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PubMed2001

The effects of lesions to the rat hippocampus or rhinal cortex on olfactory and spatial memory: retrograde and anterograde findings.

The role of the hippocampal system in retrograde and anterograde amnesia was investigated by using a novel olfactory-guided paradigm and a traditional test of spatial learning. In the retrograde study, rats were trained on a sequence of two-choice olfactory discriminations in the weeks prior to receiving neurotoxic lesions of the hippocampus or aspiration lesions of the perirhinal-entorhinal cortex. Memory tests for preoperatively learned discriminations revealed no statistical impairment for subjects with damage to the hippocampus on a problem learned remote in time from surgery (i.e., 4 weeks +) or on the two recently learned discriminations (i.e., 1-3 weeks prior to surgery). The performance of subjects with perirhinal-entorhinal damage provided an important comparison for subjects with specific hippocampal lesions. Despite showing intact memory for the remotely learned problem, perirhinal-entorhinal damage resulted in numerically (although not significantly) weaker performance on postoperative tests of retention for the discriminations learned in the 3 weeks prior to surgery. In the anterograde portion of the study, long-term memory for newly acquired discriminations was spared in subjects with damage to the hippocampus, whereas subjects in the perirhinal-entorhinal lesion group again showed the weakest memory performance on these tests of 5-day retention. Postoperative water maze learning was uniformly impaired in subjects with damage to the hippocampus and perirhinal-entorhinal cortex, thus confirming the effect of these lesions and supporting the involvement of these brain areas in spatial processes. These findings further dissociate the specific involvement of the hippocampus in tasks of a spatial-relational nature versus nonrelational tasks, such as discrimination learning and recognition memory (e.g., Duva et al., 1997; Eichenbaum, 1997; Eichenbaum, Schoenbaum, Young, & Bunsey, 1996). Moreover, the results suggest that damage to the hippocampus itself does not contribute to retrograde or anterograde memory impairments for all types of information, whereas the data suggest a more important role for the perirhinal-entorhinal cortex in recognition memory, irrespective of modality.

Animals↗
PubMed2003

Partial reversal of the effect of maternal care on cognitive function through environmental enrichment.

Maternal care influences hippocampal development in the rat. The offspring of mothers that exhibit increased levels of pup licking/grooming and arched-back nursing (High LG-ABN mothers) show increased hippocampal N-methyl-D-aspartate (NMDA) receptor binding and enhanced hippocampal-dependent spatial learning. In these studies we examined whether environmental enrichment from days 22-70 of life might reverse the effects of low maternal care. Environmental enrichment eliminated the differences between the offspring of High and Low LG-ABN mothers in both Morris water maze learning and object recognition. However, enrichment did not reverse the effect of maternal care on long-term potentiation in the dentate gyrus or on hippocampal NMDA receptor binding. In contrast, peripubertal enrichment did reverse the effects of maternal care on hippocampal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor binding. These findings provide evidence for the reversal of the effects of reduced maternal investment in early life on cognitive function in adulthood. Such effects might involve compensatory changes associated with peripubertal enrichment.

Animals↗
PubMed2002

Effects of raw garlic on physical performance and learning behaviour in rats.

The effects of garlic (Allium sativum Linn.) on physical performance and learning behaviour were evaluated in male rats (7-8 months old, weighing 250-400 g) by comparison with the effects of pentoxifylline, a haemorheological agent with antiplatelet activity. The tests were designated as experiment A and experiment B, both conducted in two consecutive 4-week sessions. In experiment A, the rats performed in a learning maze model during the first 4 weeks then followed by moving along the rope model for another 4 weeks. In experiment B, the rats were first tested in a rotarod treadmill for 4 weeks and then a step down test model for another 4 weeks. Each experiment consisted of four groups with 6-8 rats per group. Aqueous garlic homogenate at doses of 1 and 2 g (of raw garlic)/kg/day were given orally to group 1 and group 2, respectively, while pentoxifylline dispersion at a dose of 200 mg/kg/day was given to group 3. Group 4 served as the control group and was given water. All tests (maze model, rope model, rotarod model and step down model) were performed three times a week. The number of successful tasks and the acquisition time in 1 week intervals were used for the statistical analysis. The present results demonstrated that neither aqueous garlic homogenate at both doses nor pentoxifylline exhibited any benefit in the maze model or the rotarod model. Garlic only at the lower dose and pentoxifylline however, showed benefit in the rope model and step down model. These findings may provide some evidence to support the beneficial effect of long-term garlic consumption on physical performance and learning behaviour in normal subjects.

