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PubMed2005

Effect of naloxone on aluminum-induced learning and memory impairment in rats.

BACKGROUND: Uptake of aluminum may disturb the learning and memory of humans or animals. Naloxone (NAL) has been shown to exert beneficial effects on memory deficits. AIMS: We investigated the effects of naloxone on aluminum-induced learning and memory impairment in rats. SETTINGS AND DESIGN: Aluminum-induced learning and memory impairment model was established by gavage of Aluminum chloride (600 mg/kg) for 3 months. Rats were divided into three groups viz. naloxone-treated rats (NAL 0.8 mg/kg, i.p. daily for 7 days), non-treated model rats and normal controls. MATERIALS AND METHODS: The Morris water maze test was performed to study spatial learning and memory. Long-term potentiation (LTP) of the Schaffer collateral-CA1 synapse was recorded. Aluminum and zinc contents in the hippocampus were assayed with atomic absorption spectrophotometry. STATISTICAL ANALYSIS: Parameters of the hidden and visible platform trials and data of LTP were analyzed using two-way repeated measures ANOVA. RESULTS: In the hidden platform trials, escape latencies of the NAL rats were significantly shorter than that of the non-treated rats (P=0.000, 95% confidential interval low bound 14.31, upper bound 22.68). In probe trails, the number of entries in the target area of the NAL rats (6.75+/-1.28 times/min) was more than that of non-treated model rats (4.56+/-2.16 times/min, P=0.004, 95% confidence interval low bound -3.65, upper bound -0.788). The magnitudes of LTP recorded in the CA1 pyramidal neurons of the NAL-treated rats were significantly augmented when compared to the non-treated model rats (P=0.005, 95% confidence interval low bound 0.16, upper bound 0.84). CONCLUSIONS: NAL could facilitate spatial learning and memory and enhance LTP in the CA1 region of the hippocampus in aluminum-induced learning and memory impairment in rats.

Aluminum↗
PubMed1998

Characterization of perforant path lesions in rodent models of memory and attention.

Early stage Alzheimer's disease (AD) pathology is associated with neurodegeneration of systems within the temporal cortex, e.g. the entorhinal cortex, perforant pathway and hippocampus. The perforant pathway provides the major neuronal input to the hippocampus from the entorhinal cortex and thus relays multimodal sensory information derived from cortical zones into the hippocampus. The earliest symptoms of AD include cognitive impairments, e.g. deficits in short-term memory and attention. Consequently, we have investigated the effect of bilateral knife cut lesions to the perforant path on cognition in rats using models measuring primarily short-term memory (operant delayed match to position task), attention (serial five-choice reaction time task) and spatial learning (Morris water maze). Rats receiving bilateral perforant path lesions showed normal neurological function and a mild hyperactivity. The lesion produced little effect on attention assessed using the five-choice task. In contrast, animals with equivalent lesions showed a robust delay-dependent deficit in the delayed match to position task. Spatial learning in the water maze task was also severely impaired. The delay-dependent deficit in the match to position task was not reversed by tacrine (3 mg/kg) pretreatment. The present data support a selective impairment of cognitive function following perforant path lesions that was confined to mnemonic rather than attentional processing. These findings complement primate and human studies identifying a critical role of the perforant pathway and associated temporal lobe structures in declarative memory. Degeneration of the perforant pathway is likely to contribute to the mnemonic deficits characteristic of early AD. The failure of tacrine to ameliorate these deficits may be relevant to an emerging clinical literature suggesting that cholinomimetic therapies improve attentional rather than mnemonic function in AD.

Animals↗
PubMed1992

Delayed treatment with nerve growth factor improves acquisition of a spatial task in rats with lesions of the nucleus basalis magnocellularis: evaluation of the involvement of different neurotransmitter systems.

