Promotion of structural plasticity in area V2 of visual cortex prevents against object recognition memory deficits in aging and Alzheimer's disease rodents

Memory deficit,which is often associated with aging and many psychiatric,neurological,and neurodegenerative diseases,has been a challenging issue for treatment.Up till now,all potential drug candidates have failed to produce satisfa ctory effects.Therefore,in the search for a solution,we found that a treatment with the gene corresponding to the RGS14414protein in visual area V2,a brain area connected with brain circuits of the ventral stream and the medial temporal lobe,which is crucial for object recognition memory(ORM),can induce enhancement of ORM.In this study,we demonstrated that the same treatment with RGS14414in visual area V2,which is relatively unaffected in neurodegenerative diseases such as Alzheimer s disease,produced longlasting enhancement of ORM in young animals and prevent ORM deficits in rodent models of aging and Alzheimer’s disease.Furthermore,we found that the prevention of memory deficits was mediated through the upregulation of neuronal arbo rization and spine density,as well as an increase in brain-derived neurotrophic factor(BDNF).A knockdown of BDNF gene in RGS14414-treated aging rats and Alzheimer s disease model mice caused complete loss in the upregulation of neuronal structural plasticity and in the prevention of ORM deficits.These findings suggest that BDNF-mediated neuronal structural plasticity in area V2 is crucial in the prevention of memory deficits in RGS14414-treated rodent models of aging and Alzheimer’s disease.Therefore,our findings of RGS14414gene-mediated activation of neuronal circuits in visual area V2 have therapeutic relevance in the treatment of memory deficits.

Protective Effect of Mulberry Extract against Pb-induced Learning and Memory Deficits in Mice

Lead （Pb） is ubiquitous in the environment, and low-level Pb exposure can cause neurotoxicity and irreversible damage to children＇s cognition, learning and memory ability. Nutritional intervention is an effective method to prevent Pb poisoning. Mul- berry is rich in anthocyanins, possessing protective effects for nerves. This study investigated the neuroprotective effects of mulberry extract （ME） against Pb-induced learning and memory deficits in mice. The results showed that the learning and memory abilities of mice, assessed using the Morris test, improved significantly after treatment with ME at a dose of 100 mg/kg body weight. The level of Pb in the brains of mice in the three ME intervention groups decreased significantly, while NO production and anti-oxidant enzymes were significantly restored. It is suggested that ME inhibits Pb-induced neurotoxicity by reversing Pb-induced alterations in the aspect of neurotoxic effects and improving learning and memory.

Astrocytic endothelin-1 overexpression impairs learning and memory ability in ischemic stroke via altered hippocampal neurogenesis and lipid metabolism

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.

3′-Daidzein sulfonate sodium protects against memory impairment and hippocampal damage caused by chronic cerebral hypoperfusion

3′-Daidzein sulfonate sodium（DSS） is a new synthetic water-soluble compound derived from daidzein,a soya isoflavone that plays regulatory roles in neurobiology.In this study,we hypothesized that the regulatory role of DSS in neurobiology exhibits therapeutic effects on hippocampal damage and memory impairment.To validate this hypothesis,we established rat models of chronic cerebral hypoperfusion（CCH） by the permanent occlusion of the common carotid arteries using the two-vessel occlusion method.Three weeks after modeling,rat models were intragastrically administered 0.1,0.2,and 0.4 mg/kg DSS,once a day,for 5 successive weeks.The Morris water maze test was performed to investigate CCH-induced learning and memory deficits.TUNEL assay was used to analyze apoptosis in the hippocampal CA1,CA3 regions and dentate gyrus.Hematoxylin-eosin staining was performed to observe the morphology of neurons in the hippocampal CA1,CA3 regions and dentate gyrus.Western blot analysis was performed to investigate the phosphorylation of PKA,ERK1/2 and CREB in the hippocampal PKA/ERK1/2/CREB signaling pathway.Results showed that DSS treatment greatly improved the learning and memory deficits of rats with CCH,reduced apoptosis of neurons in the hippocampal CA1,CA3 regions and dentate gyrus,and increased the phosphorylation of PKA,ERK1/2,and CREB in the hippocampus.These findings suggest that DSS protects against CCH-induced memory impairment and hippocampal damage possibly through activating the PKA/ERK1/2/CREB signaling pathway.