Animals↗
PubMed2005

Insulin receptor signaling in long-term memory consolidation following spatial learning.

Evidence has shown that the insulin and insulin receptor (IR) play a role in cognitive function. However, the detailed mechanisms underlying insulin's action on learning and memory are not yet understood. Here we investigated changes in long-term memory-associated expression of the IR and downstream molecules in the rat hippocampus. After long-term memory consolidation following a water maze learning experience, gene expression of IR showed an up-regulation in the CA1, but a down-regulation in the CA3 region. These were correlated with a significant reduction in hippocampal IR protein levels. Learning-specific increases in levels of downstream molecules such as IRS-1 and Akt were detected in the synaptic membrane accompanied by decreases in Akt phosphorylation. Translocation of Shc protein to the synaptic membrane and activation of Erk1/2 were also observed after long-term memory formation. Despite the clear memory-correlated alterations in IR signaling pathways, insulin deficits in experimental diabetes mellitus (DM) rats induced by intraperitoneal injections of streptozotocin resulted in only minor memory impairments. This may be due to higher glucose levels in the DM brain, and to compensatory mechanisms from other signaling pathways such as the insulin-like growth factor-1 receptor (IGF-1R) system. Our results suggest that insulin/IR signaling plays a modulatory role in learning and memory processing, which may be compensated for by alternative pathways in the brain when an insulin deficit occurs.

Animals↗
PubMed2001

Mild prenatal stress enhances learning performance in the non-adopted rat offspring.

The present study was designed to investigate whether mild stress during pregnancy affects offspring behaviors, including learning performance. Prenatal stress was induced by short-lasting, mild restraint stress, which had previously been shown to facilitate the morphological development of fetal brain neurons. Adult offspring whose dams had been restrained in a small cage for 30min daily from gestation day 15 to 17 showed enhanced active avoidance and radial maze learning performance. In addition, the prenatally stressed rats showed weaker emotional responses than unstressed control, as indicated by decreases both in ambulation upon initial exposure to an open field and in Fos expression in the amygdala induced by physical stress. The observed effects of prenatal stress on learning performance and emotional behavior were attenuated by foster rearing by unstressed dams. Fos expression in the hypothalamic paraventricular nucleus following physical stress and corticosterone secretion during physical and psychological stress did not differ between the prenatally stressed and unstressed control rats. From these results we suggest that mild prenatal stress facilitates learning performance in the adult offspring. The enhancement of learning performance appears to be accompanied by reduced emotionality, but not by any apparent alterations in hypothalamic-pituitary-adrenal responses. In addition, the observation of differential behaviors in the adopted and non-adopted animals supports the notion that the postnatal environment modifies the behavioral effects of prenatal stress.

Amygdala↗
PubMed2002

Differential effect of corticosterone on spatial learning abilities in apolipoprotein E knockout and C57BL/6J mice.

Previously, we found that repeated exposure to predator stress corrected the deficit in spatial learning of apolipoprotein E-knockout (apoE0/0) mice, but impaired cognitive performance of wild-type mice. Here we show that elevated corticosterone concentrations, accomplished by subcutaneously implanted pellets, results in similar genotype-related effects on water maze learning: while apoE0/0 mice improved their spatial learning abilities, wild-type mice (C57/Bl6J) became impaired. These results suggest that corticosterone mediates the lasting effects of environmental challenges on apoE-genotype related cognitive performance.

Animals↗
PubMedDate not supplied

Differential effects of nucleus basalis lesions in young adult and aging rats.

To characterize age-related changes in frontal cortical plasticity, we assessed maze learning and frontal cortical pharmacology in young adult, middle-aged, and aged rats. Rats received either ibotenic acid or sham lesions of the nucleus basalis magnocellularis (NBM) and were then trained on a radial maze task. After training, we assessed [3H]desmethylimipramine (DMI), [3H]muscimol, [3H]AMPA, and [3H]QNB binding using quantitative autoradiography. Both middle-aged and aged rats were impaired on the radial maze task. DMI binding was increased in both middle-aged and aged rats, while QNB binding was decreased in aged rats. While lesions impaired maze performance at all ages, middle-aged and aged rats showed more profound lesion-induced deficits. Lesions increased GABA, and AMPA receptor binding in young adult rats only. These lesion-induced changes may reflect a compensatory response that is lost with advancing age.

Aging↗
PubMed1995

Prostacyclin analogue TTC-909 reduces memory impairment in rats with cerebral embolism.

