P7C3 Attenuates the Scopolamine-Induced Memory Impairments in C57BL/6J Mice

Memory impairment is the most common symptom in patients with Alzheimer’s disease. The purpose of this study is to evaluate the memory enhancing effects of P7C3, a recently identified compound with robust proneurogenic and neuroprotective effects, on the cognitive impairment induced by scopolamine, a muscarinic acetylcholine receptor antagonist. Different behavior tests including the Y-maze, Morris water maze, and passive avoidance tests were performed to measure cognitive functions. Scopolamine significantly decreased the spontaneous alternation and step-through latency of C57BL/6J mice in Y-maze test and passive avoidance test, whereas increased the time of mice spent to find the hidden platform in Morris water maze test. Importantly, intraperitoneal administration of P7C3 effectively reversed those Scopolamine-induced cognitive impairments in C57BL/6J mice. Furthermore, P7C3 treatment significantly enhanced the level of brain-derived neurotrophic factor (BDNF) signaling pathway in the cortex and hippocampus, and the usage of selective BDNF signaling inhibitor fully blocked the anti-amnesic effects of P7C3. Therefore, these findings suggest that P7C3 could improve the scopolamine-induced learning and memory impairment possibly through activation of BDNF signaling pathway, thereby exhibiting a cognition-enhancing potential.     

Strain differences in activity and emotionality do not account for differences in learning and memory performance between C57BL/6 and DBA/2 mice

This study examined emotionality, activity, learning and memory, as well as the influence of emotionality and activity on learning and memory performance in C57BL/6 and DBA/2 mice using a mouse-test battery. DBA/2 mice performed more poorly than C57BL/6 mice in complex learning tasks such as the water maze and object recognition tasks. In contrast, C57BL/6 mice showed attenuated habituation to novelty in the open field apparatus and poorer performance in the step-down passive avoidance task. The C57BL/6 mice were less exploratory and more anxious than the DBA/2 mice. The anxiety score (open arm entries in the elevated plus maze) was significantly correlated with all measures of learning and memory in the object recognition task, and some measures in the passive avoidance and water maze tasks. Analysis of covariance (with open arm entries as a covariate) revealed that some measures on trial 1 of the object recognition task, but not the memory scores on trial 2, were confounded by anxiety. No confounding factors of anxiety were found in the water maze or passive avoidance tasks. Similar results were obtained with the activity scores (line crossing and rearing in the open field). In conclusion, strain differences in activity and anxiety did not account for strain differences in learning and memory performance of C57BL/6 and DBA/2 mice. Nonetheless, the importance of using complete behavioural test batteries should be stressed to ensure that strain differences in learning and memory tasks are not confounded by non-cognitive factors.     

Dose dependent effects of oxytocin on cognitive defects and anxiety disorders in adult rats following acute infantile maternal deprivation stress

ABSTRACT

Maternal deprivation at an early age is a powerful stressor that causes permanent alterations in cognitive and behavioral functions during the later stages of life. We investigated the effects of oxytocin on cognitive defects and anxiety disorders caused by acute infantile maternal deprivation in adult rats. We used 18-day-old Wistar albino rats of both sexes. The experimental groups included control (C), maternally deprived (MD), maternally deprived and treated with 0.02 μg/kg oxytocin (MD-0.02 µg/kg oxy), maternally deprived and treated with 2 μg/kg oxytocin (MD-2 µg/kg oxy). When the rats were 60 days old, the open field (OF) and elevated plus maze (EPM) behavioral tests, and the Morris water maze (MWM) test for spatial learning and memory were performed. In addition, the number of neurons in the hippocampus, prefrontal cortex (PFC) and amygdala were determined using quantitative histology. We also measured vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) levels in the PFC. In both sexes, the MD group failed the learning test and the MD-2 μg/kg oxy group failed in the memory test. The MD-0.02 μg/kg oxy group spent more time in the open arm of the EPM device and their locomotor activities were greater in the OF test. The VEGF and BDNF levels in the PFC were higher in the MD-0.02 μg/kg oxy groups than the other maternally deprived groups (oxytocin ±). The number of PFC neurons was low in all male maternally deprived (oxytocin ±) groups, while the number of amygdala neurons was low in both female and male maternally deprived (oxytocin ±) groups. Male rats were more affected by maternal deprivation; administration of oxytocin had dose-dependent biphasic effects on learning, memory and anxiety.     