Delayed improvements in visual memory task performance among chronic schizophrenia patients after high-frequency repetitive transcranial magnetic stimulation

BACKGROUND Cognitive impairments are core characteristics of schizophrenia,but are largely resistant to current treatments.Several recent studies have shown that highfrequency repetitive transcranial magnetic stimulation(rTMS)of the left dorsolateral prefrontal cortex(DLPFC)can reduce negative symptoms and improve certain cognitive deficits in schizophrenia patients.However,results are inconsistent across studies.AIM To examine if high-frequency rTMS of the DLPFC can improve visual memory deficits in patients with schizophrenia.METHODS Forty-seven chronic schizophrenia patients with severe negative symptoms on stable treatment regimens were randomly assigned to receive active rTMS to the DLPFC(n=25)or sham stimulation(n=22)on weekdays for four consecutive weeks.Patients performed the pattern recognition memory(PRM)task from the Cambridge Neuropsychological Test Automated Battery at baseline,at the end of rTMS treatment(week 4),and 4 wk after rTMS treatment(week 8).Clinical symptoms were also measured at these same time points using the Scale for the Assessment of Negative Symptoms(SANS)and the Positive and Negative Syndrome Scale(PANSS).RESULTS There were no significant differences in PRM performance metrics,SANS total score,SANS subscores,PANSS total score,and PANSS subscores between active and sham rTMS groups at the end of the 4-wk treatment period,but PRM performance metrics(percent correct and number correct)and changes in these metrics from baseline were significantly greater in the active rTMS group at week 8 compared to the sham group(all P<0.05).Active rTMS treatment also significantly reduced SANS score at week 8 compared to sham treatment.Moreover,the improvement in visual memory was correlated with the reduction in negative symptoms at week 8.In contrast,there were no between-group differences in PANSS total score and subscale scores at either week 4 or week 8(all P>0.05).CONCLUSION High-frequency transcranial magnetic stimulation improves visual memory and reduces negative symptoms in schizophrenia,but these effects are delayed,potentially due to the requirement for extensive neuroplastic changes within DLPFC networks.

Neurotoxicity of cancer chemotherapy

There is accumulating clinical evidence that chemotherapeutic agents induce neurological side effects, including memory deficits and mood disorders, in cancer patients who have undergone chemotherapeutic treatments. This review focuses on chemotherapy-induced neurodegeneration and hippocampal dysfunctions and related mechanisms as measured by in vivo and in vitro approaches. These investigations are helpful in determining how best to further explore the causa mechanisms of chemotherapy-induced neurological side effects and in providing direction for the future development of novel optimized chemotherapeutic agents.

No spatial memory deficit exists in Kunming mice that recently recovered from motor defects following 3-nitropropionic acid intoxication

Objective Numerous studies have described both motor defects and cognitive impairments in several strains of rodents following 3-nitropropionic acid （3-NP） intoxication. In the present study, we investigated spatial recognition memory in Kunming mice that just recovered from motor defects induced by 3-NP. Methods Mouse model was made by systemic subacute 3-NP treatment, and spatial recognition memory was measured through the Y-maze Test, a simple two-trial recognition test. Results （1） On day 15 following 3-NP treatment, affected Kunming mice did not show motor defects in the Rotarod test and presented normal gait again. （2） In the following Y-maze test after lh interval, the percentage （90.0%） of mice showing novel ann preference in 3-NP treatment group was significantly higher than the random chance level （50%）, although it was only slightly higher than that （83.3%） in control group. On day 45 after 3-NP treatment, mice failed to choose unfamiliar novel arm as first choice, and the same occured in the control group. （3） For both post-intoxicated （on day 15 and day 45 following 3-NP treatment） and control groups, the duration in the novel ann and the frequency of entering it, were longer and higher compared with familiar start and other arms. For these mice that recently recovered from motor defects following 3-NP intoxication, no spatial memory deficits were observed through Y-maze Test. Conclusion Kunming mice used in our assays might possess resistance to cognitive impairment induced by 3-NP, which is consistent with previous findings in Swiss EPM-M1 mice.

