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PubMed2004

Involvement of kappa-opioid receptors and sigma receptors in memory function demonstrated using an antisense strategy.

Although antinociceptive effects of U-50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide methanesulfonate and (-)-pentazocine have been reported to influence kappa-opioid receptors, the involvement of kappa-opioid receptors in learning and/or memory is still controversial. We have recently reported that the memory improving effect of (-)-pentazocine was antagonized by sigma1 receptor antagonist. In this study, we examined the effects of several antisense oligodeoxynucleotides (antisenses) to kappa1-opioid receptors and sigma1 receptor on memory and nociceptive function. Male ddY mice were treated subcutaneously (s.c.) with scopolamine (1.65 mumol/kg) and/or test drugs 30 min before a Y-maze test. U-50,488H significantly improved the scopolamine-induced impairment of spontaneous alternation behavior. Twenty micrograms of antisense targeting exons 2 and 3 of the kappa1-opioid receptor significantly reversed the effects of U-50,488H, but antisense targeting exon 1 and mismatch sense did not. The antisense targeting exon 3 was most effective. These antisenses themselves did not affect normal mice, indicating that kappa1-opioid receptors do not tonically regulate memory function. All three antisenses equally prevented U-50,488H-induced antinociceptive effects in the acetic-acid-induced writhing test. Pretreatment with antisense targeting sigma1 receptors (AS-sigma1) completely prevented the memory-improving effects of (-)- and (+)-pentazocine, although U-50,488H ameliorated the scopolamine-induced impairment of spontaneous alternation behavior in AS-sigma1-treated mice. These results suggest that kappa1-opioid receptors containing different exons have a distinct function in memory and nociceptive functions. Furthermore, kappa-opioid receptors agonist showing analgesic effects act on kappa-opioid receptors or sigma receptors and play important roles only when memory function is impaired, but the two neuronal systems regulate memory function independently.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMedDate not supplied

Motor dysfunction in a mouse model for Down syndrome.

Motor deficits are among the most frequently occurring features of Down syndrome (DS). Individuals with DS exhibit disturbances in the dynamics of movement production and postural control that are thought to have a significant impact in delaying their acquisition of motor skills. The origin of these deficits has been hypothesized to be cerebellar. The Ts65Dn mouse is the most robust and genetically sound animal model for DS currently available. Ts65Dn mice show many DS-like features, including significant learning deficits in different behavioral tasks and neurodegeneration of cholinergic neurons. In the present study, we investigate the motor function of these animals. We have analyzed hind paw print patterns during walking, running speeds, rotarod performance, grip force production, swim paths, and swimming speeds. Our results indicate that Ts65Dn mice present mild to severe dysfunction according to all of the above assessments. The most evident impairments presented by these mice were related to equilibrium and motor coordination, which agrees with reported clinical observations made on individuals with DS. Because none of these findings were readily apparent by simple inspection of these animals, these findings reiterate the need for a careful evaluation of any mutant mouse strain for which there is reason to suspect motor deficits. The identification of motor dysfunction in Ts65Dn mice may have important consequences for the interpretation of some previous assessments of learning and memory of these animals that assumed intact motor function, and further strengthens the use of this aneuploid mouse strain as a model for DS.

Animals↗
PubMed1998

Repeated blockade of mineralocorticoid receptors, but not of glucocorticoid receptors impairs food rewarded spatial learning.

Corticosteroids from the adrenal cortex influence a variety of behaviours including cognition, learning and memory. These hormones act via two intracellular receptors, the mineralo-corticoid receptor (MR) and the glucocorticoid receptor (GR). These two receptor types display a high concentration and distinct distribution in the hippocampus, a brain region which is directly involved in the regulation of spatial orientation and learning. In this study, repeated subcutaneous administration of the mineralocorticoid receptor antagonist RU28318 (1.0 mg/100 g body weight), the glucocorticoid receptor blocker RU38486 (2.5 mg/100 g body weight), or a combination of both antagonists were investigated for their effects on working--and reference memory in morning and afternoon trials during 8 subsequent days in food rewarded spatial learning in a hole board task. Each rat received one dose of either vehicle (2% ethanol in PEG 400), RU28318, RU38486 or the combination of both antagonists directly after the first trial on training days 1, 3, 5, and 7. The experiments demonstrated that repeated blockade of mineralocorticoid receptors impairs reference memory reflected in the morning--as well as in the afternoon trial, whereas blockade of glucocorticoid receptors has little effect on this type of cognitive behaviour. Furthermore, combined blockade of MRs and GRs resulted in a decrease, in both daily trials, in reference memory as well as working memory performance. These findings suggest that in this spatial learning paradigm, the impairment of working memory required blockade of both receptor types, while reference memory performance involves predominantly the mineralocorticoid receptors.

