Step-down Inhibitory Avoidance Test Research Articles

Cross state-dependent memory retrieval between tramadol and ethanol: involvement of dorsal hippocampal GABAA receptors.

Tramadol and ethanol, as psychoactive agents, are often abused. Discovering the molecular pathways of drug-induced memory creation may contribute to preventing drug addiction and relapse. The tramadol- and ethanol-induced state-dependent memory (SDM) and cross-SDM retrieval between tramadol and ethanol were examined in this study. Moreover, because of the confirmed involvement of GABAA receptors and GABAergic neurotransmission in memory retrieval impairment, we assessed cross-SDM retrieval between tramadol and ethanol with a specific emphasis on the role of the GABAA receptors. The first hypothesis of this study was the presence of cross-SDM between tramadol and ethanol, and the second hypothesis was related to possible role of GABAA receptors in memory retrieval impairment within the dorsal hippocampus. The cannulae were inserted into the hippocampal CA1 area of NMRI mice, and a step-down inhibitory avoidance test was used to evaluate state dependence and memory recovery. The post-training and/or pre-test administration of tramadol (2.5 and 5 mg/kg, i.p.) and/or ethanol (0.5 and 1 g/kg, i.p.) induced amnesia, which was restored after the administration of the drugs 24 h later during the pre-test period, proposing ethanol and tramadol SDM. The pre-test injection of ethanol (0.25 and 0.5 g/kg, i.p.) with tramadol at an ineffective dose (1.25 mg/kg) enhanced tramadol SDM. Moreover, tramadol injection (1.25 and 2.5 mg/kg) with ethanol at the ineffective dose (0.25 g/kg) promoted ethanol SDM. Furthermore, the pre-test intra-CA1 injection of bicuculline (0.0625, 0.125, and 0.25 μg/mouse), a GABAA receptor antagonist, 5 min before the injection of tramadol (5 mg/kg) or ethanol (1 g/kg) inhibited tramadol- and ethanol-induced SDM dose-dependently. The findings strongly confirmed cross-SDM between tramadol and ethanol and the critical role of dorsal hippocampal GABAA receptors in the cross-SDM between tramadol and ethanol.

Antisense oligonucleotides targeting basal forebrain ATXN2 enhances spatial memory and ameliorates sleep deprivation-induced fear memory impairment in mice.

Regulation of brain-derived neurotrophic factor (BDNF) in the basal forebrain ameliorates sleep deprivation-induced fear memory impairments in rodents. Antisense oligonucleotides (ASOs) targeting ATXN2 was a potential therapy for spinocerebellar ataxia, whose pathogenic mechanism associates with reduced BDNF expression. We tested the hypothesis that ASO7 targeting ATXN2 could affect BDNF levels in mouse basal forebrain and ameliorate sleep deprivation-induced fear memory impairments. Adult male C57BL/6 mice were used to evaluate the effects of ASO7 targeting ATXN2 microinjected into the bilateral basal forebrain (1 μg, 0.5 μL, each side) on spatial memory, fear memory and sleep deprivation-induced fear memory impairments. Spatial memory and fear memory were detected by the Morris water maze and step-down inhibitory avoidance test, respectively. Immunohistochemistry, RT-PCR, and Western blot were used to evaluate the changes of levels of BDNF, ATXN2, and postsynaptic density 95 (PSD95) protein as well as ATXN2 mRNA. The morphological changes in neurons in the hippocampal CA1 region were detected by HE staining and Nissl staining. ASO7 targeting ATXN2 microinjected into the basal forebrain could suppress ATXN2 mRNA and protein expression for more than 1 month and enhance spatial memory but not fear memory in mice. BDNF mRNA and protein expression in basal forebrain and hippocampus was increased by ASO7. Moreover, PSD95 expression and synapse formation were increased in the hippocampus. Furthermore, ASO7 microinjected into the basal forebrain increased BDNF and PSD95 protein expression in the basal forebrain of sleep-deprived mice and counteracted sleep deprivation-induced fear memory impairments. ASOs targeting ATXN2 may provide effective interventions for sleep deprivation-induced cognitive impairments.

