Number Of Reference Memory Errors Research Articles

Testosterone Influence on Microtubule-Associated Proteins and Spine Density in Hippocampus: Implications on Learning and Memory

The thorny protrusions or spines increase the neuronal surface area, facilitate synaptic interconnections among neurons, and play an essential role in the hippocampus. Increasing evidence suggests that testosterone, the gonadal hormone, plays an important role in neurogenesis and synaptic plasticity. The role of testosterone on microtubule-associated proteins on dendritic neurite stability in the hippocampus and its impact on learning disability is not elucidated. Adult male Wistar albino rats were randomly selected for the control, castrated, castrated + testosterone, and control + testosterone groups. Bilateral orchidectomy was done, and the testosterone propionate was administered during the entire trial period, i.e., 14 days. The learning assessments were done using working/reference memory versions of the 8-arm radial maze and hippocampal tissues processed for histological and protein expressions. There were reduced expressions of microtubule-associated protein 2 (MAP2), postsynaptic density protein 95 (PSD95), and androgen receptor (AR) and increased expression of pTau in the castrated group. Conversely, the expression of MAP2, PSD95, and AR was increased, and the pTau expression was reduced in the hippocampus of the castrated rat administrated with testosterone. Androgen-depleted rats showed impaired synaptic plasticity in the hippocampus associated with contracted microtubule dynamics. Along with learning disability, there was an increased number of reference memory errors and working memory errors in castrated rats. Observations suggest that androgen regulates expression of neural tissue-specific MAPs and plays a vital role in hippocampus synaptic plasticity and that a similar mechanism may underlie neurological disorders in aging and hypogonadal men.

S52. SPATIAL MEMORY DEFICITS IN SCHIZOPHRENIA: NEUROLOGICAL SOFT SIGNS DIFFERENTIALLY INFLUENCE PERFORMANCES IN 3-D VIRTUAL VERSUS TACTILE RECOGNITION TASKS

BackgroundCognitive impairment is a core meta-dimension in schizophrenia. Cognitive function interfaces with brain neural substrate and some of the observed neurocognitive deficits in the disease parallels with various brain structural and functional abnormalities found in schizophrenia, in particular neural dysconnectivity. The motor dysfunctions in schizophrenia such as evidenced by neurological soft signs (NSS) are also viewed as the consequence of this neural deregulation. NSS are seen both state- and trait-related features of schizophrenia and thus critical to identify schizophrenia subtypes. Although association between NSS and cognitive performance is well recognized in schizophrenia, the links between these subtle neurological sensory integration/motor deficits and cognitive abilities to represent space (spatial memory) has not been studied yet.Here, we tested the spatial memory performances of schizophrenia patients using both tactile and 3D-virtual tests and examine whether the presence of NSS influenced the used strategies to perform a recognition task and examine spatial representation by dissociating spatial reference frameworksWe presumed that spatial memory will be differently affected in schizophrenia patients depending on the type of cues (local vs distal and tactile vs visual), as a function of the presence or not of NSS.MethodsA total of 20 antipsychotic-treated, clinically stable, schizophrenia patients (SCZ) and 20 healthy matched controls (HC) gave their informed consent to participate in the study. We examined the strategies used by the participants in a protocol using two types of identical radial mazes (3-D virtual and perceptual). The same sequence of tasks was used for both mazes and included: exploration, acquisition, and conflict trials. Participants were proposed to freely explore the maze in order to identify their reinforced arm during the exploration trial. No specific advices were given regarding the use of local/distal or visual/tactile cues during the trials. Psychopathology and cognitive performances were assessed using PANSS, WCST, Digit Symbol Substitution test (DSST); medical and medication history was also evaluated. NSS were assessed using the NSS scale developed in French by Krebs et al. The number of reference memory errors (RME) made during the maze tasks was the main study variableResultsNSS- and NSS+ patients did not differ in terms of PANSS score or antipsychotic medication. Typicals (haloperidol, loxapine, fluphenazine) and atypicals (risperidone, olanzapine and aripiprazole) were equally distributed within the 2 groups.Among patients 13 had criteria for NSS (NSS+) and 7 did not meet criteria for NSS (NSS-). None of the HC exhibited NSS. NSS+ patients had more cognitive impairment than NSS- in the WCST.While HC exhibited acquisition abilities for both spatial maze tasks, NSS+ patients were unable to learn any of them. NSS- patients, failed to learn during the virtual task but behave like control subjects in the tactile task. Data from rotation and permutation tasks in both virtual and tactile mazes could show that NSS+ and NSS- relied on different strategies and cues to try to solve the task. While NSS+ patients were totally unable to succeed the various tasks in the virtual and the tactile maze, NSS- individuals approached the HC performance in the tactile maze by using compensatory strategies but not in the virtual maze.DiscussionSpatial memory is differently affected in schizophrenia patients as a function NSS. Spatial strategies differs in HC, NSS-, and NSS+ as a function of the type of cues (local vs distal) and the type of maze (virtual versus tactile) indicating that not only performance should be taken into account during the appraisal of spatial memory in schizophrenia