The effects of the stable prostacyclin analogue TTC-909 on memory impairment in the water maze task and on neuronal damage were studied in rats with cerebral embolism induced by injecting polyvinyl acetate (PVA) into the right internal carotid artery and the ensuing embolism extending out into the right middle cerebral artery. Areas supplied by the lenticulostriate artery were most markedly damaged. In the water maze test, the PVA-embolized rats took longer to reach the platform than did the nontreated control rats. To some extent, repeated administrations of TTC-909 (200 ng/kg, IV) overcame this impairment in water maze learning in the rats. We assume that the vasodilating effects of TTC-909 maintain this blood supply to the ischemic area and that TTC-909 prevents the development of thrombosis around the PVA particles in the arterial capillaries, as a result of antiplatelet aggregative effects. These two mechanisms are likely to be involved in memory improvement. TTC-909 may prove effective for treating subjects with stroke and other cerebrovascular disorders.

Animals↗
PubMed2005

Behavioural phenotypes of hypomorphic KCC2-deficient mice.

Hyperpolarizing fast inhibitory neurotransmission by gamma-aminobutyric acid and glycine requires an efficient chloride extrusion mechanism in postsynaptic neurons. A major effector of this task in adult animals is the potassium-chloride co-transporter KCC2 that is selectively and abundantly expressed postsynaptically in most CNS neurons. Yet, the role of KCC2 in adult brain at the systems level is poorly known. Here, we characterize the behaviour of mice doubly heterozygous for KCC2 null and hypomorphic alleles that retain 15-20% of normal KCC2 protein levels in the brain. These hypomorphic KCC2-deficient mice were viable and fertile but weighed 15-20% less than wild-type littermates at 2 weeks old and thereafter. The mice displayed increased anxiety-like behaviour in several tests including elevated plus-maze and were more susceptible to pentylenetetrazole-induced seizures. Moreover, the mice were impaired in water maze learning and showed reduced sensitivity to tactile and noxious thermal stimuli in von Frey hairs, hot plate and tail flick tests. In contrast, the mice showed normal spontaneous locomotor activity in open field and Y-maze tests, and intact motor coordination in rotarod and beam tests. The results suggest that requirements for KCC2-dependent fast hyperpolarizing inhibition may differ among various functional systems of the CNS. As shunting inhibition is expected to be intact in KCC2-deficient neurons, these mice may provide a useful tool to study the specific functions and relative importance of hyperpolarizing fast synaptic inhibition in adult CNS that may have implications for human neuropsychiatric disorders, such as epilepsy, pain and anxiety.

Analysis of Variance↗
PubMed1996

Long-term impoverished housing effects on Morris maze performance after a fimbria lesion.

Male Wistar rats received bilateral Fimbria lesions and were postoperatively housed in either standard social conditions or in impoverished conditions (one rat per cage) for 2 weeks in experiment I, and for 7 months in experiment II. The effects of lesion and housing conditions were investigated in the Morris maze spatial orientation task. Fimbria lesions increased the latency to reach the platform during acquisition in both experiments, which indicates that functional recovery of the Morris maze impairment does not occur in 7 months time. Post-operative impoverishment for 2 weeks or for 7 months reduced the lesion induced deficit in Morris maze acquisition, while it had a more general effect in the trial without platform. Interestingly, the impoverishment effects were not more severe after 7 months, but even less easily detected. These findings are interpreted as if impoverishment effects the reactiveness of animals to external stimuli, which may help the animal to compensate for the lesion-induced-deficit in Morris maze learning.

Animals↗
PubMed2004

A synthetic neural cell adhesion molecule mimetic peptide promotes synaptogenesis, enhances presynaptic function, and facilitates memory consolidation.

The neural cell adhesion molecule (NCAM) plays a critical role in development and plasticity of the nervous system and is involved in the mechanisms of learning and memory. Here, we show that intracerebroventricular administration of the FG loop (FGL), a synthetic 15 amino acid peptide corresponding to the binding site of NCAM for the fibroblast growth factor receptor 1 (FGFR1), immediately after training rats in fear conditioning or water maze learning, induced a long-lasting improvement of memory. In primary cultures of hippocampal neurons, FGL enhanced the presynaptic function through activation of FGFR1 and promoted synapse formation. These results provide the first evidence for a memory-facilitating effect resulting from a treatment that mimics NCAM function. They suggest that increased efficacy of synaptic transmission and formation of new synapses probably mediate the cognition-enhancing properties displayed by the peptide.