Neuroprotective effect of derris indica seed extract attenuates amyloid beta plaques induce Alzheimer’s in mice model

The progression of Alzheimer's disease type dementia is carried on by the neurotoxic effects of amyloid beta (Aβ25-35) peptide accumulation. The hypothalamic-pituitary-adrenal(HPA) axis malfunctions and leads to higher levels of amyloid beta(Aβ) accumulation. In this work, we looked at how Derris indica extract affected mice brains that had undergone neurodegeneration caused by the Aβ. Derris indica seed extract(DISE) were administered to mice over the course of 21 days in two dosages (50 mg/kg and 100 mg/kg). On the 21st day, tests for spatial learning, habituation memory, short-and long-term memory, and stepdown inhibitory responses were carried out. Pro-and anti-inflammatory cytokines and antioxidants were assessed in brain tissues. A significant (p<0.01) improvement in habituation memory and the step-down inhibitory avoidance test was seen after receiving the DISE therapy, reduced escape delay considerably (p<0.01) enhanced cognitive progress in spatial learning. DISE may have an impact on neuroprotection as seen by the significant (p<0.01) decrease in proinflammatory and enhancement in IL-10 along with improved antioxidant indicators. According to investigations, the DISE enhance cognition by controlling neuro-inflammation and neuroimmune function, which are both controlled by the HPA axis, which mitigates stress. DISE might be promising therapeutics for neurodegeneration disorders such as AD.

EFFECT OF HEPTRAL ON THE COGNITIVE FUNCTIONS OF RATS AFTER CHRONIC 153 ALCOHOL INTOXICATION

The aim of this study was assess the effect of the heptral on the cognitive functions of female rats exposed to chronic alcohol intoxication (CAI). CAI was modeled with 6-month replacement of drinking water with a 10% solution of ethyl alcohol with sucrose (50 g/l). The "One-way step-down inhibitory (“passive”) avoidance test", "Extrapolation escape task test", "Novel object recognition test" and "Barnes maze test" were carried out at the age of 16 months. The experimental data obtained indicate that there is impairment in preservation of the memory track in female rats after CAI. Heptral neutralized cognitive impairment in animals exposed to prolonged alcohol abuse.

Methylmercury exposure during prenatal and postnatal neurodevelopment promotes oxidative stress associated with motor and cognitive damages in rats: an environmental-experimental toxicology study

The environmental contamination by methylmercury (MeHg) is a major concern for public health. The effects of MeHg in the central nervous system (CNS) of adult animals have been extensively investigated; however, little is known about the effects of MeHg exposure during intrauterine and lactation periods on motor and cognitive functions of adolescent rats. Therefore, this study aimed to investigate the effect of MeHg exposure during intrauterine life and lactation on both motor and cognitive functions of offspring rats. Ten female Wistar rats were exposed to 40 μg/kg/day of MeHg through cookie treats from the first day of pregnancy until the last day of breastfeeding. Both motor and cognitive functions of offspring male rats were assessed by open field, rotarod, and step-down inhibitory avoidance tests. Forty-one days after birth, the hippocampus and cerebellum were collected to determine total Hg content, antioxidant capacity against peroxyl radicals (ACAP), reduced glutathione (GSH) levels, lipid peroxidation (LPO), and nitrite levels. MeHg exposure during CNS development increased Hg levels in both hippocampal and cerebellar parenchymas, triggered oxidative stress throughout ACAP and GSH decrease, increased LPO and nitrite levels. These alterations resulted in reduced spontaneous and stimulated locomotion and short- and long-term memory deficits. Therefore, damages triggered by MeHg exposure during intrauterine life and lactation had detrimental effects on oxidative biochemistry and motor and cognitive functions of offspring rats.