Effect of a herbal psychotropic preparation, BR-16A (Mentat), on performance of mice on elevated plus-maze.

Effect of BR-16A on various parameters of anxiety and transfer latency (TL) was studied in mice using elevated plus-maze. BR-16A (50-500 mg/kg) reduced the percentage of time spent in open arms and the percent preference of open arms for the first arm entry following acute as well as chronic drug administration. The total number of arm entries and the percentage of open arm entries remained unaffected. In combination with FG 7142 (10 mg/kg), BR-16A (100-500 mg/kg) further reduced the exploration of open arms. BR-16A reversed scopolamine (0.3 mg/kg)-induced delay in TL on 1st day. The reversal effect of BR-16A was enhanced by aniracetam (50 mg/kg). The data suggest anxiogenic and nootropic actions of BR-16A.     

二氢杨梅素改善慢性社会挫败应激小鼠认知与情感障碍*

目的:探索二氢杨梅素(DHM)对慢性社会挫败应激小鼠认知与情感障碍的作用及其可能机制。方法:将C57BL/6J小鼠随机分成对照组(Control)、慢性社会挫败应激组(CSDS)和慢性社会挫败应激+DHM组(CSDS+DHM),每组14只,每天将两个应激组小鼠放入ICR攻击鼠的饲养笼中10 min,之后取出放于ICR攻击鼠饲养笼的旁边笼中,连续应激10 d,在应激5 d后,每天按10 ml/kg的量分别腹腔注射一次2%的DMSO或20 mg/kg的DHM(分散于2% DMSO中),连续注射5 d,之后每组取10只小鼠进行新颖物体识别测试、Y迷宫测试、社会交互和旷场测试、行为学测试,剩余4只小鼠于实验结束后24 h内断头取脑,采用Western blot法检测海马组织SIRT1水平。结果:与Control组比较,CSDS组小鼠的学习记忆显著降低,焦虑水平显著升高,在悬尾测试(TST)和强迫游泳测试(FST)中的不动时间显著升高,海马SIRT1蛋白水平显著降低(P均＜0.05或P＜0.01);与CSDS组比较,CSDS+DHM组小鼠学习记忆显著提高,小鼠焦虑水平显著降低,在TST和FST中不动时间显著降低,海马SIRT1蛋白水平显著升高(P均＜0.05或P＜0.01)。结论:DHM可改善CSDS诱导小鼠的认知障碍、焦虑样行为和抑郁样行为,并提高海马SIRT1蛋白的表达水平。     

Chronic administration of parecoxib exerts anxiolytic-like and memory enhancing effects and modulates synaptophysin expression in mice

Background

Previous studies have shown that cyclooxygenase-2, a key enzyme that converts arachidonic acid to prostaglandins, is involved in anxiety and cognitive processes, but few studies have investigated the effects of chronic administration of cyclooxygenase-2 inhibitors on anxiety, learning and memory under normal physiological conditions. The aim of the study was to investigate the effects of chronic administration of parecoxib, a cyclooxygenase-2 inhibitor, on anxiety behavior and memory performance under normal physiological conditions and to explore the possible neural mechanism underlying parecoxib-mediated effects.

Methods

Adult male ICR mice were randomly divided into four groups: the control group and three parecoxib groups. Mice received normal saline or parecoxib (2.5, 5.0 or 10 mg/kg) intraperitoneal injection once a day for 21 days, respectively. Elevated plus-maze, novel object recognition and Y maze tests were conducted on day 23, 24 and 26, respectively. Four additional groups that received same drug treatment were used to measure synaptophysin protein levels by western blot and prostaglandin E2 (PGE2) levels by ELISA in the amygdala and hippocampus on day 26.

Results

Chronic parecoxib exerted an anxiolytic-like effect in the plus-maze test test, and enhanced memory performance in the novel object recognition and Y maze tests. Western blot analysis showed that chronic parecoxib down-regulated synaptophysin levels in the amygdala and up-regulated synaptophysin levels in the hippocampus. ELISA assay showed that chronic parecoxib inhibited PGE2 in the hippocampus but not amygdala.

