Morris Water Maze Escape Latency Research Articles

Comparison of Malondialdehyde, Acetylcholinesterase, and Apoptosis-Related Markers in the Cortex and Hippocampus of Cognitively Dysfunctional Mice Induced by Scopolamine

Objectives: Until now, many researchers have conducted evaluations on hippocampi for analyses of cognitive dysfunction models using scopolamine. However, depending on the purposes of these analyses, there are differences in the experimental results for the hippocampi and cortexes. Therefore, this study intends to compare various analyses of cognitive dysfunction after scopolamine administration with each other in hippocampi and cortexes. Methods: Scopolamine was administered at three dosages in mice: 0.5, 1, and 3 mg/kg. And this study evaluates the differences in cognitive function and the expression of malondialdehyde (MDA), acetylcholinesterase (AChE), and brain-derived neurotrophic factor (BDNF) in mice’s hippocampi and cortexes based on scopolamine dosages. Results: The Morris water maze test was conducted between 1 and 3 h after scopolamine injection to assess its duration. A significant decrease in behavioral ability was evaluated at 1 h, and we observed a similar recovery to the normal group at 3 h. And the Morris water maze escape latency showed differences depending on scopolamine concentration. While the escape waiting time in the control group and scop 0.5 administration group remained similar to that seen before administration, the administration of scop 1 and 3 increased it. In the experimental group administered scop 1 and 3, cerebral MDA levels in the cerebral cortex significantly increased. In the hippocampus, the MDA level in the scopolamine-administered groups slightly increased compared to the cortex. A Western blotting assay shows that Bax and Bcl-xl showed a tendency to increase or decrease depending on the concentration, but BDNF increased in scop 0.5, and scop 1 and 3 did not show a significant decrease compared to the control at the cerebral cortex. In the hippocampus, BDNF showed a concentration-dependent decrease in expression. Conclusions: This study’s findings indicate that chemical analyses for MDA and AChE can be performed in the cerebral cortex, while the hippocampus is better suited for protein analysis of apoptosis and BDNF.

What Threshold of Amyloid Reduction Is Necessary to Meaningfully Improve Cognitive Function in Transgenic Alzheimer's Disease Mice?

Amyloid-β plaques (Aβ) are associated with Alzheimer's disease (AD). Pooled assessment of amyloid reduction in transgenic AD mice is critical for expediting anti-amyloid AD therapeutic research. The mean threshold of Aβ reduction necessary to achieve cognitive improvement was measured via pooled assessment (n = 594 mice) of Morris water maze (MWM) escape latency of transgenic AD mice treated with substances intended to reduce Aβ via reduction of beta-secretase cleaving enzyme (BACE). Machine learning and statistical methods identified necessary amyloid reduction levels using mouse data (e.g., APP/PS1, LPS, Tg2576, 3xTg-AD, control, wild type, treated, untreated) curated from 22 published studies. K-means clustering identified 4 clusters that primarily corresponded with level of Aβ: untreated transgenic AD control mice, wild type mice, and two clusters of transgenic AD mice treated with BACE inhibitors that had either an average 25% "medium reduction" of Aβ or 50% "high reduction" of Aβ compared to untreated control. A 25% Aβ reduction achieved a 28% cognitive improvement, and a 50% Aβ reduction resulted in a significant 32% improvement compared to untreated transgenic mice (p < 0.05). Comparatively, wild type mice had a mean 41% MWM latency improvement over untreated transgenic mice (p < 0.05). BACE reduction had a lesser impact on the ratio of Aβ42 to Aβ40. Supervised learning with an 80% -20% train-test split confirmed Aβ reduction was a key feature for predicting MWM escape latency (R2 = 0.8 to 0.95). Results suggest a 25% reduction in Aβ as a meaningful treatment threshold for improving transgenic AD mouse cognition.

Neuroprotection by Polyherbal Medicine Divya-Medha-Vati Against Scopolamine-Induced Cognitive Impairment Through Modulation of Oxidative Stress, Acetylcholine Activity, and Cell Signaling.