Rats received bilateral lesions of the nucleus basalis magnocellularis by infusion of ibotenic acid. Fourteen days later, osmotic minipumps releasing human recombinant nerve growth factor (0.3 micrograms/day) were implanted subcutaneously. Starting one month after the lesion, spatial learning of the animals was tested using the Morris water maze. Acquisition of the task was impaired by the lesion, but treatment with nerve growth factor reduced the average latency to find the platform by approximately 9 s, which represents 28% of the lesion-induced behavioral deficit. Retention of this task and spatial acuity, tested in a trial in which the platform was not present, did not show a statistically significant improvement. Lesions of the nucleus basalis magnocellularis reduced the choline acetyltransferase activity in the neocortex, but not in the hippocampus. Treatment with nerve growth factor increased the choline acetyltransferase activity in the neocortex but not in the hippocampus. There was no significant difference in the levels of norepinephrine, dopamine, serotonin or their metabolites in the cortex or hippocampus between nerve growth factor-treated animals and lesioned control animals. There was no significant correlation between any of these neurochemical changes and behavioral performance (acquisition and spatial acuity). Treatment with nerve growth factor did not increase the number or the size of nerve growth factor receptor-immunoreactive neurons in the nucleus basalis magnocellularis. These data suggest that delayed treatment with nerve growth factor results in an improvement of spatial learning in rats with lesions of the nucleus basalis magnocellularis. A possible role for cholinergic mechanisms in this effect is discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Nitric oxide, the enigmatic neuronal messenger: its role in synaptic plasticity.

The discovery of the intercellular messenger nitric oxide (NO) stimulated new concepts of how synaptic plasticity could be induced in the nervous system. While initial reports found evidence that NO is of importance for the formation of long-term potentiation of synaptic transmission (LTP) and spatial learning in rats, later reports failed to confirm these results. Novel approaches such as deletion of the gene that encodes NO synthase in mice showed that the neuronal and the endothelial isoforms are expressed in neurones. Deletion of both isoforms reduced the inducibility of LTP. Furthermore, novel selective inhibitors of NO synthase impaired spatial learning. These results support the hypothesis that NO plays an important role in synaptic transmission and explain some but not all previously contradictory results.

Animals↗
PubMed1989

ACTH 4-9 analog can retard spatial alternation learning in brain damaged and normal rats.

Thirty adult male hooded rats (Long-Evans strain) were assigned randomly to one of three lesion groups (n = 10) and prepared with medial frontal, posterior parietal, or sham neocortical injuries. Following a recovery interval of 10-12 days, access to water was limited to 30 min per day and the rats were shaped to traverse a T-maze for a reward of sweetened water. After a pretraining criterion was attained, osmotic minipumps (Alzet 2002) were installed subcutaneously. The minipumps delivered chronically for the next 14 to 15 days either 0 or 1.2 micrograms of ACTH 4-9 dissolved in bacteriostatic saline per day while the rats were trained on a reinforced spatial alternation task. Analysis of the number of errors made to a criterion of at least 80% correct alternations in two consecutive training sessions, or a ceiling of 62 errors (attained by two rats with parietal lesions), revealed that learning was impaired in the rats with parietal injuries. Contrary to our hypothesis, animals receiving ACTH 4-9 committed more errors than their counterparts receiving only saline.

Adrenocorticotropic Hormone↗
PubMed1999

Fragile X mouse: strain effects of knockout phenotype and evidence suggesting deficient amygdala function.

Fragile X syndrome is an X-linked form of mental retardation resulting from the absence of expression of the fragile X mental retardation 1 gene. The encoded protein is a ribosome-associated, RNA-binding protein thought to play a role in translational regulation of selective messenger RNA transcripts. A knockout mouse has been described that exhibits subtle deficits in spatial learning but normal early-phase long-term potentiation. We expanded these studies by examination of late-phase hippocampal long-term potentiation, the protein synthesis-dependent form of long-term potentiation, in the Fmrl knockout mice. Here, late-phase long-term potentiation was normal, suggesting either that absence of fragile X mental retardation protein has no influence on long-term potentiation or that any influence is too subtle to be detected by this technique. Alternatively, the hippocampus may not be the primary site affected by the absence of this protein. Accordingly, we examined spatial learning in the knockout mice using the hippocampus-dependent Morris water maze. Contrary to earlier reports, near-normal performance was observed. Since the knockout line used in this study has been back-crossed to C57BL/6 for more than 15 generations, whereas the line used in the earlier studies contained a substantial strain 129 contribution, we examined F1 siblings of knockout and 129 crosses. Here, significant but subtle increased swim latencies in reversal trials were observed, in agreement with the previous studies. These data suggest strain differences between C57BL/6 and 129 that influence the Fmrl knockout phenotype. In order to investigate a paradigm less dependent on hippocampal function, the knockout mice were examined using the conditional fear paradigm. Here, the knockout animals displayed significantly less freezing behavior than their wild-type littermates following both contextual and conditional fear stimuli. These data suggest that amygdala disturbances may also be involved in fragile X syndrome.