Conclusions

Chronic parecoxib exerts anxiolytic-like and memory enhancing effects, which might be mediated through differential modulation of synaptophysin and PGE2 in the amygdala and hippocampus.

     

Differences in anxiety-related behavior between apolipoprotein E-deficient C57BL/6 and wild type C57BL/6 mice

The influence of ApoE gene deletion on the anxiety state has not been previously investigated. The elevated plus maze was used in this study to determine differences in anxiety-related behavior between apoE-deficient and wild type C57BL/6 mice. The apoE-deficient mice demonstrated less anxiety on the elevated plus maze by spending more time in the open arms of the elevated plus maze compared to wild type mice (p<0.001). Additionally, female apoE-deficient mice visited the open arm of the maze more often than their apoE-deficient male counterpart (p<0.05). The anxiety state and/or sex are possible variables to be considered when designing physiological and/or behavioral studies involving mice that are apoE-deficient.     

Behavior of mice from different strains: modifications produced by noopept

Genotype-dependent behavioral effects were demonstrated in BALB/c, C57BL/6J [Russian character: see text] DBA/2J mice after injections of nootropic drug Noopept. In an elevated plus maze, drug administration induced an increase in the number of enterings into bright arms in BALB/c mice, whereas the opposite effect was observed in C57BL/6J. After the Noopept administration, animals from all the three strains increased the number of active avoidance reactions in stress-inducing slip-funnel test. A significant intensification of exploration behavior was observed in a closed plus-maze in BALB/c and C57BL/6J. The Noopept affected weakly or had no effect on the behavior of DBA/2J mice.     

Progesterone protects normative anxiety-like responding among ovariectomized female mice that conditionally express the HIV-1 regulatory protein,Tat, in the CNS

Increased anxiety is co-morbid with human immunodeficiency virus (HIV) infection. Actions of the neurotoxic HIV-1 regulatory protein, Tat, may contribute to affective dysfunction. We hypothesized that Tat expression would increase anxiety-like behavior of female GT-tg bigenic mice that express HIV-1 Tat protein in the brain in a doxycycline-dependent manner. Furthermore, given reports that HIV-induced anxiety may occur at lower rates among women, and that the neurotoxic effects of Tat are ameliorated by sex steroids in vitro, we hypothesized that 17β-estradiol and/or progesterone would ameliorate Tat-induced anxiety-like effects. Among naturally-cycling proestrous and diestrous mice, Tat-induction via 7 days of doxycycline treatment significantly increased anxiety-like responding in an open field, elevated plus maze and a marble-burying task, compared to treatment with saline. Proestrous mice demonstrated less anxiety-like behavior than diestrous mice in the open field and elevated plus maze, but these effects did not significantly interact with Tat-induction. Among ovariectomized mice, doxycycline-induced Tat protein significantly increased anxiety-like behavior in an elevated plus maze and a marble burying task compared to saline-treated mice, but not an open field (where anxiety-like responding was already maximal). Co-administration of progesterone (4 mg/kg), but not 17β-estradiol (0.09 mg/kg), with doxycycline significantly ameliorated anxiety-like responding in the elevated plus maze and marble burying tasks. When administered together, 17β-estradiol partially antagonized the protective effects of progesterone on Tat-induced anxiety-like behavior. These findings support evidence of steroid-protection over HIV-1 proteins, and extend them by demonstrating the protective capacity of progesterone on Tat-induced anxiety-like behavior of ovariectomized female mice.     

Genotype-dependent mice behavior in cognitive tasks. Effect of noopept

The interstrain differences in performance of C57BL/6J, BALB/c and DBA/2J male mice in two cognitive tasks were found. Mice C57BL/6J showed good learning ability and preservation of memory traces tested 10 days after performance in a simplified version of Morris water maze. Mice BALB/c learned the task but, virtually, no long-term memory traces were revealed, whereas DBA/2J demonstrated poor learning. The effect of nootropic drug Noopept (GVS-111, N-phenil-acetyl-L-prolylglycin ethyl ether) was shown to be genotype-dependent. Its administration (0.5 mg/kg i.p., 15 min before learning) improved the long-term memory in Morris test in BALB/c mice but failed to produce any improvement in C57BL/6J. The ability of mice for extrapolation of the direction of stimulus movement differently changed after Noopept injections: the proportion of correct task solutions increased in C57BL/6J and BALB/c mice, whereas the performance of DBA/2J did not change.     