Alzheimer disease is associated with cognitive impairments and neuronal damages. In this study, Scopolamine, a model drug used for the generation of Alzheimer-like symptoms induced cognitive dysfunction in C57BL/6 mice. It also elevated acetylcholine esterase (AcHE) activity, and reduced antioxidant (superoxide dismutase and catalase) activity in cortex tissue. Scop reduced neuronal density and increased pyknotic neurons in hippocampus tissue. In mouse neuroblastoma (Neuro2a) cells, Scop triggered a dose-dependent loss of cell viability and neurite outgrowth reduction. Scop-treated Neuro2a cells showed oxidative stress and reduction in mRNA expression for brain-derived neurotrophic factor (BDNF), nerve growth factor-1 (NGF-1), and Synapsin-1 (SYN-1) genes. Mice treated with Divya-Medha-Vati (DMV), an Ayurvedic polyherbal medicine showed protection against Scop-induced cognitive impairment (Morris Water Maze Escape Latency, and Elevated Plus Maze Transfer Latency). DMV protected against Scop-induced AcHE activity, and loss of antioxidant activities in the mice brain cortex while sustaining neuronal density in the hippocampus region. In the Neuro2a cells, DMV reduced Scop-induced loss of cell viability and neurite outgrowth loss. DMV protected the cells against induction of oxidative stress and promoted mRNA expression of BDNF, NGF-1, and SYN-1 genes. Phytochemical profiling of DMV showed the presence of Withanolide A, Withanolide B, Bacopaside II, Jujubogenin, Apigenin, Gallic acid, Caffeic acid, and Quercetin that are associated with antioxidant and neurostimulatory activities. In conclusion, the study showed that Divya-Medha-Vati was capable of promoting neuronal health and inhibiting Alzheimer-like cognitive dysfunction through enhanced antioxidant activities and modulation of neuronal activities.

Effects of Yizhi Tiaoshen acupuncture on learning and memory function and the expression of phosphorylated tau protein in the hippocampus of Alzheimer's disease model rats

To observe the effects of Yizhi Tiaoshen (benefiting mental health and regulating the spirit) acupuncture on learning and memory function, and the expression of phosphorylated tubulin-associated unit (tau) protein in the hippocampus of Alzheimer's disease (AD) model rats, and explore the effect mechanism of this therapy on AD. A blank group and a sham-operation group were randomly selected from 60 male SD rats, 10 rats in each one. AD models were established in the rest 40 rats by the intraperitoneal injection of D-galactose and okadaic acid in the CA1 region of the bilateral hippocampus. Thirty successfully-replicated model rats were randomly divided into a model group, a western medication group and an acupuncture group, 10 rats in each one. In the acupuncture group, acupuncture was applied to "Baihui" (GV 20), "Sishencong" (EX-HN 1), "Neiguan" (PC 6), "Shenmen" (HT 7), "Xuanzhong" (GB 39) and "Sanyinjiao" (SP 6); and the needles were retained for 10 min. Acupuncture was given once daily. One course of treatment was composed of 6 days, with the interval of 1 day; the completion of treatment included 4 courses. In the western medication group, donepezil hydrochloride solution (0.45 mg/kg) was administrated intragastrically, once daily; it took 7 days to accomplish one course of treatment and a completion of intervention was composed of 4 courses. Morris water maze (MWM) and novel object recognition test (NORT) were used to assess the learning and memory function of the rats. Using HE staining and Nissl staining, the morphological structure of the hippocampus was observed. With Western blot adopted, the protein expression of the tau, phosphorylated tau protein at Ser198 (p-tau Ser198), protein phosphatase 2A (PP2A) and glycogen synthase kinase-3β (GSK-3β) in the hippocampus was detected. There were no statistical differences in all of the indexes between the sham-operation group and the blank group. Compared with the sham-operation group, in the model group, the MWM escape latency was prolonged (P<0.05), the crossing frequency and the quadrant stay time in original platform were shortened (P<0.05), and the NORT discrimination index (DI) was reduced (P<0.05); the hippocampal cell numbers were declined and the cells arranged irregularly, the hippocampal neuronal structure was abnormal and the numbers of Nissl bodies decreased; the protein expression of p-tau Ser198 and GSK-3βwas increased (P<0.05) and that of PP2A decreased (P<0.05). When compared with the model group, in the western medication group and the acupuncture group, the MWM escape latency was shortened (P<0.05), the crossing frequency and the quadrant stay time in original platform were increased (P<0.05), and DI got higher (P<0.05); the hippocampal cell numbers were elevated and the cells arranged regularly, the damage of hippocampal neuronal structure was attenuated and the numbers of Nissl bodies were increased; the protein expression of p-tau Ser198 and GSK-3β was reduced (P<0.05) and that of PP2A was increased (P<0.05). There were no statistically significant differences in the above indexes between the acupuncture group and the western medication group (P>0.05). Acupuncture therapy of "benefiting mental health and regulating the spirit" could improve the learning and memory function and alleviate neuronal injure of AD model rats. The effect mechanism of this therapy may be related to the down-regulation of GSK-3β and the up-regulation of PP2A in the hippocampus, and then to inducing the inhibition of tau protein phosphorylation.

