampal dentate gyrus of adult mice that received intraperitoneal administration of scopolamine for 4 weeks. Expression of neuronal nuclear antigen(Neu N; a neuronal marker) and Fluoro-Jade B(a marker for the localization of neuronal degeneration) was also detected. After scopolamine treatment, mouse hippocampal neurons did not die, and Ki-67(a marker for proliferating cells)-immunoreactive cells were reduced in number and reac hed the lowest level at 4 weeks. Doublecortin(DCX; a marker for newly generated neurons)-immunoreactive cells were gradually shortened in length and reduced in number with time. After scopolamine treatment for 4 weeks, nearly all of the 5-bromo-2′-deoxyuridine(Brd U)-labeled newly generated cells were located in the subgranular zone of the dentate gyrus, but they did not migrate into the granule cell layer. Few mature Brd U/Neu N double-labeled cells were seen in the subgranular zone of the dentate gyrus. These findings suggest that long-term administration of scopolamine interferes with the proliferation, differentiation and migration of nerve cells in the adult mouse hippocampal dentate gyrus, but it does not induce cell death.
基金the National Natural Science Foundation of China, No. 30170326
文摘Increasing evidence suggests that heat shock factor 1 exerts endogenous protective effects on working memory under conditions of chronic psychological stress.However,the precise underlying mechanisms remain poorly understood.This study examined the protective factors affecting working memory in heat shock transcription factor 1 gene knockout mice.The results indicated that the number of correct T maze alternations decreased following mild chronic psychological stress in knockout mice.This change was accompanied by a decrease in neurogenesis and an increase in neuronal apoptosis in the hippocampal dentate gyrus.The number of correct T maze alternations was positively correlated with neurogenesis in hippocampal dentate gyrus,and negatively correlated with neuronal apoptosis.In wild type mice,no significant difference was detected in the number of correct T maze alternations or neuronal apoptosis in hippocampal dentate gyrus.These results indicate that the heat shock factor 1 gene has an endogenous protective role in working memory during mild chronic psychological stress associated with dentate gyrus neuronal apoptosis.Moreover,dentate gyrus neurogenesis appears to participate in the protective mechanism.
文摘We investigated the effects of ethanol extracted Scutellaria baicalensis(EESB) on spatial memory function and neurogenesis in the hippocampal dentate gyrus.Adult Sprague-Dawley rats were orally administered 50,100,or 200 mg/kg of EESB for 6 successive days.The radial-arm maze test showed that 200 mg/kg of EESB improved the spatial memory of adult rats.Confocal microscopy results showed that 100 mg/kg of EESB increased the number of bromodeoxyuridine(BrdU)-and neuron-specific nuclear protein-positive cells in the granular cell layer,and that 100 and 200 mg/kg of EESB increased the number of BrdU-/neuron-specific nuclear protein-positive cells in the sub-granular zone.200 mg/kg of EESB increased the number of BrdU-/glial fibrillary acid protein-positive cells in the subgranular zone.These findings indicate that EESB can effectively promote neurogenesis in the hippocampal dentate gyrus and improve spatial memory function.