Amino Acid Sequence↗
PubMed2003

Intact spatial memory in mice with seizure-induced partial loss of hippocampal pyramidal neurons.

We generated defined neuronal loss in hippocampus of genetically identical mice by pilocarpine injections and studied the impact of these seizures on the performance of mice in spatial learning and memory. The numbers of TUNEL-positive degenerating cells paralleled the severity of the seizures. When compared to the numbers found for not-seizured control mice, mild, moderate, and severe seizures produced significant increases in TUNEL-positive neurons in CA1 and CA3 regions by 19, 25, and 63%, respectively. Water maze learning was abolished after the severe seizures. However, spatial learning was normal after mild or moderate seizures. Therefore, there was no linear correlation between the impairment of learning and memory performance with the number of degenerating neurons in hippocampus. Our data suggest that normal spatial learning and memory can be achieved without the full number of hippocampal pyramidal neurons in partially lesioned hippocampus.

Animals↗
PubMedDate not supplied

Beneficial effects of the sigma1 receptor agonists igmesine and dehydroepiandrosterone against learning impairments in rats prenatally exposed to cocaine.

In utero cocaine (IUC) exposure results in offspring rats in complex neurochemical and behavioral alterations, particularly affecting learning and memory processes. We examined here the impact of IUC exposure on memory functions in male and female offspring rats and report that selective sigma(1) (sigma(1)) receptor agonists are effective in reversing the deficits. Dams received a daily cocaine, 20 mg/kg ip, injection between gestational days E17 to E20. Learning was examined in offspring between day P30 and P41 using delayed alternation in the T-maze, water-maze learning and passive avoidance. Both male and female rats prenatally exposed to cocaine showed delayed alternation deficits and impairments of acquisition of a fixed platform position in the water maze, as shown by higher acquisition latencies and diminutions of time spent in the training quadrant during the probe test. The acquisition of a daily changing platform position also demonstrated impaired working memory. Finally, passive avoidance deficits were observed. Pretreatment with the synthetic sigma(1) agonist igmesine (0.1-1 mg/kg ip) or the neuroactive steroid dehydroepiandrosterone (DHEA 10-40 mg/kg ip) reversed the prenatal cocaine-induced learning deficits in offspring rats for each test. The sigma(1) antagonist BD1063 (1 mg/kg ip) failed to affect performances alone but blocked the igmesine and DHEA effects, confirming the involvement of the sigma(1) receptor. IUC exposure thus results in marked memory deficits, affecting spatial and nonspatial short- and long-term memories in juvenile male and female offspring rats. The activation of the sigma(1) neuromodulatory receptor allows a complete behavioral recovery of the memory functions in prenatally cocaine-exposed rats.

Animals↗
PubMed2005

Complex magnetic fields enable static magnetic field cue use for rats in radial maze tasks.

Male Wistar rats were trained in an eight-arm radial maze task (two sessions per day, delayed-non-matching-to-sample) that included an intramaze static magnetic field "cue" (185 microT) specific to the entrance point of one of the arms. Rats were exposed daily for 60 min to a complex magnetic field waveform (theta-burst pattern, 200-500 nT), presented with several different interstimulus intervals (ISIs), either immediately following training sessions or immediately preceding testing sessions. Application of the theta-burst stimulus with a 4000 ms ISI significantly improved the rats' memory for the arm of the radial maze whose position was indicated by the presence of a static magnetic field cue. Reference memory errors were homogeneously distributed among all eight arms of the maze for sham-exposed rats, and among the other seven arms of the maze for complex magnetic field-treated rats. These results suggest that static magnetic field cues may be salient orienting cues even in a microenvironment such as a radial maze, but their use as a cue during maze learning in rats is dependent on whole-body application of a specific time-varying complex magnetic field.

Animals↗
PubMed2004

Differential enantioselective effects of pentyl-4-yn-valproate on spatial learning in the rat, and neurite outgrowth and cyclin D3 expression in vitro.