Evaluating the brain renin‐angiotensin system (RAS) and sex differences in pre‐clinical models of Alzheimer’s Disease

AbstractBackgroundHypertension is linked to Alzheimer’s Disease (AD) risk, although the mechanisms remain unclear. The renin angiotensin system (RAS), critical for blood pressure homeostasis, is thought to contribute to AD pathology, and targeted RAS therapies are under current clinical investigation. To further evaluate the neurobiological mechanisms of RAS in AD, the current study leveraged two transgenic AD mouse models to compare the behavioral and cognitive deficits and the brain RAS in male and female mice.MethodsA triple‐transgenic mouse model of AD (3xTg‐AD), which exhibits both amyloid beta and tau pathology, was used for in‐house assays, while an RNA‐sequencing database using a novel mouse model on a genetically diverse background (AD‐BXD) (GEO accession number GSE119215) was used to compare expression levels of hippocampal RAS genes at 6 and 14 mos. Morris water maze (MWM) and Y‐maze alternation tests were performed at early (3‐4 mos) and middle (5‐6 mos) time points on 3xTg‐AD mice (n = 8/sex/age/genotype), followed by collection of plasma and whole brain.ResultsCompared to controls, beginning at 3.5 months, 3xTg‐AD male and female mice exhibited deficits in learning assessed by MWM escape latency (p&lt;0.01). However, beginning at 6 months, only 3xTg‐AD females had deficits in memory assessed by Y‐maze alternation below 50% (i.e. chance) (p&lt;0.05). Sex‐dependent deficits are consistent with variability in phenotype beginning at early time points. Next we assessed hippocampal RNA‐sequencing data from the AD‐BXD database. These data demonstrated a sex‐dependent increase in expression of counter‐regulatory RAS genes ACE (p&lt;0.0001) and ACE2 (p&lt;0.05) and decrease in MasR (p&lt;0.01) when comparing 6 and 14 month females, as compared to males and wild‐type controls. There was no change in classical RAS gene expression, indicating that variation in expression of neuroprotective but not classical RAS genes may be more pronounced in aging female mice.ConclusionOur results demonstrate sex and stage‐specific behavioral deficits in the 3xTg‐AD model, which may be linked to changes in hippocampal regulation of the counter‐regulatory arm of brain RAS. Additional studies are needed to further evaluate underlying mechanisms for the role of the neuroprotective arm of the brain RAS in AD and its biomarker and therapeutic targeting potential.

Electroacupuncture attenuates brain injury through α7 nicotinic acetylcholine receptor-mediated suppression of neuroinflammation in a rat model of asphyxial cardiac arrest

We determined whether electroacupuncture (EA) ameliorated brain injury following asphyxial cardiac arrest (CA) and evaluated the role of the α7 nicotinic acetylcholine receptor (α7nAChR)-mediated anti-inflammatory pathway. In CA-induced rats, EA reduced brain injury and promoted behavioral recovery. Morris water maze escape latency time reduced after Baihui (GV20) and Shuigou (DU26) stimulation. EA reduced α7nAChR downregulation after cardiopulmonary resuscitation (CPR), reducing tumor necrosis factor alpha, interleukin-1, and interleukin-6 expression and ionized calcium binding adapter molecule 1 production. The α7nAChR antagonist methyllycaconitine reversed EA effect. EA stimulation of acupuncture points alleviated brain damage after CPR and reduced the inflammatory response via α7nAChR activation.

Effect of grewia hirsuta vahl ethanolic root extract on cognition in scopolamine induced amnesia

Objective Alzheimer's illnesses are becoming medical nightmares because there is no exact solution and existing nootropic medicines (Piracetam, tacrine, and metrifonate) have significant drawbacks. The goal of this study was to see if the ethanolic root extract of Grewia hirsuta (ERGH) could improve memory in rats who had been given scopolamine.&#x0D; Materials and procedures At rats, ERGH was given orally in dosages of 200 and 400 mg/kg for 28 days, followed by Scopolamine (18 mg/kg i.p.) from the 25th to the 27th day. The usual nootropic drug was piracetam (200 mg/kg). The elevated plus maze (EPM), Morris water maze (MWM), and passive avoidance (PA) paradigms are used to assess cognitive functioning. Invivo anti-oxidant activity and brain acetylcholine esterase (AchE) activity were assessed.&#x0D; Results: At the indicated doses, ERGH extract showed a substantial memory-enhancing activity by decreasing the transfer latency in EPM, increasing the escape latency in MWM, and increasing the shock-free zone in PA. In scopolamine-induced amnesia rats, pretreatment with ERGH resulted in a significant drop in AchE enzyme, an increase in enzymatic antioxidant, and a decrease in MDA levels.&#x0D; Conclusion Because of its several favorable benefits, such as memory-improving properties, anticholinesterase activity, and antioxidant activity, ERGH may prove to be a useful drug in the current study, and it would be important to investigate its potential in the care of Alzheimer's patients.