Animals↗
PubMed2003

Dynamics of population code for working memory in the prefrontal cortex.

Some neurons (delay cells) in the prefrontal cortex elevate their activities throughout the time period during which the animal is required to remember past events and prepare future behavior, suggesting that working memory is mediated by continuous neural activity. It is unknown, however, how working memory is represented within a population of prefrontal cortical neurons. We recorded from neuronal ensembles in the prefrontal cortex as rats learned a new delayed alternation task. Ensemble activities changed in parallel with behavioral learning so that they increasingly allowed correct decoding of previous and future goal choices. In well-trained rats, considerable decoding was possible based on only a few neurons and after removing continuously active delay cells. These results show that neural activity in the prefrontal cortex changes dynamically during new task learning so that working memory is robustly represented and that working memory can be mediated by sequential activation of different neural populations.

Action Potentials↗
PubMed2006

NADPH-diaphorase histochemical changes in the hippocampus, cerebellum and striatum are correlated with different modalities of exercise and watermaze performances.

Nitric oxide is involved in memory and motor learning. We investigated possible influences of exercise on spatial memory and NADPH-diaphorase (NADPH-d) histochemical activity in the hippocampus, striatum and cerebellum. Fifteen albino Swiss mice between the 22nd and 55th post-natal days were exercised in the following modalities: voluntary (V), acrobatic (A), acrobatic/voluntary (AV) and forced (F) and compared to inactive group (I). After the exercise period, all subjects were tested in the water maze for 3 days. Animal brains were processed for NADPH-d histochemistry. Densitometry of the neuropil of the hippocampus, striatum and cerebellum and morphometric analysis of NADPHd+ type I neurons of the striatum were done. Exercise groups presented higher levels of NADPH-d activity in the molecular and polymorphic layers of dentate gyrus and lacunosum molecular layer of CA1. The A group presented higher NADPH-d activity in the cerebellar granular layer than all other groups. Branching points and dendritic segment densities of NADPH-d type I neurons were higher in V, A and AV than in F and I groups. Exercise groups revealed best performances on water maze tests. Thus, different modalities of exercise increases in different proportions for the nitrergic activity in the hippocampus, striatum and cerebellum, and these changes seem to be beneficial to spatial memory.

Analysis of Variance↗
PubMed1999

Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex.

Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived neurotrophic factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived neurotrophic factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.

Age Factors↗
PubMed2005

Reproductive experience differentially affects spatial reference and working memory performance in the mother.

The transition to motherhood results in a number of hormonal, neurological, and behavioral changes necessary to ensure offspring survival. Once motherhood is established, further neurological and behavioral changes may result with additional parity and mothering. Recent research has shown that motherhood enhances both hippocampal-dependent learning and memory and oxytocin-induced long-term potentiation, suggesting that the hippocampus is affected by mothering. In turn, degree of maternal behavior, either high or low, has been shown to affect spatial learning and memory performance in adult offspring. The present experiment aimed to investigate the effect of reproductive experience (nulli-, primi-, and multiparity and mothering) and degree of maternal behavior on hippocampus-dependent learning and memory in the mother. Results show that regardless of error type, primiparous rats make fewer errors compared to nulliparous rats, while multiparous rats show a trend towards making fewer errors compared to nulliparous rats. In addition, mothers who spend less time licking and nursing offspring had fewer reference memory errors. Perhaps the enhanced learning and memory in the inexperienced, new mother allows her to effectively acquire the suite of maternal behaviors necessary to ensure offspring survival and achieve reproductive success with subsequent reproductive experience.

Animals↗
PubMed1999

Effects of diazepam or chronic alcohol treatment on spatial reversal learning in mice.