Previously, we demonstrated the racemic form of the valproate (VPA) analogue, 2-n-pentyl-4-pentynoic acid ([+/-]pentyl-4-yn-VPA), to be neuritogenic in vitro and to enhance cognition in vivo. To determine the enantioselectivity of these effects, the racemate and purified enantiomers of [+/-]pentyl-4-yn-VPA (84 mg/kg, i.p.) were administered to rodents 20 min prior to multi-session water maze training. The racemate and R-enantiomer significantly reduced escape latencies during water maze learning and enhanced its recall in a probe trial 3 days later. In contrast, S-pentyl-4-yn-VPA did not influence these behavioural parameters. The enantiomer-specific effects of [+/-]pentyl-4-yn-VPA were further discriminated in vitro using neuro 2A neuroblastoma and C6 glioma cell lines. In neuro 2A, the S-enantiomer induced profound neurite outgrowth at concentrations up to 0.5 mm, with the R-enantiomer and racemate being less neuritogenic. Immunoblot analysis of cyclin D3 expression in C6 glioma indicated the racemate and S-pentyl-4-yn-VPA to induce dose-dependent up-regulation of this protein, similar to that associated with G1-phase cell cycle arrest mediated by VPA, whereas R-pentyl-4-yn-VPA was without effect. These results indicate that the cognition-enhancing effects of pentyl-4-yn-VPA are due to the actions of the R-enantiomer, and that cyclin D3 up-regulation and associated anti-proliferative and pro-differentiative actions are predominantly associated with the S-enantiomer.

Animals↗
PubMed1995

NS-3(CG3703), a TRH analog, ameliorates scopolamine-induced memory disruption in rats.

The effects of a metabolically stable TRH analog, N-[[(3R, 6R)-6-methyl-5-oxo-3-thiomorpholinyl]carbonyl]-L-histidyl-L- prolinamide tetrahydrate (NS-3, CG3703) on the scopolamine-induced memory disruption in maze performance tests were investigated in rats. a) In the delayed nonmatching-to-sample (DNMS) task using a T-maze, NS-3 (0.3 mg/kg) produced a significant reversal of the marginal disruption of choice accuracy induced by scopolamine (0.3 mg/kg) at the short (5 s) and long (120, 480 s) interval delays. Physostigmine (0.5 mg/kg) produced a significant reversal only at a 5-s interval delay. b) In the eight-arm radial maze task, NS-3 (0.3 mg/kg) significantly reversed the deficit of choice accuracy induced by scopolamine (0.3 mg/kg), whereas neither TRH (3-30 mg/kg) nor physostigmine (0.1-1 mg/kg) had any effect. The consistent reversal of these maze-learning performances by NS-3, but not by TRH or physostigmine, may be due to its potent enhancement of cholinergic and noradrenergic neuronal activities.

Animals↗
PubMed1999

Role of an enriched environment on the restoration of behavioral deficits in Lurcher mutant mice.

Lurcher mutant mice, characterized by massive degeneration of the cerebellar cortex, and normal littermate controls were reared from birth either in standard conditions or in an enriched environment. The effects of this manipulation on motor functions, landmark water maze learning, exploration, and anxiety were evaluated at 3 months of age. Under standard conditions, Lurcher mutants were impaired in comparison to controls on tests of sensorimotor function and had altered exploratory tendencies. The enriched housing improved the motor coordination of Lurcher mutants and decreased the number of trials before reaching criterion in the landmark water maze. In addition to its effects in Lurcher mutants, enriched rearing also increased some behavioral abilities in normal mice. It is hypothesized that enriched housing altered brain morphology or neurochemistry in both normal and cerebellar-damaged animals.

Animals↗
PubMed1987

Cerebral activating properties of indeloxazine hydrochloride.

The cerebral-activating properties of indeloxazine hydrochloride [(+/-)-2-[(inden-7-yloxy) methyl]morpholine hydrochloride, YM-08054] were examined in comparison with those of calcium hopantenate (a cerebral metabolic enhancer), dihydroergotoxine (a cerebral vasodilator), viloxazine and amitriptyline (antidepressants). Indeloxazine enhanced the acquisition of learned behavior (passive avoidance, active avoidance and maze learning) and desynchronized the spontaneous EEG in rats. Amnesia in scopolamine-treated rats, disturbances of consciousness in concussed mice and synchronized EEG in rabbits with lesions of the internal capsule were improved by the administration of indeloxazine. Calcium hopantenate and dihydroergotoxine also showed cerebral-activating properties in the majority of behavioral and electroencephalographic paradigms; however neither improved scopolamine-induced amnesia and calcium hopantenate had no effects on learning. Neither viloxazine nor amitriptyline enhanced the acquisition of learned behavior. The results indicate that indeloxazine possesses activating effects on cerebral functions, including learning and the EEG, and that the pharmacological profile of indeloxazine is wider than those of dihydroergotoxine and calcium hopantenate in cerebral-activating activity.

Amnesia↗