Aggregate Trends of Apolipoprotein E on Cognition in Transgenic Alzheimer's Disease Mice.

Background:Apolipoprotein E (APOE) genotypes typically increase risk of amyloid-β deposition and onset of clinical Alzheimer’s disease (AD). However, cognitive assessments in APOE transgenic AD mice have resulted in discord.Objective:Analysis of 31 peer-reviewed AD APOE mouse publications (n = 3,045 mice) uncovered aggregate trends between age, APOE genotype, gender, modulatory treatments, and cognition.Methods:T-tests with Bonferroni correction (significance = p < 0.002) compared age-normalized Morris water maze (MWM) escape latencies in wild type (WT), APOE2 knock-in (KI2), APOE3 knock-in (KI3), APOE4 knock-in (KI4), and APOE knock-out (KO) mice. Positive treatments (t+) to favorably modulate APOE to improve cognition, negative treatments (t–) to perturb etiology and diminish cognition, and untreated (t0) mice were compared. Machine learning with random forest modeling predicted MWM escape latency performance based on 12 features: mouse genotype (WT, KI2, KI3, KI4, KO), modulatory treatment (t+, t–, t0), mouse age, and mouse gender (male = g_m; female = g_f, mixed gender = g_mi).Results:KI3 mice performed significantly better in MWM, but KI4 and KO performed significantly worse than WT. KI2 performed similarly to WT. KI4 performed significantly worse compared to every other genotype. Positive treatments significantly improved cognition in WT, KI4, and KO compared to untreated. Interestingly, negative treatments in KI4 also significantly improved mean MWM escape latency. Random forest modeling resulted in the following feature importance for predicting superior MWM performance: [KI3, age, g_m, KI4, t0, t+, KO, WT, g_mi, t–, g_f, KI2] = [0.270, 0.094, 0.092, 0.088, 0.077, 0.074, 0.069, 0.061, 0.058, 0.054, 0.038, 0.023].Conclusion:APOE3, age, and male gender was most important for predicting superior mouse cognitive performance.

Effects of Eugenol on Memory Performance, Neurogenesis, and Dendritic Complexity of Neurons in Mice Analyzed by Behavioral Tests and Golgi Staining of Brain Tissue.

Eugenol, as the main component in clove, has neuroprotective abilities, including its effect to learning memory of mice. However, there is no evidence showing whether eugenol can expand the growth of dendrites in the brain. The objective of this research was to examine the effects of eugenol towards dendritic complexity of neurons, neurogenesis, and memory performance in hippocampus. A total of 21 mice were divided into three groups; (i) mice were administered 30 mg/kg bw eugenol orally, (ii) mice were administered 100 mg/kg bw eugenol orally, and (iii) mice were administered distilled water as control. Mice were kept for 30 consecutive days following the standard animal housing. The memory performance was observed through the Y-arm maze alternation, Novel Object Recognition (NOR), and Morris Water Maze (MWM) test. The brain was dissected and stained with FD Rapid Golgi StainingTM kit to observe dendrites in the dentate gyrus (DG) and cornu ammonis 1 (CA1) region; and Haematoxylin-Eosin (HE) staining to assess neurogenesis in the DG. Our results showed that eugenol enhanced putative neural stem cells (NPCs) and granular cells (GC) number, and also decrease neuronal cell death in DG (p<0.0001). Eugenol also increased dendritic complexity of neurons in DG region; while in CA1, eugenol has given a positive effect only on the basal area. Eugenol increased spatial and recognition memory in mice, indicated by a higher number of correct alternations and discrimination ratio compared to the control group (p<0.05), although escape latency in MWM did not show significant effect (p>0.05). As analyzed by behavioral tests and Golgi staining of brain tissue, eugenol can increase memory performance, neurogenesis, and dendritic complexity of neurons in the DG and CA1 basal region of brain in mice.