Inhibition of Piezo1/Ca2+/calpain signaling in the rat basal forebrain reverses sleep deprivation-induced fear memory impairments

In this study, we tested the hypothesis that the Piezo1/Ca2+/calpain pathway of the basal forebrain (BF) modulates impaired fear conditioning caused by sleep deprivation. Adult male Wistar rats were subjected to 6 h of total sleep deprivation using the gentle handling protocol. Step-down inhibitory avoidance tests revealed that sleep deprivation induced substantial short- and long-term fear memory impairment in rats, which was accompanied by increased Piezo1 protein expression (P < 0.01) and increased cleavage of full-length tropomyocin receptor kinase B (TrkB-FL) (P < 0.01) in the BF area. Microinjection of the Piezo1 activator Yoda1 into the BF mimicked these sleep deprivation-induced phenomena; TrkB-FL cleavage was increased (P < 0.01) and short- and long-term fear memory was impaired (both P < 0.01) by Yoda1. Inhibition of Piezo1 by GsMTx4 in the BF area reduced TrkB-FL degradation (P < 0.01) and partially reversed short- and long-term fear memory impairments in sleep-deprived rats (both P < 0.01). Inhibition of calpain activation, downstream of Piezo1 signaling, also improved short- and long-term fear memory impairments (P = 0.038, P = 0.011) and reduced TrkB degradation (P < 0.01) in sleep-deprived rats. Moreover, sleep deprivation induced a lower pain threshold than the rest control, which was partly reversed by microinjection of GsMTx4 or PD151746. Neither sleep deprivation nor the abovementioned drugs affected locomotion and sedation. Taken together, these results indicate that BF Piezo1/Ca2+/calpain signaling plays a role in sleep deprivation-induced TrkB signaling disruption and fear memory impairments in rats.

Hippocampal Impairment Triggered by Long-Term Lead Exposure from Adolescence to Adulthood in Rats: Insights from Molecular to Functional Levels.

Lead (Pb) is an environmental and occupational neurotoxicant after long-term exposure. This study aimed to investigate the effects of systemic Pb exposure in rats from adolescence to adulthood, evaluating molecular, morphologic and functional aspects of hippocampus. For this, male Wistar rats were exposed to 50 mg/kg of Pb acetate or distilled water for 55 days by intragastric gavage. For the evaluation of short-term and long-term memories, object recognition and step-down inhibitory avoidance tests were performed. At the end of the behavioral tests, the animals were euthanized and the hippocampus dissected and processed to the evaluation of: Pb content levels in hippocampal parenchyma; Trolox equivalent antioxidant capacity (TEAC), glutathione (GSH) and malondialdehyde (MDA) levels as parameters of oxidative stress and antioxidant status; global proteomic profile and neuronal degeneration by anti-NeuN immunohistochemistry analysis. Our results show the increase of Pb levels in the hippocampus of adult rats exposed from adolescence, increased MDA and GSH levels, modulation of proteins related to neural structure and physiology and reduced density of neurons, hence a poor cognitive performance on short and long-term memories. Then, the long-term exposure to Pb in this period of life may impair several biologic organizational levels of the hippocampal structure associated with functional damages.

Ganoderma lucidum Ameliorates Neurobehavioral Changes and Oxidative Stress Induced by Ethanol Binge Drinking.

Ganoderma lucidum, mushroom used for centuries by Asian peoples as food supplement, has been shown interesting biological activities, including over the Central Nervous System. Besides, these mushroom bioactive compounds present antioxidant and anti-inflammatory activities. On the side, binge drinking paradigm consists of ethanol exposure that reflects the usual consumption of adolescents, which elicits deleterious effects, determined by high ethanol consumption, in a short period. In this study, we investigated whether the Aqueous Extract of G. lucidum (AEGl) reduces the behavioral disorders induced by alcohol. Male (n = 30) and female Wistar rats (n = 40), seventy-two days old, were used for behavioral/biochemical and oral toxicity test, respectively. Animals were exposed to 5 binges (beginning at 35 days old) of ethanol (3 g/kg/day) or distilled water. Twenty-four hours after the last binge administration, animals received AEGl (100 mg/kg/day) or distilled water for three consecutive days. After treatment protocol, open field, elevated plus maze, forced swim, and step-down inhibitory avoidance tests were performed. Oxidative stress parameters were measured to evaluate the REDOX balance. Our results demonstrated that AEGl elicited the recovery of spontaneous horizontal exploration capacity, anxiogenic- and depressive-profile, as well as short-term memory damage induced by binge-ethanol exposure. The behavioral effects of the extract were associated to the reequilibrium of the animals' REDOX balance. Thus, AEGl, a medicinal mushroom, ameliorates behavioral alteration on a model of motor, cognitive and psychiatric-like disorders induced by binge drinking paradigm and emerges as a useful tool as a food supplement in the management of disorders of alcoholic origin.

