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At least 793 records · Page 44Linked to original sources
PubMed1995

Long-term potentiation and glutamate release in the dentate gyrus: links to spatial learning.

Long-term potentiation (LTP) in the dentate gyrus of the anaesthetized rat is associated with a persistent increase in the concentration of glutamate in the extracellular compartment. At the in vitro level, this is mirrored by an increase in the ability of slices or synaptosomes from potentiated tissue to release glutamate in response to a depolarizing stimulus. In both cases, the activity-induced enhancement of glutamate release is dependent on the activation of the NMDA receptor. A similar increase in glutamate release in vitro is observed in the dentate gyrus prepared from rats trained in a variety of learning tasks, including classical conditioning and the Morris water maze. These results are consistent with the hypothesis that similar presynaptic mechanisms are engaged in LTP and learning.

Animals↗
PubMed1996

Deficits of spatial learning and working memory in spontaneously hypertensive rats.

It is possible that behavioral dysfunction, including cognitive, perceptual and psychomotor impairments in hypertensive subjects, can be the result of the high blood pressure. The aim of this study was to evaluate the performance of the spontaneously hypertensive rats (SHR) in the acquisition and execution of tasks in an 8-arm radial maze. Male Wistar normotensive rats (CON, n = 11) and SHR (n = 12), 3 months old, were first submitted to a series of training sessions to enter each of the 8 arms once in a given session (task acquisition), and errors (revisiting an arm in the same session) were computed. Errors before and after two delay intervals (5 s and 1 h, introduced between the fourth and fifth arm choice) were measured. These delayed tests allowed us to evaluate the working memory in different terms. It was observed that the SHR group made slightly more errors during the acquisition sessions and in the execution of the post-delay of 5-s interval tests, and significantly in the execution of the post-delay of 1-h interval tests compared to the CON. These results show that the SHR has a deficiency in the performance of the radial maze, suggestive of impairment of learning and working memory, mainly for a long-term memory, corroborating the hypothesis about the possible behavioral consequences of hypertension.

Animals↗
PubMedDate not supplied

Spatial learning and memory in the radial maze: a longitudinal study in rats from 4 to 25 months of age.

This longitudinal study was designed to investigate whether previous experience may influence performances and strategies of rats tested in the radial maze without external cues when aged 4, 13, and 25 months. Their performances and strategies were compared with those of another group of rats tested only when aged 25 months. Expert old animals showed a good retention of previous experiences, whereas age-matched nonexpert animals exhibited some acquisition deficits. On the contrary, in the course of aging, the animals kept modifying their strategies independently of experience. In summary, we can conclude that previous experience is likely to influence performances of the aged rat but not the strategies adopted which are strictly age-dependent and independent of acquired experience.

Aging↗
PubMed1992

D-cycloserine, a modulator of the N-methyl-D-aspartate receptor, improves spatial learning in rats treated with muscarinic antagonist.

The results of the present study indicate that D-cycloserine, a partial agonist at the glycine binding site, which is a positive modulation site of the N-methyl-D-aspartate receptor, could improve dose dependently the acquisition of a water maze task in rats treated with scopolamine, a muscarinic antagonist. The low to moderate doses of D-cycloserine which improved learning did not affect swimming speed in scopolamine-treated rats. The higher dose did not improve learning, but it increased swimming speed in scopolamine-treated rats. These results show a dissociation between impaired acquisition and abnormal behavioral activity in scopolamine-treated rats in the water maze task. Furthermore, the present results suggest that D-cycloserine can act as a cognitive enhancer at the appropriate doses.

Amnesia↗
PubMed2006

Cerebral glucose transporters expression and spatial learning in the K-ATP Kir6.2(-/-) knockout mice.

K-ATP channels formed of the Sur and Kir subunits are widely distributed in the brain. Sur1-Kir6.2 is the most common combination of K-ATP channel subunits in the brain and Kir6.2 plays an important role in glucose metabolism through pancreatic insulin secretion or hypothalamic glucose sensing. K-ATP channels have also been reported to play a role in memory processing. Therefore, the aim of the present experiment is to assess the gene and protein expression of GLUT1, GLUT3 and GLUT4 in various brain regions of Kir6.2(-/-) K-ATP knockout mice and to test their working memory performance. GLUT4 was measured using two antibodies, one recognizing an intracellular epitope and the other, an extracellular epitope. Relative to their corresponding wild type, semi-quantitative immunohistochemistry showed that GLUT4 protein expression as measured by a GLUT4 antibody recognizing an extracellular epitope was increased in the Kir6.2(-/-) K-ATP mice. However, there was only a small increase in GLUT4 labeling using the GLUT4 antibody recognizing the intracellular epitope. These results suggest a compensatory higher GLUT4 inclusion at the cellular neuronal membrane in the cerebral cortex, hippocampus and cerebellum of the Kir6.2(-/-) K-ATP knockout mice. However, there was no change in GLUT4 gene expression assessed by TaqMan PCR except for a decrease in the cerebellum of these mice. Working memory performance of the Kir6.2(-/-) K-ATP mice was disrupted at age of 12 weeks but not at 5 weeks. The mild glucose intolerance that is observed in the Kir6.2 knockout mice is unlikely to have created the memory deficits observed. Rather, in light of the effects of K-ATP channel modulators on memory, the memory deficits in the Kir6.2(-/-) K-ATP mice are more likely due to the absence of the Kir6.2 and possible disruption of the GLUT4 activity in the brain.