Aqueous Root Bark Extract of Daniellia oliveri (Hutch. & Dalz.) (Fabaceae) Protects Neurons against Diazepam‐Induced Amnesia in Mice

Daniellia oliveri (DO) is a traditional medicinal plant used for the treatment of diseases such as inflammation, schizophrenia, and epilepsy in Nigeria, Kenya, Congo, and Cameroon. This study was carried out to evaluate the potential neuroprotection effect of the aqueous root bark extract of Daniellia oliveri against diazepam-induced amnesia in mice. Thirty-six adult male mice were distributed into six groups: the three test groups received Daniellia oliveri root bark extract (100, 200, and 300 mg/kg), the normal control group received distilled water (10 ml/kg), a positive control group received piracetam (150 mg/kg), and the negative control received diazepam (2.5 mg/kg). Learning and memory were evaluated using the radial arm maze and the T-maze. Biomarkers of oxidative stress were also quantified in mice brains. Statistical analyses were performed using two-way ANOVA followed by Tukey's post hoc test. Daniellia oliveri root bark aqueous extract decreased the number of working memory errors and number of reference memory errors in amnesic mice evaluated in the radial arm maze. Also, an increase in glutathione activity and a decrease in malondialdehyde levels were noted in the hippocampi homogenate of the extract-treated mice as compared to the diazepam-demented but untreated group. Moreover, pretreatment with Daniellia oliveri aqueous root bark extract reversed the decrease in hippocampal cell density observed in the nontreated diazepam group. Taken together, these results suggest that the aqueous extract of DO leaves possesses antioxidant potential and might provide an opportunity for the management of neurological abnormalities in amnesic conditions.

Complex Neurobehavioral Testing of a Rat Model of the Irritable Bowel Syndrome

In albino Wistar rats, the irritable bowel syndrome (IBS) was induced by chronic restraint stress (restriction of the animals in plastic containers, 6 h per day during 7 days). In the Y-like maze, IBS rats demonstrated smaller numbers of spontaneous alternations (indices of immediate spatial memory; P < 0.05) than control animals. In the elevated plus maze, IBS rats showed a significantly reduced time spent in the open arms (P < 0.03) compared to the controls, suggesting anxiety-like effects. Moreover, episodes of stretching in this maze were more numerous in the IBS group (P < 0.05), also suggesting anxiogenic effects. Some depression-like behavior of IBS rats was observed in the forced swimming test, as was demonstrated by a significantly shorter mobility time, as compared to the control group (P < 0.05). In the radial 8-arm maze, however, chronic stress-induced IBS did not significantly affect the number of reference memory errors and time necessary for completing the task. Still, some working memory deficit was observed in the IBS group in this test, as the number of the respective errors was significantly greater (P < 0.05) in such rats vs. controls within some time intervals. In the open field test, suppression of locomotor activity (reduced number of square crossings), significantly increased number of rearings (suggesting higher anxiety), and altered fecal elimination in the IBS group were obvious (P < 0.05). Also, an increased time of grooming was observed in IBS rats in the above test (characterizing a higher anxiety level in the stress-exposed IBS group). When zoosocial behavior was tested in a three-chambered apparatus (10-min-long period of testing), rats of the IBS group spent significantly more time in the empty compartment (without a stranger rat) and less time in the compartment with a conspecific of the same age and weight (P < 0.01), which indicates decreased social motivation in the IBS group. Our results suggest that the aforementioned chronic stress-induced IBS model results in increased anxiety, depression, and suppressed social behavior. The IBS affects immediate and working memory (with nearly no effect, however, on reference memory).

Protective effect of Eclipta alba against aluminum induced neurotoxicity and associated memory deficits in rats.