Successful Brain Delivery of Andrographolide Loaded in Human Albumin Nanoparticles to TgCRND8 Mice, an Alzheimer's Disease Mouse Model.

Andrographolide (AG) was encapsulated in human albumin nanoparticles (AG NPs), and their crossing properties of the blood-brain barrier (BBB), brain distribution, and effects in TgCRND8 mice were evaluated. The development of appropriate NP formulations is mandatory because of the scarce BBB permeability properties of AG. Developed NPs had proper size (mean size: 159.2 ± 4.5 nm), size distribution (PDI nearby 0.12 ± 0.01), and ζ potential (-24.8 ± 1.2 mV), which were not affected by sodium fluorescein (NAF) loading. When AG was loaded to NPs, it slightly affected their size (210.4 ± 3.2 nm) and ζ potential (-20.3 ± 1.5) but not the PDI. Both NAF and AG had a remarkable encapsulation efficiency (more than 99%). The in vitro release of AG from the NPs reached the highest percentage (48%) after 24 h, and the Higuchi’s equation was found to be the best fitting model (R2 = 0.9635). Both AG and AG NPs did not alter the viability of N2a murine neuroblastoma cells when compared with the untreated control cells. In the step-down inhibitory avoidance test, AG NPs administered to TgCRND8 mice significantly improved their performance (P < 0.0001), reaching levels comparable to those displayed by wild-type mice. In the object recognition test, treated and untreated animals showed no deficiencies in exploratory activity, directional movement toward objects, and locomotor activity. No cognitive impairments (discrimination score) were detected in TgCRND8 mice (P < 0.0001) treated with AG NPs. After acute intravenous administration (200 µl), NPs loaded with the probe NAF were detected in the brain parenchyma of TgCRND8 mice. Immunofluorescent analyses evidenced the presence of NPs both in the pE3-Aβ plaque surroundings and inside the pE3-Aβ plaque, indicative of the ability of these NPs to cross the BBB and to penetrate in both undamaged and damaged brain tissues. Furthermore, the immunohistochemical analysis of GFAP-positive astrocytes in the hippocampus of Tg mice evidenced the anti-inflammatory activity of AG when AG NPs were intraperitoneally administered. AG was not effective in counteracting amyloid Aβ aggregation and the resulting toxicity but significantly decreased the oxidative stress levels. In conclusion, AG NPs have extraordinary versatility, nontoxicity, nonimmunogenicity, strong biocompatibility, high biodegradability, and astonishing loading capacity of drug.

Myricitrin attenuates memory impairment in a rat model of sepsis-associated encephalopathy via the NLRP3/Bax/Bcl pathway.