Intracerebroventricular transplantation of human amniotic epithelial cells ameliorates spatial memory deficit in the doubly transgenic mice coexpressing APPswe and PS1△E9.deleted genes

Background Human amniotic epithelial cells （HAECs）, which have characteristics of both embryonic and pluripotent stem cells, are therefore a candidate in cell therapy without creating legal or ethical problems. In the present study, we aimed to investigate the effects of intracerebroventricular transplantation of HAECs on doubly transgenic mice of Alzheimer＇s disease （AD） coexpressing presenilin-1 （PS1） and mutant Sweden amyloid precursor protein （APPswe） genes. Methods The offspring mice genotypes were detected using PCR identification of APPswe and PS1 gene. The doubly transgenic （TG） mice （n=20） and wild-type （WT） mice （n=20） were randomly divided into two groups respectively： the transplantation group treated with HAECs and the control group with phosphate buffered saline. Six radial arm water maze test was used to assess the spatial memory in the TG and WT mice. Amyloid plaques and neurofibrillary tangles were analyzed using congo red and acid-silver methenamine staining respectively. was used to track the survival of HAECs. Immunohistochemistry was used octamer-binding protein 4 （Oct-4） and Nanog in the HAECs. High performance measure acetylcholine in hippocampus. The density of cholinergic neurons in hippocampus was measured using acetylcholinesterase staining. Immunofluorescence cytochemistry to determine the expression of quid chromatography was used to basal forebrain and nerve fibers in Results Amyloid deposition occurred in hippocampus and frontal cortex in the double TG mice aged 8 months, but not in WT mice. The results also showed that transplanted HAECs can survive for at least 8 weeks and migrate to the third ventricle without immune rejection. The graft HAECs can also express the specific marker Oct-4 and Nanog of stem cell. Compared with the control group, transplantation of HAECs can not only significantly improve the spatial memory of the TG mice, but also increase acetylcholine concentration and the number of hippocampal cholinergic neurites. Conclusions These results demonstrate that intracerebroventricular transplantation of HAECs can improve the spatial memory of the double TG mice. The higher content of acetylcholine in hippocampus released by more survived cholinergic neurites is one of the causes of this improvement.

Paroxetine ameliorates prodromal emotional dysfunction and late-onset memory deficit in Alzheimer’s disease mice

Background Neuropsychiatric symptoms(NPS)such as depression,anxiety,apathy,and irritability occur in prodromal phases of clinical Alzheimer’s disease(AD),which might be an increased risk for later developing AD.Here we treated young APP/PS1 AD model mice prophylactically with serotonin-selective re-uptake inhibitor(SSRI)paroxetine and investigated the protective role of anti-depressant agent in emotional abnormalities and cognitive defects during disease progress.Methods To investigate the protective role of paroxetine in emotional abnormalities and cognitive defects during disease progress,we performed emotional behaviors of 3 months old APP/PS1 mouse following oral administration of paroxetine prophylactically starting at 1 month of age.Next,we tested the cognitive,biochemical and pathological,effects of long term administration of paroxetine at 6 months old.Results Our results showed that AD mice displayed emotional dysfunction in the early stage.Prophylactic administration of paroxetine ameliorated the initial emotional abnormalities and preserved the eventual memory function in AD mice.Conclusion Our data indicate that prophylactic administration of paroxetine ameliorates the emotional dysfunction and memory deficit in AD mice.These neuroprotective effects are attributable to functional restoration of glutamate receptor(GluN2A)in AD mice.

Neuropsychological study of patients with obsessive-compulsive disorder and their parents in China: searching for potential endophenotypes

Objective The existence of neuropsychological deficits has been implicated in obsessive-compulsive disorder （OCD）, particularly memory, attention, and executive functions. However, few studies have focused on neuropsychological deficits in the relatives of OCD patients. The aim of this study was to investigate cognitive deficits in OCD patients and their parents. Methods Forty patients with OCD, 48 parents of these patients, and 87 healthy controls completed a neuropsychological testing battery. Results Both OCD patients and their parents showed impairments in delayed verbal memory and delayed visual memory. Furthermore, they performed worse than healthy controls in problem-solving ability. Conclusion Our study demonstrated familial aggregation of delayed memory deficits and impaired problem-solving ability, which may be the potential neuropsychological endophenotypes of hereditary susceptibility to OCD.