Abstract Aim: To evaluate the Protective effect of Eclipta alba against aluminum induced neurotoxicity and associated memory deficits in rats. Methods: Six groups of five Wistar rats each were used and all but the normal group was administered Aluminum chloride (4.2mg/Kg i.p). Methanolic extract of Eclipta alba leaves was given to drug treated groups. Anti-Alzheimer drug donepezil was given to standard group. Memory impairment was evaluated on Radial Eight Arm Maze in terms of average time spent in the correct (baited) arms and average number of reference memory errors (RME) and working memory errors (WME) during acquisition trails and retrieval trials. Brain tissue was evaluated for lipid peroxidation (TBARS), Superoxide anion generation (SAG), nitrite, GSH, Catalase and Total Protein Contents levels. Hippocampal regions of the brain tissue were evaluated histologically using Haematoxylin-Eosin Staining. Results: Al administration resulted in a decrease in the Average time Spent in the correct arms and an increase in the RME and WME. Moreover there as an increase in the levels of oxidative stress markers and decrease in the levels of free radical scavenging enzymes. Histologically, Al administration resulted in severe neuroinflammatory changes in hippocampal region of brain. All the above-mentioned behavioral, biochemical and histological effects were dose dependently reversed by administration of methanolic extract of Eclipta alba leaves at doses of 100 mg/Kg and 200 mg/Kg p.o. Conclusion: Aluminum induced oxidative stress could be implicating factor in neuroinflammation and dementia. Effect of Eclipta alba extract could possibly be attributed to the antioxidant activity of its phytoconstituents.

Robust and enduring atorvastatin-mediated memory recovery following the 4-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion in middle-aged rats

Chronic cerebral hypoperfusion (CCH) is a common condition associated with the development and/or worsening of age-related dementia. We previously reported persistent memory loss and neurodegeneration after CCH in middle-aged rats. Statin-mediated neuroprotection has been reported after acute cerebral ischemia. Unknown, however, is whether statins can alleviate the outcome of CCH. The present study investigated whether atorvastatin attenuates the cognitive and neurohistological outcome of CCH. Rats (12–15months old) were trained in a non-food-rewarded radial maze, and then subjected to CCH. Atorvastatin (10mg/kg, p.o.) was administered for 42days or 15days, beginning 5h after the first occlusion stage. Retrograde memory performance was assessed at 7, 14, 21, 28, and 35days of CCH, and expressed by “latency,” “number of reference memory errors” and “number of working memory errors.” Neurodegeneration was then examined at the hippocampus and cerebral cortex. Compared to sham, CCH caused profound and persistent memory loss in the vehicle-treated groups, as indicated by increased latency (91.2% to 107.3%) and number of errors (123.5% to 2508.2%), effects from which the animals did not spontaneously recover across time. This CCH-induced retrograde amnesia was completely prevented by atorvastatin (latency: −4.3% to 3.3%; reference/working errors: −2.5% to 45.7%), regardless of the treatment duration. This effect was sustained during the entire behavioral testing period (5weeks), even after discontinuing treatment. This robust and sustained memory-protective effect of atorvastatin occurred in the absence of neuronal rescue (39.58% to 56.45% cell loss). We suggest that atorvastatin may be promising for the treatment of cognitive sequelae associated with CCH.

An examination of the consequences of chronic exposure to Mitragyna speciosa during adolescence on learning and memory in adulthood

Although an emerging drug of concern in the United States and Europe, the active alkaloids associated the Mitragyna speciosa plant have long been utilized for a number of purposes ranging from use as an antitussive to that of anti-inflammatory or analgesic purposes. Known by a number of common names, in the United States it is normally legally sold as Kratom. However, little is known about the consequences of the main constituent, mitragynine or any of the more than two dozen identified plant alkaloids on neuropsychological development, learning and memory, and behavior. In the present experiment, adolescent rats were given repeated injections of saline, 15 mg/kg, or 50 mg/kg of Mitragyna speciosa extract. Once the animals reached 107 days of age, they were assessed for general activity, retention on a step-down passive avoidance task, trained using tasks with spatial components of various levels of difficulty, a spatial learning set task, and a plus maze response learning task. In some but not all of the Morris water maze tasks, escape latencies for the 50 mg/kg but not 15 mg/kg rats were significantly longer than that of saline control animals. Nonetheless, performance across groups on probe trials was comparable. In addition, during learning set testing the escape times for the three groups were comparable and, more important, they were able to respond on trial two on the basis of what they learned on the first trial by the end of training. For plus maze response learning testing, all three groups made a comparable number of reference memory errors. Conversely, the 50 mg/kg drug group made significantly more total and working memory errors than the saline-treated animals. The results suggest that chronic exposure to the alkaloids present in legally available Kratom during adolescence is capable of producing a variety of subtle but lasting changes affecting spatial and working memory performance in adulthood, well after the exposure to Kratom has ended.