The present investigation determined the protective effect of myricitrin against sepsis-associated encephalopathy in rats. Sepsis was induced by cecal ligation and puncture (CLP); rats were treated with 30 or 100 mg/kg of myricitrin for 5 days prior to the induction of CLP. The effect of myricitrin was observed by determining the neurological function using the open field test and step-down inhibitory avoidance test. Cerebral oedema and the levels of inflammatory and oxidative stress mediators were determined in brain tissues. Moreover, the expression levels of Bcl-2, Bax, IκB-α, nuclear factor κB (NF-κB), caspase-3 and NLRP3 were estimated in brain tissues by Western blotting and the mRNA expression of NF-κB, caspase-3 and NLRP3 in brain tissues was estimated by real-time polymerase chain reaction. An immunofluorescence assay was performed to estimate inflammasome activity. The results suggest that treatment with myricitrin protects neuronal function in rats with CLP-induced sepsis. Decreases in inflammation and oxidative stress mediators were observed in the brain tissues of the myricitrin-treated group compared to the CLP group. Moreover, treatment with myricitrin ameliorated the altered Bcl-2, Bax, IκB-α, NF-κB, caspase-3 and NLRP3 protein and mRNA expression levels in the brain tissues of septic rats. The data reveal that myricitrin ameliorated neuroinflammation and improved memory in rats with CLP-induced sepsis by regulating the NLRP3/Bax/Bcl signalling pathway.

Hypericum perforatum chronic treatment affects cognitive parameters and brain neurotrophic factor levels

Objective:To evaluate the effects of Hypericum perforatum (hypericum) on cognitive behavior and neurotrophic factor levels in the brain of male and female rats.Methods:Male and female Wistar rats were treated with hypericum or water during 28 days by gavage. The animals were then subjected to the open-field test, novel object recognition and step-down inhibitory avoidance test. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-line derived neurotrophic factor (GDNF) levels were evaluated in the hippocampus and frontal cortex.Results:Hypericum impaired the acquisition of short- and long-term aversive memory in male rats, evaluated in the inhibitory avoidance test. Female rats had no immediate memory acquisition and decreased short-term memory acquisition in the inhibitory avoidance test. Hypericum also decreased the recognition index of male rats in the object recognition test. Female rats did not recognize the new object in either the short-term or the long-term memory tasks. Hypericum decreased BDNF in the hippocampus of male and female rats. Hypericum also decreased NGF in the hippocampus of female rats.Conclusions:The long-term administration of hypericum appears to cause significant cognitive impairment in rats, possibly through a reduction in the levels of neurotrophic factors. This effect was more expressive in females than in males.

Effects of Caffeine on Behavioural and Cognitive Deficits in Rats.

There are many studies that have sought to find drug therapies to prevent harm arising from sepsis. Such studies have represented a progress in the support to septic patients and also in the development of new pharmacological alternatives. Our interest was to investigate the caffeine effect on sepsis behavioural and memory impairments. Male rats were anaesthetized and the surgery was made to allow exposure of the caecum, which was then squeezed to extrude a small amount of faeces from the perforation site, which was later placed back into the peritoneal cavity. This procedure, which served to generate experimental sepsis, is herein referred to as ceccum ligation and perforation (CLP). The caffeine (10mg/kg) was administered by gavage route, once daily, during 7 or 14 consecutive days to investigate the effects of acute or subchronic caffeine treatment on long-term behavioural and cognitive deficits induced by CLP. On the last day, 1hr after caffeine administration, the animals were submitted to open-field, elevated plus maze (EPM), forced swimming and step-down inhibitory avoidance tests. The results showed that caffeine increased the percentage of open arm entries and open arm time in the EPM test, and reduced the immobility time when compared to the sham-operated group. The caffeine also increased the latency in the inhibitory avoidance test platform. Our results demonstrated that the caffeine improved behavioural changes and improved the neurocognitive deficits of sepsis-surviving animals. It is possible that blockage of the adenosine receptors may be responsible for the results here observed.

Current advances of pharmacological properties of 7-chloro-4-(phenylselanyl) quinoline: Prevention of cognitive deficit and anxiety in Alzheimer's disease model.