Mice submitted to chronic alcohol consumption (CAC; 11 months) or to systemic diazepam administration were trained in a spatial reversal learning task. Although CAC-treated mice were able to learn the initial acquisition at normal rates, they were impaired during the first reversal of the discrimination and subsequent reversal sessions. In contrast, diazepam administration induced no deficits for any behavioral measure. In conclusion, CAC, but not diazepam administration, induces an exaggerated sensitivity to proactive interference. The two treatments spared, however, the development of the learning set curve. These results are congruent with clinical data showing that nondeclarative or implicit forms of memory processes are spared in diazepam-treated subjects or in chronic alcoholics.

Animals↗
PubMed1995

Distinct components of spatial learning revealed by prior training and NMDA receptor blockade.

Synaptic plasticity dependent on N-methyl-D-aspartate (NMDA) receptors is thought to underlie certain types of learning and memory. In support of this, both hippocampal long-term potentiation and spatial learning in a watermaze are impaired by blocking NMDA receptors with a selective antagonist D(-)-2-amino-5-phosphonovaleric acid (AP5) or by a mutation in one of the receptor subunits. Here we report, however, that the AP5-induced learning deficit can be almost completely prevented if rats are pretrained in a different watermaze before administration of the drug. This is not because of stimulus generalization, and occurs despite learning of the second task remaining hippocampus dependent. An AP5-induced learning deficit is, however, still seen if the animals are pretrained using a non-spatial task. Thus, despite its procedural simplicity, the watermaze may involve multiple cognitive processes with distinct pharmacological properties; although required for some component of spatial learning, NMDA receptors may not be required for encoding the spatial representation of a specific environment.

2-Amino-5-phosphonovalerate↗
PubMed2004

[Effects of tonifying shen recipe on advanced glycation end products, amyloid-beta peptide in telencephalon and hippocampus of ovariectomized rats].

OBJECTIVE: To explore the effect of Tonifying Shen recipe (TSR) on advanced glycation end products (AGEPs), amyloid-beta peptide (A beta P) in telencephalon and hippocampus of ovariectomized rats. METHODS: Female SD rats, 9 months old, were randomly divided into 3 groups: the sham operation (Sh) group, the ovariectomized (OV) group and the TSR group. Medication via gastrogavage 4 weeks was given after ovariectomy consecutively for 16 weeks. Competitive ELISA and radioimmunoassay (RIA) was used to detect AGEPs and A beta P level in rats' telencephalon and hippocampus; florescent assay was used to determine the serum and urinary soluble AGE-peptide level; and also the rats' behavioral alteration and hippocampal morphological change were observed. RESULTS: Compared with those in the Sh group, the correct escape rate in the OV group was significantly lower (P < 0.05), content of A beta P in telencephalon and serum soluble AGE-peptide levels significantly higher (P < 0.05), contents of AGEPs in telencephalon and hippocampal tissue showed an increased tendency, but without significance (P > 0.05), argyrophil stain showed that nerve fiber thickened, senile plaques appeared in temporal cortex. In the TSR group after treatment, contents of AGEPs in telencephalon, A beta P in telencephalon and hippocampus significantly decreased (P < 0.05), the urinary soluble AGE-peptide level significantly increased (P < 0.05) and with markedly improvement of learning memory capability and above-mentioned pathological changes. CONCLUSION: TSR could reduce the accumulation of AGEPs in telencephalon and the contents of A beta P in telencephalon and hippocampal tissue, and improve the impaired ability of learning and memory caused by lack of estrogen. Its mechanism might be based on the elevation in excretion of AGE-peptide via kidney.

Amyloid beta-Peptides↗
PubMedDate not supplied

[Comparative characteristics of psychoemotional patterns in Albino and Wistar rats].

Analysis of psychoemotional behavioral component in Albino and Wistar rats during solving a cognitive task showed that intra-population differences were determined by the relationship between passive and active forms of unconditioned reactions. Quick-learning rats from both populations were characterized by the dominance of active forms of psychoemotional reactions over the course of training. The learning process in slow-learning rats was accompanied mainly by passive emotional manifestations, whereas active reactions dominated at the stage of habit realization. Passive forms of manifestations prevailed over active forms over the course of training in both Albino and Wistar rats which failed to solve the task. The interpopulational psychoemotional differences were quantitative and depended only on the learning styles. Wistar strain was characterized by a decreased percent of animals which were able to solve a cognitive task (40% versus 80% in Albino rats), affective flatness and decreased tolerance to information loadings.