Chronic High Fat Diet Induced Weight Gain, Hyperglycaemia and Cognitive Impairment in Albino Mice

With the global rise in consumption of western diet, obesity is becoming a pandemic. High fat and high calorie diet (though more palatable) have been associated with a range of metabolic disorders. Oxidative stress and insulin resistance have a link to the dietary etiology of diabetes and obesity; on the other hand, neuroinflammation and abnormal brain insulin signaling is said to cause cognitive decline when high fat diet (HFD) is consumed. In this study, mice were fed a home-made HFD with a total energy content of 5340kcal/kg. The overall energy contribution of saturated and unsaturated fat was about 70%. Animals were divided into Group I and II of 5 mice each. Group I (control group) were fed normal chow and water ad libidum. Group II (test group) were fed HFD and water ad libidum. HFD significantly (p&lt;0.05) increased the body weight of the test group (40 ±7.7) as compared to control (30 ± 2.9). Blood glucose levels in the test group was also significantly higher (111.6 ± 5.2) compared to the control (77.6 ± 8.7). Morris water maze escape latency in the test group was not significantly different (68 ± 26.3) compared to the control (72 ± 20.9). Similarly, the time spent in target quadrant in the test group was not significantly different (20.8 ± 10.9) compared to the control (15.8 ± 5.6). In the Y-maze the control group had a significantly higher (29.6 ± 3.5) percentage alternations compared to the test group (21 ± 13.1). It is obvious that the chronic administration of HFD in mice altered the body's metabolic processes as evident in the significant weight gain, hyperglycemia and cognitive deficit. These can be attributed to the oxidative damage, insulin dysregulation and pro-inflammatory potentials of HFD.

0001 Activation of Nociceptin/Orphanin-FQ Peptide (NOP) Receptors Produces an Increase in Non-REM Sleep in Rats and Constitutes a Novel and Attractive Target for the Treatment of Insomnia

Abstract Introduction Treatments for insomnia have targeted GABA, histamine, serotonin, melatonin and orexin receptors. The nociceptin/orphanin-FQ peptide (NOP) receptor is widely expressed in the nervous system. High doses of NOP agonists administered systemically or locally into the CNS can result in sedation, however, the utility of targeting this receptor to treat insomnia has not been fully described. Methods V117957 is a recently described investigational oral, potent and selective NOP receptor partial agonist. We determined the brain Kp in whole brain and multiple sub-regions (50mg/kg) and receptor occupancy in the hypothalamus (30, 300mg/kg) via in vivo displacement using [3H]-NOP-1A. EEG/EMG were determined in rats chronically implanted with electrodes (cortex and dorsal neck muscle) and recorded via telemetry following dosing (3, 30, 300mg/kg); sleep stage was determined from visual analysis of EEG level. Sleep parameters were also assessed in NOP receptor knock-out rats (300mg/kg). The side-effect profile for V117957 was determined by functional observation battery, whole-body plethysmography, Morris water maze (MWM) (up to 600mg/kg) and conditioned place preference (CPP) assay (up to 300mg/kg). Results V117957 displayed limited distribution into the CNS but achieved a high level of receptor occupancy (75% at 30mg/kg). Administration of V117957 produced dose-dependent and statistically significant increases in non-REM sleep with a minimally efficacious dose of 30mg/kg; a coincident dose-dependent and statistically significant decrease in wakefulness and a non-dose-dependent effect on REM sleep occurred. These changes were not seen in knock-out animals demonstrating effects are via NOP receptors. At doses higher than those that increased non-REM sleep, V117957 had no effects in a functional observational battery, did not affect escape latency in MWM or produce CPP; additionally, V117957 did not affect respiratory parameters. Conclusion We conclude that activation of NOP receptors decreases wakefulness and increases non-REM sleep in rats with an improved preclinical profile compared to historical profiles of current treatments and, therefore, may represent a novel and attractive target for the treatment of insomnia. Support Funded by Shionogi and Imbrium Therapeutics, a subsidiary of Purdue Pharma L.P.