Deuterium-depleted water has stimulating effects on long-term memory in rats

Deuterium-depleted water (DDW) is a water which has a 6–7-fold less concentration of the naturally occurring deuterium (20–25ppm vs. 150ppm). While administrated for a longer period, it may reduce the concentration of deuterium throughout the body, thus activating cellular mechanisms which are depending on protons (channels, pumps, enzyme proteins). The aim of the present work was to study, for the first time in our knowledge, the possible influence of deuterium-depleted water (DDW) chronic administration in normal Wistar rats, as compared to a control group which received distilled water, on spatial working memory and the locomotor activity (as studied through Y-maze) or both short-term and long-term spatial memory (assed in radial 8 arms-maze task). Our results presented here showed no significant modifications in terms of spatial working memory (assessed through spontaneous alternation percentage) and locomotor activity (expressed through the number of arm entries) in Y-maze, as a result of DDW ingestion. Also, no significant differences between the DDW and control group were found in terms of the number of working memory errors in the eight-arm radial maze, as a parameter of short-term memory. Still, we observed a significant decrease for the number of reference memory errors in the DDW rats. In this way, we could speculate that the administration of DDW may generate an improvement of the reference memory, as an index of long-term memory. Thus, we can reach the conclusion that the change between the deuterium/hydrogen balance may have important consequences for the mechanisms that govern long-term memory, as showed here especially in the behavioral parameters from the eight-arm radial maze task.

P.1.g.098 Allomargaritarine as a basis for the creation of mitochondrial targeted potential neuroprotectors

Group II (SB-269970): SB-269970 1mg/kbw; Group III (NAN190): NAN-190 1mg/kbw. Working memory was assessed using the radial-arm maze test. The design of this device ensures that after checking for food at the end of each arm the animal is forced to return to the central platform before making another choice. The following measures were recorded: the number of entering an arm containing food, but previously entered (working memory errors); the number of entering an arm that was not baited (reference memory errors); time taken to consume all five baits and the number of arms entered until a repeat entry was made (entries to repeat). Facilitation of efficient search behavior required an increase in the number of novel arms entered in the first eight choices, rather than simply an increase in total arms entered during the session. The data were presented as mean ± standard deviation and significance was tested by SPSS Statistics for Windows version 17.0 and ANOVA method. Experimental protocol was implemented following the recommendations of the ‘Gr. T. Popa’ University Committee for Research and Ethical Issues guidelines for handling and use of experimental animals, according to the ethical standards of the European Community. Results: The administration of selective serotonin 5-HT7 receptor antagonist SCH-23390 resulted in a significant decreasing (p< 0.05) of the number of working memory errors (relevant for short-time memory evaluation) and of average time taken to consume all five baits (p< 0.05), but did not influence the number of reference memory errors (relevant for long-time memory quantification) compared to control group. The treatment with the selective 5-HT1 receptor antagonist NAN-190 was not associated with a significant modification of the novel choices arm entries comparing with saline group, in radial arm maze in rats. Conclusions: The results revealed that SB-269970 produced a short-time memory retention enhancement and an improvement of discriminative spatial learning, thus corresponds to favorable effects on short-time memory, without affecting long-time memory of lab animals. In our experimental conditions, 5-HT1 receptor antagonist NAN-190 intraperitoneal injection did not significantly influence the cognitive functions in rats.

Protective effects of prescription n-3 fatty acids against impairment of spatial cognitive learning ability in amyloid β-infused rats

Deposition of amyloid β peptide (Aβ) into the brain causes cognitive impairment. We investigated whether prescription pre-administration of n-3 fatty acids improves cognitive learning ability in young rats and whether it protects against learning ability impairments in an animal model of Alzheimer's disease that was prepared by infusion of Aβ(1-40) into the cerebral ventricles of rats. Pre-administration of TAK-085 (highly purified and concentrated n-3 fatty acids containing eicosapentaenoic acid ethyl ester and docosahexaenoic acid ethyl ester) at 300 mg kg(-1) day(-1) for 12 weeks significantly reduced the number of reference memory errors in an 8-arm radial maze, suggesting that long-term administration of TAK-085 improves cognitive leaning ability in rats. After pre-administration, the control group was divided into the vehicle and Aβ-infused groups, whereas the TAK-085 pre-administration group was divided into the TAK-085 and TAK-085 + Aβ groups (TAK-085-pre-administered Aβ-infused rats). Aβ(1-40) or vehicle was infused into the cerebral ventricle using a mini osmotic pump. Pre-administration of TAK-085 to the Aβ-infused rats significantly suppressed the number of reference and working memory errors and decreased the levels of lipid peroxide and reactive oxygen species in the cerebral cortex and hippocampus of Aβ-infused rats, suggesting that TAK-085 increases antioxidative defenses. The present study suggests that long-term administration of TAK-085 is a possible therapeutic agent for protecting against Alzheimer's disease-induced learning deficiencies.