Therapeutic effects of human amniotic epithelial cell transplantation on double-transgenic mice co-expressing APPswe and PS1ΔE9-deleted genes

Human amniotic epithelial cells (HAECs), which exhibit characteristics of embryonic and pluripotent stem cells, could be utilized for cell therapy without legal or ethical problems. Double-transgenic (TG) mice (n=20) and wild-type (WT) mice (n=20) were randomly assigned to two groups, respectively. The transplantation group was treated with HAECs and the control group with PBS. A six-radial arm water maze was used to assess spatial memory. Immunofluorescence was utilized to track HAEC survival. Immunohistochemistry was used to determine octamer-binding protein 4 (oct-4) and nanog expression in the HAECs. High-performance liquid chromatography (HPLC) was used to measure acetylcholine levels in the hippocampus. The density of cholinergic neurons in the basal forebrain and nerve fibers in the hippocampus was measured following acetylcholinesterase staining. Results showed that transplanted HAECs survived for at least eight weeks and migrated to the third ventricle without immune rejection. Graft HAECs also expressed the specific stem cell markers oct-4 and nanog. Compared with the control group, HAEC transplantation significantly ameliorated spatial memory deficits in TG mice, as well as increased acetylcholine levels and the number of hippocampal cholinergic neurites. Intracerebroventricular HAEC transplantation improved spatial memory in double-TG mice, and results suggested that increased acetylcholine levels in the hippocampus, released by surviving cholinergic neurites, were responsible for this improvement.

TNP-ATP is Beneficial for Treatment of Neonatal HypoxiaInduced Hypomyelination and Cognitive Decline

Our previous study together with other inves- tigations have reported that neonatal hypoxia or ischemia induces long-term cognitive through brain inflammation impairment, at least in part and hypomyelination. How- ever, the detailed mechanisms are not fully understood. Here, we used a rodent model of neonatal hypoxia by subjecting postnatal day 0 （P0） rat pups to systemic hypoxia （3.5 h）. We found that neonatal hypoxia increased the glutamate content and initiated inflammatory responses at 4 h and 1 day after hypoxia, caused hypomyelination in the corpus callosum, and impaired hippocampus-dependent learning and memory when assessed 30-60 days after hypoxia. Interestingly, much of the hypoxia-induced brain damage was ameliorated by treatment with the ATP ana- logue 21,3-0-（2,4,6-trinitrophenyl）-adenosine 5^-triphos- phate （TNP-ATP; blocks all ionotropic P2Xl-7 receptors）, whereas treatment with pyridoxalphosphate-6-azophenyl- 2＇,4＇-disulphonic acid （PPADS; inhibits P2X1-3 and P2X5- 7 receptors） was less neuroprotective. Our data indicated that activation of ionotropic ATP receptors might be par- tially, if not fully, involved in glutamate deregulation, neuroinflammation, hypomyelination, and cognitive dys- function after neonatal hypoxia.

Cymbopogon citratus aqueous leaf extract attenuates neurobehavioral and biochemical changes induced by social defeat stress in mice

Objective:Psychosocial stress has been implicated in the genesis of psychiatric disorders such as memory deficits,depression,anxiety and addiction.Aqueous leaf extract of Cymbopogon citratus(CYC)otherwise known as lemongrass tea has antidepressant,anxiolytic and anti-amnesic effects in rodents.This study was designed to evaluate if C citratus could reverse the neurobehavioral and biochemical derangements induced by social defeat stress(SDS)in the resident/intruder paradigm.Methods:Intruder male mice were divided into five groups(n=7):group 1 received saline(10 mL/kg,p.o.;non-stress control),group 2 also received saline(10 mL/kg,p.o.;SDS control)while groups 3-5 had C.citratus(50,100 and 200 mg/kg,p.o.)daily for 14 d.The SDS was carried out 30 min after each treatment from day 7 to day 14 by exposing each intruder mouse in groups 2-5 to a 10 min confrontation in the home cage of an aggressive resident counterpart.The neurobehavioral features(spontaneous motor activity-SMA,anxiety,memory,social avoidance and depression were then evaluated.The concentrations of nitrite,malondialdehyde and glutathione as well as acetylcholinesterase activity in the brain tissues were also determined.Results:C.citratus(50,100 and 200 mg/kg)attenuated hypolocomotion,heightened anxiety,depressive-like symptom,memory deficit and social avoidance induced by SDS.The altered levels of oxidative stress and acetyl-cholinesterase in SDS-mice were positively modulated by C.citratus.Conclusion:The results of this study suggest that C.citratus might mitigate psychosocial stress-induced neurologic diseases in susceptible individuals.