Animals↗
PubMed2000

Inhalation of low concentrations of toluene induces persistent effects on a learning retention task, beam-walk performance, and cerebrocortical size in the rat.

The organic solvent toluene is widely used in industry. The threshold limit value for extended occupational exposure to toluene is presently set to 200 ppm in the United States. We have investigated the effect of an inhalation exposure of 80 ppm for 4 weeks (6 h/day, 5 days/week), followed by a postexposure period of at least 4 weeks, on behavior and brain features in the rat. Toluene exposure appeared to affect spatial memory, since toluene-exposed rats showed a longer time in the correct quadrant in a Morris swim maze. This effect may indicate that the exposed rats used their praxis strategy longer before they started to look for the platform elsewhere. Toluene-exposed rats showed trends for increases in both locomotion and rearing behaviors and a significantly reduced beam-walk performance. The area of the cerebral cortex, especially the parietal cortex, was decreased by 6-10% in toluene-exposed rats, as shown by magnetic resonance imaging of living rats and autoradiograms of frozen brain sections. The K(D) and B(max) values of the dopamine D(3) agonist [(3)H]PD 128907 were not affected by toluene, as measured in caudate-putamen and subcortical limbic area using biochemical receptor binding assays and in caudate-putamen and islands of Calleja using quantitative receptor autoradiography. Hence, previously demonstrated persistent effects by toluene on the binding characteristics of radioligands binding to both D(2) and D(3) receptors seem to indicate a persistent effect of toluene selectively on dopamine D(2) receptors. Taken together, the present results indicate that exposure to low concentrations of toluene leads to persistent effects on cognitive, neurological, and brain-structural properties in the rat.

Administration, Inhalation↗
PubMed2005

Non-associative learning and anxiety in rats treated with a single systemic administration of the gastrin-releasing peptide receptor antagonist RC-3095.

The gastrin-releasing peptide receptor (GRPR) has been implicated in the modulation of emotionally-motivated memory. In the present study, we investigated the role of the GRPR on non-emotional, non-associative memory, and anxiety. Adult male Wistar rats were given a systemic injection of the GRPR antagonist [D-Tpi6, Leu(13) psi(CH2NH)-Leu14] bombesin (6-14) (RC-3095) (0.2, 1.0 or 5.0mg/kg) 30 min before exposure to an open field or an elevated plus maze. Habituation to the open field was tested in a retention trial carried out 24 h after the first exposure to the open field. Rats given RC-3095 at the doses of 1.0 or 5.0mg/kg showed impaired habituation. Animals treated with 5.0mg/kg of RC-3095 spent significantly more time in the closed arms of the elevated plus maze. No effects of RC-3095 on locomotion or exploratory behavior were observed. The results implicate the GRPR in the regulation of non-emotional, non-associative memory as well as in anxiety.

Animals↗
PubMed2000

Enhanced visuospatial memory following intracerebroventricular administration of nerve growth factor.

The present work assessed the effects of intracerebroventricular injections of rh recombined human nerve growth factor (rh NGF) (5 micrograms/2.5 microl) at postnatal days 12 and 13 upon the development of spatial learning capacities. The treated rats were trained at the age of 22 days to escape onto an invisible platform at a fixed position in space in a Morris navigation task. For half of the subjects, the training position was also cued, a procedure aimed at facilitating escape and at reducing attention to the distant spatial cues. Later, at the age of 6 months, all the rats were trained in a radial-arm maze task. Treatment effects were found in both immature and adult rats. The injection of NGF improved the performance in the Morris navigation task in both training conditions. There was a significant reduction in the escape latency and an increased bias toward the training platform quadrant during probe trials. The most consistent effect was the precocious development of an adult-like spatial memory. In the radial-arm maze, the NGF-treated rats made significantly fewer reentries than vehicle rats and this effect was particularly marked in the treated female rats. Taken together, these experiments reveal that the development and the maintenance of an accurate spatial representation are tightly related to the development of brain structures facilitated by the action of NGF. Moreover, these experiments demonstrate that an acute pharmacological treatment that leads to a transient modification in the choline acetyltransferase activity can induce a behavioral change long after the treatment.