PPKC ε mediated metalloproteinase 2 and 9 levels upon ibuprofen and lipoic acid coniugate (codrug 1) treatment in an Alzheimer disease rat brain model

Alzheimer’s Disease (AD) begins with loss of recent memory and is associated to pathological and histological hallmarks such as β amyloid plaques, neural tangles (NFT), cholinergic deficit, extensive neuronal loss and synaptic changes in the cerebral cortex and hippocampus. The amyloid cascade hypothesis implies the activity of β, γ secretases which mediate the cleavage of Amyloid Precursor Protein (APP), the formation of amyloidogenic Aβ fragment (1-42), which compacts into amyloid plaques, while the cleavage by ? secretase of APP, within the Aβ segment forms sAPP and prevents the formation of Aβ (Zetterberg et al. 2010 Exp Gerontol 45, 23-29). Among the proteases which have Aβ-degrading activity, Metalloproteinase (MMP) 2, disclosing β secretase-like activity, is included, while MMP9 seems to contribute to neuronal death (Yan et al. 2006 J Biol Chem 281, 24566-74). In addition, intracellular signalling protein Protein Kinase C (PKC) can control ? secretase, preventing the formation of β amyloid, and prolonging the life span of AD (de Barry et al. 2010 Exp Gerontol 45, 64-69). A lipophilic molecular combination (codrug 1), obtained by joining an antioxidant molecule, lipoic acid, with an anti-inflammatory compound, ibuprofen (IBU) has been synthetized in our lab and administered in a chronic treatment during intracerebroventricular infusion of Aβ (1-40) peptide in rat brains as a model of AD (Sozio et al. 2010 Arch Pharm 343,133-42). Here we show the effects exerted by codrug 1 on PKC e-mediated MMP2 and MMP9 levels regulation in Aβ (1-40) infused rat cerebral cortex. Interestingly codrug 1, lowering Metalloproteinases expression via PKC e down-modulation, seems to control Alzheimer’s disease induced cerebral amyloid deposits, neuronal death and, lastly, behavioural deterioration. Moreover the cognitive test evidences that codrug 1 treatment decreases the number of reference memory errors and the time spent to perform the test suggesting this compound as an useful therapeutical tool against AD.

Prenatal oxycodone exposure impairs spatial learning and/or memory in rats

Recent changes in demographic patterns of drug use have resulted in the increased non-medical use of prescription opiates. These users are younger and more likely to be female, which has the potential for increasing rates of in utero exposure. Therefore, we developed a rat model that simulates a prescription opiate-dependent woman who becomes pregnant. Adult female Sprague–Dawley rats were treated for 30 days via oral gavage with ascending doses of oxycodone HCl up to a final dose of 15 mg/kg/day, which was maintained during breeding and gestation. Controls were treated with water. The adult male offspring of these treated dams were tested on the radial arm maze, the Morris water maze (with a short and a long intertrial interval), and a spatial T-maze. Prenatal oxycodone exposure led to a deficit in the radial arm maze characterized by a greater number of reference memory errors, especially in the beginning of testing. In contrast, in the T-maze, prenatal oxycodone-exposed rats learned the task as well as well as the prenatal water controls. However, they had a modest deficit in retention of the task when assessed 5 days after acquisition training ended. For the Morris water maze, the intertrial interval affected the pattern of learning. While there was no deficit when the training had a short intertrial interval, when there was a long intertrial interval, prenatal oxycodone-exposed rats had poorer acquisition. The spatial learning deficit was characterized by and increased latency to find and a greater distance traveled to the platform in the prenatal oxycodone-exposed rats. These data were corroborated by analysis of the behavioral search strategy, which showed a decreased use of spatial strategies and an increase in non-spatial strategies, especially wall-hugging, in prenatal oxycodone-exposed rats as compared to prenatal water control rats on day 2 of acquisition. These results indicate that prenatal oxycodone exposure consistently impairs learning and memory in a battery of spatial tasks.