CHAPERONES AS MOLECULAR TARGET FOR ONCOLOGICAL AND NEUROLOGICAL DISEASES

Brain manganese deposition is led by liver dysfunction and/or portal-systemic shunting in minimal hepatic encephalopathy (MHE). Manganese is toxic and can cause cognitive disorders and extrapyramidal symptoms. Thus, reduction of manganese intake might be considered as a potential treatment strategy for MHE. In this study we aimed to investigate whether low- or no-manganese feed can improve the neuropsychological manifestations in MHE rats. Rats with MHE were established by partially ligating the portal vein and fed a manganese diet (MHE-M, 10 mg per kg feed; n = 24), a no-manganese diet (MHE-N; n = 24) and a half-manganese diet (MHE-H; n = 24) for 2, 4, 6 and 8 weeks, with six rats in each subgroup. Morris water maze (MWM), open-field test and narrow beam test (NBT) were used to evaluate the cognitive and locomotor situations. Fasted blood ammonia, manganese content and glutamine synthetase (GS) activity in basal ganglia and cortex were measured. A significantly longer MWM escape latency, less locomotor activity, longer NBT latency and total time, higher blood ammonia, higher brain manganese content and GS activity were found in MHE-M rats. However, a significantly shorter MWM escape latency, increased locomotor activity, shorter NBT latency and total time, lower blood ammonia, lower brain manganese content and lower GS activity were found in MHE-N rats after no-manganese feed treatment. Partial improvements were found in MHE rats with half-manganese feed treatment. Reduction of manganese intake can significantly improve the cognitive and locomotor situations in MHE rats by reducing brain manganese content and regulating GS activity.

Effect of warming yang and supplementing kidney moxibustion therapy on the NF-κB signaling pathway of vascular dementia rats

ObjectiveTo observe the effect of warming yang and supplementing kidney moxibustion therapy on the behavioristics and the expression levels of hippocampal IL-1β, TNF-α and NF-κB related genes and proteins of vascular dementia (VD) rats, and to explore the mechanism of warming yang and supplementing kidney moxibustion therapy in inhibiting VD inflammatory response. MethodsSeventy-eight SD rats, except 10 rats as sham operation group (group A), were established into VD models by applying the ischemia reperfusion method in bilateral common carotid arteries. 30 models were successful and were randomly divided into model group (group B), moxibustion group (group C) and western medication group (group D), with 10 rats in each group. After modeling, suspended moxibustion was conducted at “Dàzhuī (大椎GV 14)”, “Mìngmén (命门GV 4)” and “Guānyuán (关元CV 4)” of the rats in group C for 15 min/time. The intervention was performed for once a day, and intervention for 4 consecutive weeks was needed. Intragastric administration with nimodipine (2 mg kg−1 d−1) was carried out in the rats in group D for 4 consecutive weeks. Morris water maze test was adopted for behavioral test in the rats in each group. HE staining was conducted in order to observe the pathological changes. RT-qPCR method and Western blot method were used for detecting the expression levels of hippocampal IL-1β, TNF-α and NF-κB related genes and proteins. ResultsAfter modeling, the Morris water maze escape latency of rats in operation groups was obviously longer than that in group A (P < 0.05). According to HE staining results, the arrangement of neurons in group B was incompact, the cell membranes were undefined, the cytoplasm was heterogeneous, karyopyknosis was found, the amount of necrosis increased, and the number of inflammatory cells significantly increased. Compared with group B, the number of inflammatory cells significantly reduced in group C and group D, and the amount of neuron necrosis also reduced. After intervention, compared with group B, the expression levels of TNF-α, p-IκB and NF-κBp65 mRNA in the hippocampal of the rats in group C and group D significantly decreased (all P < 0.05), compared with group B, the expression levels of IL-1β, TNF-α and NF-κBp65 mRNA in the hippocampal of rats in group C and group D also significantly decreased (all P < 0.05). ConclusionWarming yang and supplementing kidney moxibustion therapy may inhibit the NF-κB signaling pathway and reduce the inflammatory response through lowering the expression levels of IL-1β, TNF-α and NF-κB mRNA in the brain, thus achieving the purpose of treating VD.

Effects of "nourishing liver and kidney" acupuncture therapy on expression of brain derived neurotrophic factor and synaptophysin after cerebral ischemia reperfusion in rats.