Anxiety and fear behaviors in adult male and female C57BL/6 mice are modulated by maternal separation

This study investigated the effects of maternal separation in C57BL/6 male and female mice during infancy on later adult fear and anxiety behaviors. Additionally, we observed the maternal behavior of the dams to examine aspects of maternal care that may be modulated by daily bouts of separation. In males, mice that experienced maternal separation during the neonatal period displayed significantly higher levels of anxiety and fear behavior, as measured by the open field test and elevated plus maze, compared to control, standard facility reared males. In females, however, maternal separation reduced anxiety and fear behavior in the open field test, but only when the females were in the diestrous phase of their estrous cycle. The 30-min daily observation of the dams revealed that the separation did not significantly alter the frequency of the maternal care provided by the dam at the time point measured. These results indicate that the emotionality of adult male and female mice can be modulated by maternal separation. However, this effect is dependent on the sex of the offspring and the phase of the estrous cycle of the female.     

Effects of acute and chronic administration of exorphin C on behavior and learning in white rat pups

We studied the behavior of 21- and 35-day-old white rat pups in the “open field” and the learning of 36- to 41-day-old pups in a maze with food reinforcement. An opioid fragment of wheat gluten exorphin C (YPISL) was injected to pups chronically from day 1 to day 14 of their life or immediately prior to testing. We found that an acute peptide injection did not change animal behavior. The chronic intraperitoneal administration of the peptide at the same dose of 5 mg/kg significantly increased exploratory activity, decreased anxiety, and improved learning. Delayed exorphin C effects were more expressed in female rats.     

小鼠动物实验方法系列专题(五) 应用高架十字迷宫分析小鼠焦虑行为

高架十字迷宫(the elevated plus maze,EPM)是研究小鼠焦虑行为的重要实验,本文介绍了EPM的原理和实验步骤。将小鼠置于开臂闭臂接合处,面向开臂,通过录像记录分析小鼠在EPM的表现。结果发现,两种小鼠均可成功完成实验,C57小鼠在EPM内较不活跃,闭臂滞留时间占总时间百分比显著高于129Sv小鼠。应用EPM可以简单直观地分析小鼠焦虑行为。     

Static magnetic field exposure affects behavior and learning in rats

The present work investigated the behavioral effects of a moderate exposure (1 h per day for 5 consecutive days) to a static magnetic field (SMF, 128 mT) in male rats. SMF effects were evaluated in two sets of control and SMF-exposed rats. One set of animals was used for evaluation of SMF potential effects on emotional behaviors in the elevated plus maze and in the open field. The other set of animals was tested for learning and memory abilities in different procedures of the Morris water maze task. We found no significant difference between control and SMF-exposed rats in anxiety tests. However, the ratio of open arms time in the plus maze was reduced by half in SMF-exposed rats. In the Morris water maze, SMF-exposed rats were partially impaired during the initial learning task as well as in the retention task at one week. We conclude that static magnetic field exposure altered emotional behaviors in the plus maze and led to cognitive impairments, or at least to substantial attention disorders, in the Morris water maze.     

α-Tocopherol suppresses lipid peroxidation and behavioral and cognitive impairments in the Ts65Dn mouse model of Down syndrome

It is widely accepted that oxidative stress is involved in the pathogenesis of Down syndrome, but the effectiveness of antioxidant treatment remains inconclusive. We tested whether chronic administration of α-tocopherol ameliorates the cognitive deficits exhibited by Ts65Dn mice, a mouse model of Down syndrome. α-Tocopherol was administered to pregnant Ts65Dn females, from the day of conception throughout the pregnancy, and to pups over their entire lifetime, from birth to the end of the behavioral testing period. Cognitive deficits were confirmed for Ts65Dn mice fed a control diet, revealing reduced anxiety or regardlessness in the elevated-plus maze task test and spatial learning deficits in the Morris water maze test. However, supplementation with α-tocopherol attenuated both cognitive impairments. In addition, we found that levels of 8-iso-prostaglandin F(2α) in brain tissue and hydroxyoctadecadienoic acid and 7-hydroxycholesterol in the plasma of Ts65Dn mice were higher than those of control mice. Supplementation with α-tocopherol decreased levels of lipid peroxidation products in Ts65Dn mice. Furthermore, we found out that α-tocopherol improved hypocellularity in the hippocampal dentate gyrus of Ts65Dn mice. These results imply that α-tocopherol supplementation from an early stage may be an effective treatment for the cognitive deficits associated with Down syndrome.     