Effects of 6-OHDA infusion into the hypothalamic paraventricular nucleus in mediating stress-induced behavioural responses and oxidative damage in rats

The stress response is mediated by the hypothalamo-pituitary-adrenal (HPA) system. Activity of the hypothalamic paraventricular nucleus (PVN) forms the basis of the HPAaxis. Behavioral and endocrine responsivity to threat and their ontogenetic changes may be mediated by PVN. Methods. 6-hydroxydopamine (6-OHDA) remains the most widely used substance in animal models for inducing highly reproducible brain lesions. In our study, parvocellular neurons from the PVN of male Wistar rats were chemical lesioned by right-unilateral stereotaxic injection of two different doses of 6-OHDA (8µg/3µl and 16µg/3µl) and were subjected to a battery of behavioral tests designed to assess spatial memory formation (radial arm-maze task) and anxiety (elevated plus maze). Further, we were interested in knowing whether a 6-OHDA lesion of the PVN would result in an imbalance in neuronal oxidative stress levels. Results. 6-OHDA-induced PVN lesions significantly increased the number of working memory errors, suggesting effects on short-term memory, without affecting longterm memory, explored by number of reference memory errors in radial arm-maze task. In elevated plus maze measuring anxiety, 6-OHDA significantly diminished anxiety-like behavior in a dose-dependent manner. In addition, the neurotoxin induced a reduction in superoxide dismutase (SOD) and glutathione peroxidase (GPX) specific activities, while malondialdehyde (MDA) level was found increased in the temporal lobe of rat brain, the most vulnerable cortical area to oxidative stress effects. Conclusion. Results suggest that 6-OHDA lesion of the PVN affects behavioral performance via interactions with systems governing arousal level and possibly by increasing neuronal oxidative stress.

Enriched environment restores hippocampal cell proliferation and ameliorates cognitive deficits in chronically stressed rats

Adult neurogenesis, particularly in the subgranular zone, is thought to be linked with learning and memory. Chronic stress inhibits adult hippocampal neurogenesis and also impairs learning and memory. On the other hand, exposure to enriched environment (EE) is reported to enhance the survival of new neurons and improve cognition. Accordingly, in the present study, we examined whether short-term EE after stress could ameliorate the stress-induced decrease in hippocampal cell proliferation and impairment in radial arm maze learning. After restraint stress (6 hr/day, 21 days) adult rats were exposed to EE (6 hr/day, 10 days). We observed that chronic restraint stress severely affected formation of new cells and learning. Stressed rats showed a significant decrease (70%) in the number of BrdU (5-bromo-2'-deoxyuridine)-immunoreactive cells and impairment in the performance of the partially baited radial arm maze task. Interestingly, EE after stress completely restored the hippocampal cell proliferation. On par with the restoration of hippocampal cytogenesis, short-term EE after stress resulted in a significant increase in percentage correct choices and a decrease in the number of reference memory errors compared with the stressed animals. Also, EE per se significantly increased the cell proliferation compared with controls. Furthermore, stress significantly reduced the hippocampal volume that was reversed after EE. Our observations demonstrate that short-term EE completely ameliorates the stress-induced decrease in cell proliferation and learning deficit, thus demonstrating the efficiency of rehabilitation in reversal of stress-induced deficits and suggesting a probable role of newly formed cells in the effects of EE.

The protective effect of dietary eicosapentaenoic acid against impairment of spatial cognition learning ability in rats infused with amyloid β (1–40)

Background Amyloid β (Aβ) peptide (1–40) can cause cognitive impairment. Experimental design We investigated whether dietary preadministration of eicosapentaenoic acid (EPA) is conducive to cognition learning ability and whether it protects against the impairment of learning ability in rats infused with Aβ peptide (1–40) into the cerebral ventricle. Results Dietary EPA administered to rats for 12 weeks before the infusion of Aβ into the rat brain significantly decreased the number of reference memory errors (RMEs) and working memory errors (WMEs), suggesting that chronic administration of EPA improves cognition learning ability in rats. EPA preadministered to the Aβ-infused rats significantly reduced the increase in the number of RMEs and WMEs, with concurrent proportional increases in the levels of corticohippocampal EPA and docosahexaenoic acid (DHA) and in the DHA/arachidonic acid molar ratio. Decrease in oxidative stress in these tissues was evaluated by determining the reactive oxygen species and lipid peroxide levels. cDNA microarray analysis revealed that altered genes included those that control synaptic signal transduction, cell communication, membrane-related vesicular transport functions, and enzymes and several other proteins. Conclusion The present study suggests that EPA, by acting as a precursor for DHA, ameliorates learning deficits associated with Alzheimer's disease and that these effects are modulated by the expression of proteins involved in neuronal plasticity.