The aim of the present study was to investigate the effect of "nourishing liver and kidney" acupuncture therapy on motor and cognitive deficits, and the underlying mechanism following cerebral ischemia-reperfusion (I/R) via increasing the expression of brain derived neurotrophic factor (BDNF) and synaptophysin (SYN) in the hippocampus. Healthy adult male SD rats were randomly divided into sham operation group (n=51), model group (n=51), acupuncture group (n=51) and acupuncture control group (n=51). The middle cerebral I/R model was established. Acupunctures were performed in the acupuncture group and acupuncture control group at acupoints of Taixi (K103), Taichong (ST09) of both sides, for 30 min once daily every morning. The animals in the sham operation group and model group were conventionally fed in the cage, without any intervention therapy. The rats of each group were assessed with modified neurological severity scores (mNSS). The expression of BDNF and SYN in the hippocampus was detected by immunohistochemical SP method and the synaptic structure in hippocampus area was assessed morphologically and quantitatively at the 3rd, 7th and 14th day. The Morris water Maze (MWM) test was used to evaluate the rats' learning and memory abilities on the 15th day after acupuncture. The animals in the acupuncture control group and sham operation group presented no neurological deficit. In the acupuncture group, the nerve functional recovery was significantly better than that in the model group at the 7th and 14th day after modeling. The average MWM escape latency in the acupuncture group was shorter than that in the model group at the 3rd, 4th and 5th day. The number of crossings of the platform quadrant in the acupuncture group was significantly more than that in the model group. At the each time point, the expression levels of BDNF and SYN in the hippocampal regions increased significantly in the model group as compared with the sham operation group and the acupuncture control group. In the acupuncture group, the expression levels of BDNF at the 7th and 14th day increased more significantly than those in the model group. In the acupuncture group, the expression levels of SYN at the each time point increased more significantly than those in the model group. The post-synaptic density (PSD) was significantly increased and the synapse cleft width was narrowed in the acupuncture group as compared with other groups. The synaptic curvatures were improved obviously in the acupuncture group in contrast to the model group. It was concluded that the "nourishing liver and kidney" acupuncture therapy has positive effects on behavioral recovery, as well as learning and memory abilities, probably by promoting the expression of BDNF and SYN, and synaptic structure reconstruction in the ipsilateral hippocampus after I/R in rats. The "nourishing liver and kidney" acupuncture therapy can promote the functional recovery in rats after cerebral ischemia injury.

Reduction of manganese intake improves neuropsychological manifestations in rats with minimal hepatic encephalopathy

Brain manganese deposition is led by liver dysfunction and/or portal-systemic shunting in minimal hepatic encephalopathy (MHE). Manganese is toxic and can cause cognitive disorders and extrapyramidal symptoms. Thus, reduction of manganese intake might be considered as a potential treatment strategy for MHE. In this study we aimed to investigate whether low- or no-manganese feed can improve the neuropsychological manifestations in MHE rats. Rats with MHE were established by partially ligating the portal vein and fed a manganese diet (MHE-M, 10mg per kg feed; n=24), a no-manganese diet (MHE-N; n=24) and a half-manganese diet (MHE-H; n=24) for 2, 4, 6 and 8weeks, with six rats in each subgroup. Morris water maze (MWM), open-field test and narrow beam test (NBT) were used to evaluate the cognitive and locomotor situations. Fasted blood ammonia, manganese content and glutamine synthetase (GS) activity in basal ganglia and cortex were measured. A significantly longer MWM escape latency, less locomotor activity, longer NBT latency and total time, higher blood ammonia, higher brain manganese content and GS activity were found in MHE-M rats. However, a significantly shorter MWM escape latency, increased locomotor activity, shorter NBT latency and total time, lower blood ammonia, lower brain manganese content and lower GS activity were found in MHE-N rats after no-manganese feed treatment. Partial improvements were found in MHE rats with half-manganese feed treatment. Reduction of manganese intake can significantly improve the cognitive and locomotor situations in MHE rats by reducing brain manganese content and regulating GS activity.

Rostral Intralaminar Thalamic Deep Brain Stimulation Triggered Cortical and Hippocampal Structural Plasticity and Enhanced Spatial Memory

Background/Aims: Rostral intralaminar thalamic nucleus (ILN) has been shown to modulate cognition through indirect connection with the hippocampus and prefrontal cortex. We explored the effects of deep brain stimulation (DBS) to the rostral ILN on spatial memory acquisition, brain neuronal activation and cortical and hippocampal synaptic changes in rats. Methods: The Morris water maze (MWM) task was used to evaluate the spatial memory of the rats. The expression of c-fos, an immediate early gene, was used to identify neural activation in the cerebral cortex and hippocampus. Synaptic changes in the somatosensory cortical and hippocampal neurons were explored with dendritic spine analysis following Golgi-Cox staining. Results: Our results showed that a barrage of DBS to the rostral ILN of normal rats significantly shortened their escape latency in MWM compared with sham-stimulated and untreated control rats. Rats with enhanced spatial memory had more c-fos immunoreactive cells in layer IV of the somatosensory cortex. Layer III cortical and CA1 hippocampal pyramidal neurons showed over 50% increase of dendritic spines, while only the proximal apical dendrites of layer V cortical pyramidal neurons had more dendritic spines. Conclusions: Rostral ILN-DBS activated neurons in the cerebral cortex and triggered cortical and hippocampal structural plasticity in association with spatial memory enhancement.