Amygdala↗
PubMed2001

N-tert-butyl-alpha-phenylnitrone, a free radical scavenger with anticholinesterase activity does not improve the cognitive performance of scopolamine-challenged rats.

Reversible inhibitors of acetylcholinesterase improve spatial learning and memory in animal models of cognitive impairment. Here we investigate if the beneficial effects of free radical scavenger N-tert-butyl-alpha-phenylnitrone (PBN) on cognitive performance could be explained by its recently discovered anticholinesterase activity. Morris water maze experiment was performed to examine the effect of PBN on the impairment of spatial learning and memory induced by the antagonist of cholinergic muscarinic transmission scopolamine. In situ hybridization histochemistry experiment was performed to study its effects on the induction of immediate early gene expression (c-fos, c-jun) by dopamine D1 receptor agonist SKF-82958 and on the augmentation of the SKF-82958-induced expression of these genes by scopolamine. In both experiments, the effects of PBN were compared to the effects of reversible anticholinesterase physostigmine. We found that physostigmine but not PBN significantly reversed the cognitive impairment in scopolamine-challenged rats, prevented the induction of c-fos and c-jun mRNAs by SKF-82958 and attenuated the augmentation of the SKF-82958-induced expression of these genes by scopolamine. The present experiments did not reveal a significant in vivo anticholinesterase activity of PBN.

Animals↗
PubMed2000

Maternal care, hippocampal synaptogenesis and cognitive development in rats.

We report that variations in maternal care in the rat promote hippocampal synaptogenesis and spatial learning and memory through systems known to mediate experience-dependent neural development. Thus, the offspring of mothers that show high levels of pup licking and grooming and arched-back nursing showed increased expression of NMDA receptor subunit and brain-derived neurotrophic factor (BDNF) mRNA, increased cholinergic innervation of the hippocampus and enhanced spatial learning and memory. A cross-fostering study provided evidence for a direct relationship between maternal behavior and hippocampal development, although not all neonates were equally sensitive to variations in maternal care.

Animals↗
PubMed1998

Impaired spatial navigation learning in transgenic mice over-expressing heme oxygenase-1.

Transgenic mice expressing heme oxygenase-1 (HO-1) using the neuron-specific enolase promoter were impaired in learning the Morris water maze compared to nontransgenic littermates. The memory of the HO-1 mice for the location of the platform was similarly impaired when tested using a probe trial after 7 training blocks, but performance on visible platform trials was similar for both groups of mice. Importantly, both HO-1 and nontransgenic mice had normal sensorimotor function, and performed the same on a Y-maze alternation task, highlighting the specificity of memory deficit in the spatial navigation task. These results suggest that carbon monoxide, one product of HO-1 activity, interferes in the development of spatial navigation memory, and may play a role in normal memory function.

Animals↗
PubMed1993

Age-related changes in correlation between behavioral and biochemical parameters in Lewis rats.