Long-term treatment with fish oil prevents memory impairments but not hippocampal damage in rats subjected to transient, global cerebral ischemia

Cerebral ischemia leads to neurodegeneration and cognitive impairment. Fish oil (FO) constitutes a rich dietary source of omega-3 polyunsaturated fatty acids especially docosahexaenoic acid (DHA). The objective of the present study was to investigate whether long-term treatment with commercial, high concentration DHA-containing FO could be effective in alleviating both the cognitive and neurodegenerative deficits caused by transient, global cerebral ischemia (TGCI) in rats. Naive rats were trained for 10 days in an 8-arm radial maze task and then subjected to TGCI for 15 minutes (4-VO model) 3 days later (day 13). Retention of the previously acquired cognition (ie, memory) was assessed weekly on days 20, 27, 34, 41, 48, and 55 and measured by 3 behavioral parameters as follows: (i) latency to find the goal box, (ii) number of reference memory errors, and (iii) number of working memory errors. The extent of pyramidal cell death in the hippocampus was examined at the end of the behavioral analysis on day 43. Fish oil (300 mg/kg DHA, gavage) administration occurred once daily beginning 3 days before TGCI (the last day of training) and continued until day 41. Transient, global cerebral ischemia markedly disrupted memory performance measured by all 3 parameters (P < .0001 vs sham). This amnesic effect of ischemia persisted until the end of the behavioral analysis. Treatment with FO progressively reversed the TGCI-induced retention deficit until rats achieved control levels. This protective effect of FO on learning/memory function was clearly observed after both daily and cumulative data analysis (P < .001-0.01 vs vehicle). Such memory improvements remained statistically significant, even after cessation of FO treatment, indicating a sustained effect of FO. In contrast, FO failed to prevent ischemia-induced hippocampal damage in areas CA1, CA2, or CA4. Therefore, the present findings suggest that long-term FO treatment is able to facilitate functional recovery after ischemic brain damage, an effect that was distinct from hippocampal damage.

Effects of acute systemic and intra-cerebral stimulation of cannabinoid receptors on sensorimotor gating, locomotion and spatial memory in rats

Cannabinoid CB(1) receptors in the brain are targets of both endocannabinoid signalling and the psychoactive compounds of the hemp plant. They mediate neuronal effects of their ligands in various corticolimbic and striatal circuits by presynaptic regulation of transmitter release. This study investigates acute systemic effects of the full CB(1) receptor agonist WIN 55,212-2 (WIN) on prepulse inhibition (PPI) of the acoustic startle response (ASR), locomotor activity and spatial memory retrieval in an eight-arm radial-maze task. Furthermore, we tested the effect of local intra-cerebral micro-infusions of WIN into the nucleus accumbens (NAc), ventral tegmental area (VTA), dorsal (dHIP) and ventral (vHIP) hippocampus and medial prefrontal cortex (mPFC). Systemic WIN (1.2 mg/kg) reduced PPI without affecting ASR, had no effect on locomotion in the open field, but impaired retrieval of spatial memory. Infusions of 5 microg/0.3 microl WIN into either NAc (core or shell), dHIP or VTA did not affect PPI and locomotion immediately afterwards. However, PPI was significantly reduced after intra-mPFC and intra-vHIP infusion of WIN. Furthermore, WIN infusion into dHIP increased the number of reference memory errors in the maze, suggesting impairment of memory retrieval. Our data support the notion that CB(1) receptor stimulation impairs sensorimotor gating most likely by modulation of neurotransmitter release in mPFC and vHIP. The lack of effects of local WIN infusions in NAc and VTA might be due to low receptor abundance in these regions. Additionally, CB(1) receptor activation in dHIP impairs spatial memory retrieval. Taken together, cortico-hippocampal cannabinoid receptors play an essential role in the regulation of cognitive and behavioural processes.

Prenatal testosterone improves the spatial learning and memory by protein synthesis in different lobes of the brain in the male and female rat