Age Factors↗
PubMed2002

Learning power of single behavioral units in acquisition of a complex spatial behavior: an observational learning study in cerebellar-lesioned rats.

By combining an observational spatial learning paradigm with a cerebellar lesion that blocks the acquisition of new spatial strategies, it is possible to separate a complex spatial behavior into its fundamental units to study which relationships among units have to be maintained so that the entire behavior might be acquired. Normal rats were first allowed to observe demonstrator rats performing single explorative behaviors (circling, extended searching, direct finding), then were hemicerebellectomized and, finally, tested in the Morris water maze. In spite of the cerebellar lesion, the observer rats displayed exploration abilities that closely matched the previously observed behaviors. These results indicate that the single facets that form the strategy repertoire can be independently acquired.

Animals↗
PubMed2005

Effects of maternal deprivation on melatonin production and cognition in adolescent male and female rats.

OBJECTIVES: It is known that maternal deprivation (MD) may alter cognitive functions such as learning and memory in adult life by effecting normal growth and development. However, the mechanisms of these cognitive alterations are unknown. The aim of this study is to investigate the effects of maternal deprivation on cognition and melatonin production in adolescent male and female rats. METHODS: The litters were separated daily from their mothers for 6 hours on postnatal days 2 to 20. The spatial memory performance was evaluated using a Morris water maze between the postnatal 26th and 32nd days. Plasma melatonin levels were determined on postnatal days 42. RESULTS: MD-rats had longer escape latencies at the second, third and fifth days of training days and spend significantly less time in probe trial, compared to control animals. MAIN FINDINGS: The repeated maternal deprivation caused low blood melatonin levels and there was a significant negative correlation between blood melatonin levels and spatial memory performance in both of male and female adolescent rats. CONCLUSION: These results suggest an association between melatonin production and neurodevelopment. Further studies are needed to determine the interaction between maternal deprivation and pineal gland maturation/function.

Animals↗
PubMed2003

Global perception in small brains: topological pattern recognition in honey bees.

A series of experiments with honey bees demonstrate that their small brains nevertheless possess the ability for topological perception. Bees rapidly learned to discriminate patterns that are topologically different, and they generalized the learned cue to other novel patterns. By contrast, discrimination of topologically equivalent patterns was learned much more slowly and not as well. Thus, although the global nature of topological properties makes their computation difficult, topology may be a fundamental component of the vocabulary by which visual systems represent and characterize objects.

Animals↗
PubMed2006

Comparison of monoamine and corticosterone levels 24 h following (+)methamphetamine, (+/-)3,4-methylenedioxymethamphetamine, cocaine, (+)fenfluramine or (+/-)methylphenidate administration in the neonatal rat.

We have previously shown that neonatal administration of (+/-)3,4-methylenedioxymethamphetamine and (+)fenfluramine produce deficits in spatial and path integration learning, whereas (+)methamphetamine causes deficits in spatial learning. Conversely, cocaine and (+/-)methylphenidate have no effect on either form of learning following neonatal administration. The purpose of the present study was to determine whether corticosterone and/or monoamine levels were changed following subcutaneous administration of 10 mg/kg (+)methamphetamine, (+/-)3,4-methylenedioxymethamphetamine, (+)fenfluramine, (+/-)methylphenidate or cocaine every 2 h (total of four injections) on postnatal day 11. Twenty-four hours after the first dose, plasma, striatum and hippocampus were collected. Corticosterone levels were increased in methamphetamine-, fenfluramine-, methylenedioxymethamphetamine- and methylphenidate-treated rats relative to levels in saline-treated rats, whereas cocaine-treated rats were unaffected. In the striatum and hippocampus, serotonin and 5-hydroxyindolacetic acid were reduced in animals treated with methylenedioxymethamphetamine or fenfluramine, compared with levels in saline controls. Dopamine levels were not changed by any of the drugs, although 3,4-dihydroxyphenylacetic acid was decreased following methylenedioxymethamphetamine or methamphetamine. Minimal effects were seen in neurotransmitter levels following injection of cocaine or methylphenidate. These data suggest that drugs that affect corticosterone and hippocampal serotonin are associated with both spatial learning and path integration deficits, and those that affect corticosterone and 3,4-dihydroxyphenylacetic acid are associated with spatial learning deficits only.

3,4-Methylenedioxyamphetamine↗