This study evaluated aging by using a correlational analysis of behavior and biochemistry in young (4 months old) and old (24 months old) Lewis rats. The rats were subjected to different learning tasks (spatial discrimination learning in the Morris task and cone-field task, temporal discrimination learning, one-trial inhibitory avoidance task) and noncognitive tests (emotional reactivity, motor coordination, and food motivation) and the relation between the various parameters was assessed. In the learning tasks, except for the inhibitory avoidance task, the first part of the learning curve was taken as an index of learning. Blood glucose (baseline and blood glucose regulation) and hippocampal choline acetyltransferase (ChAT) activity were also measured. There was no correlation between the different parameters of learning in young and old rats. This indicates that there are individual differences in performance in different learning and memory tasks. Measures of noncognitive behavior (food motivation, emotional reactivity, and motor performance) did not predict performance in the learning tasks. Hippocampal ChAT activity did not correlate with learning performance in old rats, whereas blood glucose level was found to correlate with spatial learning in old rats. These results suggest that an impaired regulation of blood glucose may be related to cognitive performance in aging.

Age Factors↗
PubMed2006

Effects of microcystins over short- and long-term memory and oxidative stress generation in hippocampus of rats.

Microcystins produced by cyanobacteria are potent inhibitors of some protein phosphatases, but recent evidence also indicates its potential to generate oxidative stress. In the present study, the effects of microcystin raw extracts (Mic; 0.01 and 20microg/L) and purified okadaic acid (OA; 0.01 and 10microg/L) on short- and long-term memory alteration and antioxidant and oxidative damage were investigated in hippocampus of rats. The results showed an amnesic effect with 0.01 and 20microg/L Mic on retrieval and only with 0.01microg/L Mic on spatial learning. Parallel to these effects oxidative damage was observed as evidenced by augmented levels of lipid peroxides and DNA damage and the absence of antioxidant responses in terms of total oxyradical scavenging capacity. Phase II reactions catalyzed by glutathione-S-transferase were not modified after microcystins exposure. Overall this study showed physiological events (retrieval and spatial learning) that can be related to the classical toxic effects of microcystins (i.e., phosphatase inhibition). In addition, evidence of alternative toxicity mechanisms via oxidative stress generation was also obtained. The fact that organic anion transporter polypeptides (OATP) involved in microcystins uptake are expressed not only in liver but also in brain points to the environmental relevance of the observed effects.

Animals↗
PubMed1999

Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein.

In Alzheimer's disease (AD), a progressive decline of cognitive functions is accompanied by neuropathology that includes the degeneration of neurons and the deposition of amyloid in plaques and in the cerebrovasculature. We have proposed that a fragment of the Alzheimer amyloid precursor protein (APP) comprising the carboxyl-terminal 100 amino acids of this molecule (APP-C100) plays a crucial role in the neurodegeneration and subsequent cognitive decline in AD. To test this hypothesis, we performed behavioral analyses on transgenic mice expressing APP-C100 in the brain. The results revealed that homozygous APP-C100 transgenic mice were significantly impaired in cued, spatial and reversal performance of a Morris water maze task, that the degree of the impairment in the spatial learning was age-dependent, and that the homozygous mice displayed significantly more degeneration of neurons in Ammon's horn of the hippocampal formation than did heterozygous or control mice. Among the heterozygotes, females were relatively more impaired in their spatial learning than were males. These findings show that expression of APP-C100 in the brain can cause age-dependent cognitive impairments that are accompanied by hippocampal degeneration.

Age Factors↗
PubMed2006

NT-1, an active constituent extracted from Tiaoxin Recipe, enhances long-term potentiation of CA1 subfield in rat hippocampal slices.

Previous studies demonstrated that Tiaoxin Recipe (TXR), a traditional Chinese medicinal prescription, could alleviate cognitive dysfunction. NT-1, an active constituent isolated from this prescription under guidance of bioactive evaluation, was preliminarily proved to enhance the ability of spatial learning and memory in rats. In the present study, using hippocampal slice preparations, we investigated the mechanisms by which NT-1 improves cognitive dysfunction contributed to corticosterone (CORT). NT-1 ameliorated the inhibition of LTP by CORT more significantly than TXR did. These results suggested that enhancing LTP induction is one mechanism by which NT-1 improves spatial learning and memory impaired by CORT.