Abstract The high density of the steroid hormone receptors in the structures of temporal lobe involved in learning and memory, such as the hippocampus, perirhinal cortex, entorhinal cortex and amigdaloid complex, shows that there must be a direct relationship between gonadal hormones and organizational effects of steroid hormones in those structures during development of the nervous system. The present study was undertaken in order to investigate the effect of testosterone administration during the third week of gestation on the spatial memory formation of the offspring rats and the level of soluble proteins in the temporal lobe and frontal lobe of brain, as evidence of important organizational effects of androgens during prenatal development in brain sexual dimorphism. Animals have received testosterone undecanoate on days 14, 15, 16 and 19, 20, 21 of gestation. Learning and memory tests were started 100 days after the testosterone treatment. At the end of the experiments, the temporal and frontal lobes of brain were removed for assessing the level of soluble proteins. Testosterone treatment significantly improved spontaneous alternations percentage of male offspring in Y-maze task comparative with female offspring and reference memory in radial 8 arm-maze task (decreasing in number of reference memory errors in both male and female offspring groups), suggesting effects of both short and long-term memory. Also, testosterone significantly increased the brain soluble protein level of treated female rats in 14–16 prenatal days compared with the control group as well as the brain soluble protein level of treated male rats. These results suggest that steroid hormones play an important role in the spatial learning and memory formation by means of protein synthesis in different lobes of the brain.

Tacrolimus (FK506) reduces hippocampal damage but fails to prevent learning and memory deficits after transient, global cerebral ischemia in rats

Transient, global cerebral ischemia (TGCI) leads to hippocampal damage and disruption of spatial learning and memory. The immunosuppressant, tacrolimus (FK506), prevents TGCI-induced hippocampal neurodegeneration, but its effectiveness in promoting the recovery of learning and memory performance after TGCI has been little investigated. Here, we use a confined version of the aversive, non-food rewarded radial maze to evaluate further the effects of FK506 on TGCI-induced learning and memory deficits. In the first experiment, rats were rendered ischemic (15 min 4-VO) and 20 days later were tested for acquisition of the radial maze task over 15 consecutive days (post-operative training). In the second experiment, naive rats were trained for 10 days and subjected to TGCI (pre-operative training); retention of task performance was assessed on days 31, 35 and 39 post-ischemia. Acquisition and retention performances were expressed as a) latency to find a goal box, b) number of reference memory errors, and c) number of working memory errors. Data are presented both across daily training sessions (15 days, 3-day blocks) and as a total value (summed over the 15 days). Histological examination was performed on the day after behavioral testing. In both experiments, FK506 (1.0 mg/kg) was given i.v. at the beginning of reperfusion, followed by doses applied intraperitoneally (i.p.) 6, 24, 48 and 72 h post-ischemia. TGCI markedly disrupted both acquisition and retention performance ( p < 0.0001–0.05). Treatment with FK506 did not prevent the TGCI-induced acquisition and retention deficits, independently of whether performances were quantified ‘daily’ or as a ‘total’ value. In contrast, FK506 reduced hippocampal damage significantly compared to the vehicle alone ( p < 0.001–0.05). We conclude that the present study did not confirm our earlier behavioral data, and suggest that FK506 is not effective in treating the behavioral outcomes of TGCI, despite its efficacy in reducing CA1, hippocampal damage. However, further studies including other behavioral tasks and more extensive neurohistological analysis, are needed to better elucidate the effectiveness of FK506 in promoting functional recovery in models of transient, global cerebral ischemia.

Effects of pre- and postnatal exposure to 5-methoxytryptamine and early handling on an object-place association learning task in adolescent rat offspring

A reduction in 5-HT1A receptor response enhances learning and memory performance in rats. Pre- and postnatal treatment with 5-methoxytryptamine (5MT), a non-selective serotonergic agonist, and early handling, reduce the number of 5-HT1A receptors in neonatal and pre-pubertal rat progeny. The aim of this study was to investigate in adolescent male rats the consequences of pre- and postnatal treatment with 5MT and its interaction with early handling on an object-place association learning task, the “Can test”, a motivated, non-aversive, spatial/object discrimination task. Results show that a single daily injection of 5MT from gestational days 12 to 21 (1 mg/kg s.c.) and from postnatal days 2 to 18 to pups (0.5 mg/kg s.c.), increases the level of activity and the number of correct responses, and decreases the number of reference memory errors in the progeny as adolescent, compared to vehicle-treated rats. Similar effects are observed following a daily, brief, maternal separation of the pups from postnatal days 2 until 21. Furthermore, when 5MT-treated rats underwent to early handling procedure, the effects induced by 5MT increased handling-induced facilitation of the object-place association. These results suggest that pre- and postnatal treatment with 5MT enhances learning in the “Can test”, probably due to a reduction in 5-HT1A receptors in the hippocampus. Whether the potentiation exerted by pre- and postnatal 5MT on early handling effects may be related to a further damping of 5-HT1A receptor response is not yet assessed; however, our data demonstrate that this association is able to induce long-term facilitative effects on spatial learning performance in a non-aversive spatial/object discrimination task in the adolescent rat offspring.