This study investigated the effect of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) at a dose of 1 mg/kg in memory impairment and anxiety in an Alzheimer's disease (AD) model induced by amyloid β-peptide (Aβ) (fragment 25-35) in mice. The involvement of acetylcholinesterase (AChE) activity and lipid peroxidation in hippocampus and cerebral cortex was evaluated. Male Swiss mice were pretreated with 4-PSQ (1 mg/kg, intragastrically (i.g.), daily) for fourteen days. Thirty minutes after the first treatment with 4-PSQ, the animals received a single injection of Aβ (3 nmol/3 μl/per site, intracerebroventricular (i.c.v.)). Mice were submitted to the behavioral tasks (open-field, elevated plus maze, Barnes maze, object recognition and location, and step-down inhibitory avoidance tests) from the fifth day onwards. On the fifteenth day, blood was removed for analysis of biochemical markers (glucose, triglycerides, urea, aspartate (AST) and alanine (ALT) aminotrasferases), and cerebral cortex and hippocampus for determination of AChE activity and thiobarbituric acid reactive species (TBARS) levels. Aβ caused memory impairment, anxiogenic behavior, increased AChE activity in the cerebral structures and TBARS levels in the cerebral cortex. 4-PSQ was effective to protect against behavioral changes, AChE activity and TBARS levels. In conclusion, 4-PSQ protected against learning and memory impairment and anxiety in a mouse model of AD induced by Aβ, and anticholinesterase and antioxidant actions are involved in the pharmacological effect of the compound.

English

Sepsis has become one of the most frequent causes of mortality in intensive care centres. So far, there is no effective pharmacotherapy that can prevent or improve the neurological consequences and enhance survival. The goal of this study is to investigate the neuroprotective effect of lemon balm (Melissa officinalis) on behavioural dysfunctions produced in sepsis-surviving rats. Adult male rats were subjected to caecal ligation and puncture and the control animals were submitted to the sham operation. Lemon balm ethanolic extract or saline, given orally, was administered for one week after surgery procedures. Locomotion, anxiety, depressive behaviour and memory were investigated. In the elevated plus-maze (EPM), the percentage of open arm entries and open arm time was very significant in the animals treated with lemon balm extract, similar to the diazepam response in sham-operated and sepsis-surviving rats. Locomotion in open field tests and the enclosed arm entries in the EPM were not significantly altered by treatments. In the forced swimming (FS) test, the extract was effective at reducing the immobility time as that demonstrated by fluoxetine. In the step-down inhibitory avoidance test, the extract eased the effects on memory of sepsis-surviving animals. Collectively, these results demonstrate that lemon balm ethanolic extract could be used for the prevention of cognitive and mood-related deficits that may be associated with sepsis sequelae. Key words: Anxiety, depression, locomotion, Melissa officinalis, memory.

Petiveria alliacea exerts mnemonic and learning effects on rats

Ethnopharmacological relevancePetiveria alliacea L. (Phytolaccaceae) is a perennial shrub native to the Amazon region and other tropical areas such as Central America and the Caribbean. Popularly known as mucuracaá, P. alliacea is used in the folk medicine for a broad variety of therapeutic purpose and also in religious ceremonies by slaves as a sedative, which highlights its properties on the Central Nervous System (CNS). Aim of the studyThe present study evaluated the effects of the P. alliacea leaves hydroalcoholic extract (PaLHE) on the cognition, including learning and memory. Material and methodsThree-month-old male and female Wistar rats (n=8–10/group) were administered with 900mg/kg of PaLHE. The behavioral assays included Step-down Inhibitory avoidance (IA) and Morris Water Maze (MWM) tests. ResultsConsistent with our previous reports, P. alliacea improved long-term memory. It also exerted previously unreported effects on short-term and spatial memory improvement, and increased learning in the tasks. ConclusionsThe P. alliacea extract elicited mnemonic effects and improved the learning process in both IA and MWM tests. Our results highlight the importance of further studies in order to identify the active substances of the PaLHE and investigate the pharmacological mechanisms that underlies the reported effects.