Animals↗
PubMed2004

Influence of a combination of two tetrachlorobiphenyl congeners (PCB 47; PCB 77) on thyroid status, choline acetyltransferase (ChAT) activity, and short- and long-term memory in 30-day-old Sprague-Dawley rats.

The important role of thyroid hormones in growth and development, maintenance of body temperature, digestion, cardiac function, and normal brain development can be disrupted by environmental contaminants like polychlorinated biphenyls (PCB). Polychlorinated biphenyls are environmental contaminants that are widespread, persistent, lipophilic, and bioaccumulate through food webs, concentrating in adipose tissue. Placental and lactational PCB exposure of offspring causes metabolic and endocrine disruptions including hypothyroxinemia, spatial learning and memory deficits, neurochemical and neurobehavioral alterations, and reproductive problems. Previous studies in our lab using the individual congeners PCB 47 (2,2',4,4'-tetrachlorobiphenyl, ortho-substituted) and PCB 77 (3,3',4,4'-tetrachlorobiphenyl, non-ortho-substituted) have demonstrated alterations in thyroid hormone levels, alterations in brain choline acetyltransferase (ChAT) activity, and spatial learning deficits. In the present study, pregnant Sprague-Dawley rats were fed a diet with or without a mixture of PCB 47/77 at 1.25 ppm, 12.5 ppm or 25.0 ppm (w/w). Rat pups were swum in the Morris water maze four times a day on days 21-29 in order for the animals to learn the position of a submerged fixed platform. A probe test was run on day 24 (30 min after last swim) for short-term memory, and on day 29 (24 h after the last swim) for long-term memory after removal of the platform. Time spent in the quadrant previously containing the platform was recorded. Rats were decapitated on day 30, serum collected and frozen at -20 degrees. ChAT activity was measured radiometrically in basal forebrain and hippocampus. All PCB-treated animals experienced a depression in both triiodothyronine (T3) and thyroxine (T4). The present study found that all doses of PCB depressed ChAT activity in hippocampus with no significant alteration in the basal forebrain. In PCB-treated animals, short-term memory showed a trend toward improvement and long-term memory toward depression, but these trends were not significant. The consequences likely stem from endocrine disruption, especially with regard to the thyroid.

Animals↗
PubMed1999

Spatial working memory in rats: no differences between the sexes.

In a number of mammalian species, males appear to have superior spatial abilities to females. The favoured explanations for this cognitive difference are hormonal, with higher testosterone levels in males than females leading to better spatial performance, and evolutionary, where sexual selection has favoured males with increased spatial abilities for either better navigational skills in hunting or to enable an increased territory size. However, an alternative explanation for this sex difference focuses on the role of varying levels of oestrogen in females in spatial cognition (the 'fertility and parental care' hypothesis). One possibility is that varying oestrogen levels result in variation in spatial learning and memory so that, when tested across the oestrous cycle, females perform as well as males on days of low oestrogen but more poorly on days of high oestrogen. If day in the oestrous cycle is not taken into account then, across an experiment, any sex differences found would always produce male superiority. We used a spatial working memory task in a Morris water maze to test the spatial learning and memory abilities of male and female rats. The rats were tested across a number of consecutive days during which the females went through four oestrous cycles. We found no overall sex differences in latencies to reach a submerged platform in a Morris water maze but, on the day of oestrus (low oestrogen), females took an extra swim to learn the platform's location (a 100% increase over the other days in the cycle). Female swim speed also varied across the oestrous cycle but females were no less active on the day of oestrus. These results oppose the predictions of the fertility and parental care hypothesis.

Animals↗
PubMed1989

Medial versus lateral hyperstriatal lesions in pigeons: effects on autoshaping, non-matching-to-sample and spatial discrimination learning at short and long intertrial intervals.