Omega-3 fatty acids and rodent behavior

This paper reviews the role of the n-3 fatty acids in the regulation of cognitive functions, locomotor and exploratory activity and emotional status in rodents. There are disparate data on the performance of n-3 fatty acid deficient animals in the open field test and elevated plus maze. Results obtained in our laboratory indicated slower habituation to the open field in deficient mice, which affects total locomotor and exploratory parameters. We also observed no change in plus maze performance of deficient mice under low-stress but elevated anxiety under high-stress conditions. There is some evidence of elevated aggression and increased immobility time in the forced swimming test caused by n-3 fatty acid deficiency in rodents. Effects of n-3 fatty acid deficiency and supplementation on learning in several tests such as the Morris water maze, two odor olfactory discriminations, radial arm maze performance and avoidance tasks are reviewed in detail. There is some evidence of an enhanced vulnerability to stress of n-3 fatty acid deficient animals and this factor can influence performance in a variety of tests. Thus, behavioral tasks that involve a higher level of stress may better differentiate behavioral effects related to brain docosahexaenoic acid (DHA) status. It is suggested that a fruitful area for future investigations of functional alterations related to brain DHA status will be the delineation of the factors underlying changes in performance in behavioral tasks. The possible role of non-cognitive factors like emotionality and attention in the impaired performance of n-3 fatty acid deficient animals also requires further investigation.     

Obestatin improves memory performance and causes anxiolytic effects in rats

Obestatin is a peptide hormone that is derived from the same polypeptide precursor (preprogrelin) as ghrelin, but it acts in opposing way on ingestive behavior. Our previous studies showed that ghrelin affects memory and anxiety. Here, we studied the possible effects of icv obestatin injection in rats upon memory retention (using two different paradigms), anxiety like behavior (plus maze test), and food intake. Obestatin induces an increase in the percentage of open arms entries (Obestatin 3.0nmol/rat: 61.74+/-1.81), and percentage of time spent in open arms (Obestatin 3.0nmol/rat: 72.07+/-4.21) in relation to the control (33.31+/-1.54; 25.82+/-1.68), indicating an anxiolytic effect. The two doses of obestatin increased latency time in a step down test and the percentage time of novel object exploration, suggesting that the peptide influences learning and memory processes that involve the hippocampus and the amygdala. This report provides evidence indicating that obestatin effects are functionally opposite on anxiety and hunger to the ghrelin effects, while both these related peptides increase memory retention.     

Abnormal vibrissa‐related behavior and loss of barrel field inhibitory neurons in 5xFAD transgenics

A recent study reported lower anxiety in the 5xFAD transgenic mouse model of Alzheimer's disease, as measured by reduced time on the open arms of an elevated plus maze. This is important because all behaviors in experimental animals must be interpreted in light of basal anxiety and response to novel environments. We conducted a comprehensive anxiety battery in the 5xFAD transgenics and replicated the plus‐maze phenotype. However, we found that it did not reflect reduced anxiety, but rather abnormal avoidance of the closed arms on the part of transgenics and within‐session habituation to the closed arms on the part of wild‐type controls. We noticed that the 5xFAD transgenics did not engage in the whisker‐barbering behavior typical of mice of this background strain. This is suggestive of abnormal social behavior, and we suspected it might be related to their avoidance of the closed arms on the plus maze. Indeed, transgenic mice exhibited excessive home‐cage social behavior and impaired social recognition, and did not permit barbering by wild‐type mice when pair‐housed. When their whiskers were snipped the 5xFAD transgenics no longer avoided the closed arms on the plus maze. Examination of parvalbumin (PV) staining showed a 28.9% reduction in PV+ inhibitory interneurons in the barrel fields of 5xFAD mice, and loss of PV+ fibers in layers IV and V. This loss of vibrissal inhibition suggests a putatively aversive overstimulation that may be responsible for the transgenics' avoidance of the closed arms in the plus maze .