Further evidence for an anti-inflammatory role of artesunate in experimental cerebral malaria

BackgroundCerebral malaria (CM) is a clinical syndrome resulting from Plasmodium falciparum infection. A wide range of clinical manifestations follow the disease including cognitive dysfunction, seizures and coma. CM pathogenesis remains incompletely understood and without treatment this condition is invariably fatal. Artesunate has been accepted as the most effective drug for treating severe malaria. Besides its antiparasitic activity, an anti-inflammatory property has also been reported. In the current study, the immunomodulatory role of artesunate was investigated using a Plasmodium berghei ANKA model of CM, trough evaluation of behavioural changes and cytokines expression in hippocampus and in frontal cortex.MethodsC57Bl/6 mice were infected with P. berghei by intraperitoneal route, using a standardized inoculation of 106 parasitized erythrocytes. Memory function was evaluated using the step-down inhibitory avoidance test. The mRNA expression of IFN-γ, IL-1β, IL-6 and TNF in the frontal cortex and hippocampus of control and infected mice on day 5 post-infection were estimated by quantitative real time PCR. Plasmodium berghei -infected mice also received intraperitoneally a single dose of artesunate (32 mg/kg) on day 4 post-infection, and 24 hours after treatment behavioural and immunological analysis were performed. The protein levels of cytokines IL-2, IL-6, IL-10, IL-17, IFN-γ, TNF in the serum, frontal cortex and hippocampus of controls and P. berghei -infected mice treated or not treated with artesunate were determined using a cytometric bead array (CBA) kit. The survival and neurological symptoms of CM were also registered.ResultsCM mice presented a significant impairment of aversive memory compared to controls on day 5 post-infection. A higher mRNA expression of pro-inflammatory cytokines was found in the hippocampus and frontal cortex of infected mice. A single dose of artesunate was also able to decrease the expression of inflammatory cytokines in the hippocampus and frontal cortex of P. berghei-infected mice. In parallel, a significant improvement in neurological symptoms and survival were observed in artesunate treated mice.ConclusionsIn summary, the current study provided further evidence that CM affects key brain areas related to cognition process. In addition, different patterns of cytokine expression during the course of CM could be modulated by a single administration of the anti-malarial artesunate.

Synaptic plasticity alterations associated with memory impairment induced by deletion of CB2 cannabinoid receptors

In this study, the role of CB2r on aversive memory consolidation was further evaluated. Mice lacking CB2r (CB2KO) and their corresponding littermates (WT) were exposed to the step-down inhibitory avoidance test (SDIA). MAP2, NF200 and synaptophysin (SYN)-immunoreactive fibers were studied in the hippocampus (HIP) of both genotypes. The number of synapses, postsynaptic density thickness and the relation between the synaptic length across the synaptic cleft and the distance between the synaptic ends were evaluated in the HIP (dentate gyrus (DG) and CA1 fields) by electron microscopy. Brain-derived neurotrophic factor (BDNF), glucocorticoid receptor (NR3C1) gene expressions and mTOR/p70S6K signaling cascade were evaluated in the HIP and prefrontal cortex (PFC). Finally, the effects of acute administration of CB2r-agonist JWH133 or CB2r-antagonist AM630 on memory consolidation were evaluated in WT mice by using the SDIA.The lack of CB2r impaired aversive memory consolidation, reduced MAP2, NF200 and SYN-immunoreactive fibers and also reduced the number of synapses in DG of CB2KO mice. BDNF and NR3C1 gene expression were reduced in the HIP of CB2KO mice. An increase of p-p70S6K (T389 and S424) and p-AKT protein expression was observed in the HIP and PFC of CB2KO mice. Interestingly, administration of AM630 impaired aversive memory consolidation, whereas JWH133 enhanced it. Further functional and molecular assessments would have been helpful to further support our conclusions.These results revealed that CB2r are involved in memory consolidation, suggesting that this receptor could be a promising target for developing novel treatments for different cognitive impairment-related disorders.