Three experiments contrasted the effects of medial and lateral hyperstriatal lesions in pigeons. Expt. 1 found that both types of lesion obtained slower acquisition of autoshaping, compared to unoperated controls. No group differences in maintained rate of autoshaped responding were found. Expt. 2 found that lateral but not medial lesions disrupted choice performance in a non-matching-to-sample (NMTS) task, in which initial preference was for the correct stimulus; birds with lateral lesions responded more slowly to the sample stimulus than did birds with medial lesions. Expt. 3 found that medial but not lateral lesions disrupted both acquisition and reversal of a spatial discrimination at a long, but not at a short intertrial interval (ITI). Medial lesions damage primarily the hyperstriatum accessorium and lateral lesions, the hyperstriatum ventrale; but no significant correlations between the extent of damage to either of these structures and severity of behavioural disruption were obtained. Implications of these findings for theoretical accounts of hyperstriatal involvement in learning processes are discussed.

Animals↗
PubMed1997

ACEA 1021, a glycine site antagonist with minor psychotomimetic and amnestic effects in rats.

Antagonists of the allosteric glycine site of the NMDA receptor complex have been suggested to be beneficial in the treatment of neurodegenerative disorders. However, unwanted side effects like psychomotor stimulation and amnesia must be expected. ACEA 1021 (5-nitro-6,7-dichloro-1,4-dihydroquioxaline-2,3dione) is one of the first high-selective glycine site antagonists which passes the blood-brain barrier and which has promising anticonvulsive and neuroprotective properties. In the present study the effects of ACEA 1021 (5, 7.5, 8, 10, 15 and 20 mg/kg i.p.) on sniffing stereotypy, locomotor activity, prepulse inhibition of the acoustic startle response, the anti-cataleptic properties and spatial learning were tested. Only 7.5 mg/kg ACEA 1021 induced a sniffing stereotypy which was antagonized by the partial glycine site agonist D-cycloserine (D-4-amino-3-isoxazolidinone). ACEA 1021 had neither an effect on motor behavior measured in the open field nor on the acoustic startle response in the prepulse inhibition paradigm nor on the acquisition of spatial learning in the 8-arm-radial maze. Anti-cataleptic properties of ACEA 1021 in dopamine D2 (haloperidol (4'fluoro-4-(1-(4-hydroxy-4-p-chlorophenyl-piperidino)-butyrophe non)) or D1 (SCH 23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pin e hydrochloride)) receptor antagonist-pretreated rats were only minor. Thus, ACEA 1021 is a glycine site antagonist with minimal psychotomimetic side effects and with no amnesia properties. However, it has only minor anti-parkinsonian effects.

Amnesia↗
PubMed1996

Dextromethorphan reduces functional deficits and neuronal damage after global ischemia in rats.

Glutamate antagonists have been shown to be neuroprotective in animal models of cerebral ischemia. Global cerebral ischemia in rats leads to selective neuronal damage in the hippocampus and striatum. Following ischemia a transient locomotor hyperactivity and a deficit in spatial learning and memory occurs. The aim of the present study was to investigate the potential neuroprotective effect of dextromethorphan, an antagonist at the N-methyl-D-aspartate receptor, with behavioural and histological measures of global ischemia in rats. Global ischemia was induced by four-vessel occlusion (4VO) for 20 min in rats. Dextromethorphan was administered 20 min before induction of ischemia at a dose of 10 or 50 mg/kg. Before and on day 1, 3 and 5 after operation the spontaneous locomotor activity was measured. One week after surgery spatial learning was tested in the Morris water maze. After behavioural testing the animals were sacrificed and the neuronal damage was assessed. Treatment with 50 mg/kg of dextromethorphan reduced the increase in locomotor activity observed on day 1 and 3 after ischemia. In the water maze dextromethorphan reduced the increase in escape latency and in swim distance induced by 4VO. Furthermore, the ischemia-induced reduction in time spent in the quadrant of the former platform position during the probe trial was increased by treatment with dextromethorphan. Neuronal damage in the CA1 sector of the hippocampus and in the dorsolateral striatum produced by 4VO was significantly attenuated by dextromethorphan. The present results demonstrate that protective effects on neuronal damage may be related to an attenuation of deficits in spatial leaning and memory following global ischemia.

Animals↗