Preferential enhancement of working memory in mice lacking adenosine A2A receptors

There is evidence that adenosine acting at A2A receptors (A2AR) can influence striatal plasticity and cognitive functions. We examined spatial working memory in wild-type (WT) and A2A receptor knock-out (KO) mice using two assessments: the eight arm radial maze and a repeated trial Morris water maze (MWM) paradigm. Compared to WT littermates, A2AR KO mice displayed enhanced working memory as evidenced by a decrease in escape latency in trial 2 compared to trial 1 in the repeated trial MWM, and by a reduction in working memory errors in the radial arm maze. Both MWM and radial maze results indicated that this enhancement of working memory in A2AR KO mice was selective for this specific short-term memory. The decrease in escape latency in MWM was detected with an inter-trial interval of 15 s but not with intervals of 10 or 60 min. In the radial maze, spatial reference memory and memory retention after prolonged training (15 days but not 6 days) were not affected by the A2AR KO. These results demonstrate preferential improvement in spatial working memory by genetic inactivation of the A2AR and support a modulatory role of the A2AR in spatial working memory in mice.

Long-term cognitive dysfunction following experimental subarachnoid hemorrhage: New perspectives

Cognitive dysfunction is increasingly recognized as a significant long-term complication following subarachnoid hemorrhage (SAH), affecting up to 60% of survivors. We proposed to determine the incidence and explore potential mechanisms of cognitive dysfunction in a rat model. The effects of intracisternal blood, saline and sham injections were compared. At five weeks, Morris water maze escape latency (P=0.001) and swimming distance (P=0.001) were significantly different between groups, with increased latencies and distances recorded in the blood group in spite of increased swimming speed. The number of morphologically intact cortical (r=−0.75, P=0.0001) and hippocampal CA1 (r=−0.80, P<0.0001) neurons correlated with escape latency. In spite of only slight early reductions in proximal cerebral arterial diameters, pronounced and prolonged reductions in regional cerebral blood flow were observed in SAH rats, suggesting microvascular dysfunction. In concordance, cerebral microangiographic perfusion remained incomplete even after 2 weeks. 8-hydroxydeoxyguanosine immunohistochemistry also revealed microvascular as well as neuronal oxidative DNA damage. These results provide new insights into the pathogenesis of cognitive dysfunction in SAH. They reveal a surprisingly prolonged time course of diffuse cerebrovascular insufficiency, most likely due to reversible microvascular dysfunction. Similar to findings in experimental models of vascular dementia, the data indicate a potentially important role for prolonged cerebrovascular insufficiency, probably due to microvascular dysfunction, and selective cortical and subcortical neuronal loss in cognitive failure following SAH.

Learning-memory deficit with aging in APP transgenic mice of Alzheimer's disease and intervention by using tetrahydroxystilbene glucoside

Objective To investigate learning-memory deficit in different ages of AD-like APP transgenic mice and to observe the protective effects of 2,3,5,4′-tetrahydroxystilbene-2- O-β- d-glucoside (TSG), which is the main component of Polygonum multiflorum, on learning-memory abilities. Methods PDAPPV717I transgenic (Tg) mice were randomly divided into 3 model groups (4, 10 and 16 months old mice) and TSG treated (at doses 120 and 240 μmol/kg/d) groups. TSG was administered to some Tg mice with an age range 4–10 months. In untreated 10 months old Tg mice, the TSG was administrated to those falling in the age range 10–16 months. For the control group we adopted the same age and background C57BL/6J mice. The learning-memory ability was measured by applying Morris water maze (MWM) and object recognition test (ORT). Results In the 4 months old PDAPPV717I Tg mice, the learning-memory deficit was detected. The escape latency in MWM was prolonged, and the discrimination index decreased in ORT. In the 10 months old Tg mice, the learning-memory deficit was aggravated. TSG improved all spatial learning-memory impairment in MWM as well as the object recognition impairment in ORT. In the 16 months old Tg mice, the learning-memory deficit remained to exist but abated a lot. TSG showed significant improvement in learning-memory ability in both MWM and ORT. Conclusion PDAPPV717I transgenic mice with an age range 4–16 months revealed the existence of learning-memory deficit compared with the control group. Tetrahydroxystilbene glucoside not only prevents, i.e. at an early stage, the learning-memory deficit in AD-like model, but also can reverse the learning-memory deficit in the late stage of AD-like model. Thus, TSG could be considered among the future therapeutic drugs indicated for the treatment of AD.