Environmental stimulation influence the cognition of developing mice by inducing changes in oxidative and apoptosis status

Environment condition has been shown to play an important role in brain development. The present study examined the effects of enriched and impoverished environment on both spatial and emotional learning and memory of young mice and explored the underlying mechanisms. 3-week-old mice were housed in enriched environment (n=10, 10 mice in a large cage with toys and a running wheel), or standard environment (n=10, 10 mice in a large cage without objects), or impoverished environment (n=10, single mice in a small cage without objects) for 6weeks. Then, the spatial and emotional cognition of mice were evaluated by the water maze and step-down inhibitory avoidance test, respectively. To explore the underlying mechanisms, oxidation measurement in hippocampus and medial-temporal lobe cortex (MTLC) and apoptosis examination in hippocampus were performed. Results showed that compared with standard environment group, enriched and impoverished mice exhibited high and low performance levels in behavior tests, respectively. The oxidative status of hippocampus and MTLC were decreased in enriched group but increased in impoverished group. Moreover, changes in apoptosis of hippocampus in these two groups showed the same tendency with oxidative status. These results suggest that environment condition can simultaneously influence spatial and emotional learning and memory, which may result from inducing changes in the oxidative and apoptosis status in associated brain regions. Here, we firstly report using young mice to examine the oxidative status as a primary and direct factor to explore the mechanism of effects of different environment on both spatial and emotional cognition.

NMDA preconditioning prevents object recognition memory impairment and increases brain viability in mice exposed to traumatic brain injury

Recent studies have focused on the role of N-methyl-d-aspartate (NMDA) in brain injury. The present study is aimed at verifying memory, anxiety/depression parameters, and cellular viability in the brain of mice preconditioned with NMDA and subjected to the model of mild traumatic brain injury. For this purpose, male albino CF-1 mice were pre-treated with NMDA (75mg/kg) and subjected to brain trauma, and after 24h submitted to memory tasks and anxiety and depression-like behavioral tests. The memory tests were evaluated at 1.5h, 24h, and 7days after the training. In addition, the cellular viability was evaluated in the cerebral cortex and hippocampus 96h after the trauma. It was observed that the cellular viability was reduced in the hippocampus of the mice subjected to trauma and the preconditioning with NMDA was able to protect this damage. All mice learnt the task in the habituation test, but in the object recognition task the mice preconditioned with NMDA were protected against impairment induced by TBI in both short and long-term memory. On the other hand, in the step-down inhibitory avoidance test, only the mice treated with NMDA showed impairment of long-term memory (7days after training session). The evaluation of anxiety/depression behavior showed no changes after TBI. In conclusion, NMDA preconditioning induced impairment of the long-term memory; however, it was able to protect against the novel recognition memory impairment and increase the cellular survival in the hippocampus of mice exposed to traumatic brain injury.

Selective down-regulation of α4β2 neuronal nicotinic acetylcholine receptors in the brain of uremic rats with cognitive impairment

Cognitive impairment is common in patients with chronic kidney disease. Brain nicotinic acetylcholine receptors modulate cognitive functions, such as learning and memory. Pharmacological cholinergic enhancement is useful in patients with cognitive dysfunction. The major nicotinic acetylcholine receptor subtypes in the brain are heteromeric α4β2 and homomeric α7 receptors. To study the involvement of neuronal acetylcholine receptors in cognitive impairment in uremic rats, bilateral nephrectomy was performed. 24weeks after nephrectomy, memory was assessed using the one trial step-down inhibitory avoidance test. Neuronal nicotinic acetylcholine receptors in the brain were studied by radioligand binding, immunoprecipitation, Western blot and sucrose gradient experiments. We demonstrated that rats with severe renal failure show disorders of short term memory. Long term memory was not altered in these rats. The number of functional α4β2 heteromeric neuronal nicotinic receptors was decreased in the brains of rats with severe renal failure. There was a significant correlation between the degree of renal impairment and the number of heteromeric nicotinic acetylcholine receptors in the brain. The down-regulation of functional α4β2 receptors in the brains of rats with severe renal failure was not due to a reduction of α4 or β2 subunit proteins. The number of α7 homomeric neuronal nicotinic acetylcholine receptors was not altered. These findings may have important clinical significance for the management of cognitive impairment in patients with chronic kidney disease.