Age Factors↗
PubMed2006

Behavioral inhibition and impaired spatial learning and memory in hypothyroid mice lacking thyroid hormone receptor alpha.

Thyroid hormone insufficiency leads to impaired neurogenesis, behavioral alterations and cognitive deficits. Thyroid hormone receptors, expressed in brain regions involved in these behaviors, mediate the effects of thyroid hormone deficiency or excess. To determine the contribution of thyroid hormone receptor alpha (TRalpha) in these behaviors, we examined the behavior of euthyroid as well as hypo- and hyperthyroid mice lacking all isoforms of the TRalpha (TRalpha(o/o)). The hypothyroxinemic TRalpha(o/o) mice demonstrated behavioral inhibition, manifested in decreased activity and increased anxiety/fear in the open field test (OFT) and increased immobility in the forced swim test (FST) compared to C57BL/6J mice. TRalpha(o/o) mice also showed learning and recall impairments in the Morris water maze (MWM), which were exaggerated by hypothyroidism in TRalpha(o/o) mice. These impairments were concurrent with increased thigmotaxis, suggesting an increased anxiety-like state of the TRalpha(o/o) mice in the MWM. Expression of genes, known to be involved in processes modulating learning and memory, such as glucocorticoid receptor (GR), growth-associated protein 43 (GAP-43) and neurogranin (RC3), were significantly decreased in the hippocampus of TRalpha(o/o) mice. GR expression was also decreased in the frontal cortex and amygdala of TRalpha(o/o) mice, indicating that expression of GR is regulated, probably developmentally, by one or more isoforms of TRalpha in the mouse brain. Taken together these data demonstrate behavioral alterations in the TRalpha(o/o) mice, indicating the functional role of TRalpha, and a delicate interaction between TRalpha and TRbeta-regulated genes in these behaviors. Thyroid hormone-regulated genes potentially responsible for the learning deficit found in TRalpha(o/o) mice include GR, RC3 and GAP-43.

Analysis of Variance↗
PubMed2004

Spatial learning and exploration of environmental stimuli in 24-month-old female APP23 transgenic mice with the Swedish mutation.

Transgenic mice overexpressing the betaAPP gene with the Swedish mutation under the control of the murine thy1 promoter show Alzheimer-like characteristics such as Abeta plaques in cerebral cortex and vessel walls. By comparison to age-matched non-transgenic controls, 2-year-old female APP23 transgenic mice crossed more segments in the open-field and had a higher number of fast ambulatory and stereotyped movements in a photocell activity chamber. In addition, APP23 mice entered more often and spent more time in the open arms of the elevated plus-maze. The acquisition of place learning in the Morris water maze was impaired in APP23 transgenic mice, but not in probe and visible platform subtasks. These results indicate that hyperactivity and impaired learning abilities characterize this mouse model of Alzheimer's disease and cerebral angiopathy.

Age Factors↗
PubMed2005

Long-term homocysteine exposure induces alterations in spatial learning, hippocampal signalling and synaptic plasticity.

Abnormally high levels of homocysteine (HCY) have been linked to neurodegenerative diseases, but it remains unclear whether this is the cause or effect of degenerative processes. Here, we investigated the effects of prolonged HCY exposure on cognitive abilities and physiological parameters by injecting rats daily with either 20 or 200 mg/kg HCY over a period of up to 14 weeks. Notwithstanding a significant weight reduction in the 200 mg HCY group, HCY-exposed animals did not show a behavioural deficit when tested repeatedly (in weeks 1, 3, 5, 7 and 13) in a reference memory version of the water maze. Unexpectedly, some improvement in repeated reversal learning was observed in HCY exposed animals compared to controls. Pre-treatment with HCY for 3 weeks before water maze training did not uncover any cognitive alterations. Increased plasma concentrations of HCY were revealed only for the 200 mg HCY group after 14 weeks of injections, but no evidence for DNA damage was obtained. Immunocytochemically, HCY was detected in the brain after 14 weeks of treatment (both 20 and 200 mg/kg), but not after 5 weeks. Bidirectional changes in basic synaptic transmission and long-term potentiation of hippocampal CA1 pyramidal cells were observed at 5, 7 and 14 weeks in both HCY groups, indicative of complex, multifactorial time- and concentration-dependent changes. Overall, it is concluded that healthy adult rats are able to cope with continuous exposure to HCY. While HCY affects growth and neuronal excitability, this does not precipitate into an immediate impairment of cognitive function.

Animals↗
PubMed2004

Nitric oxide synthase and intermittent hypoxia-induced spatial learning deficits in the rat.

Intermittent hypoxia (IH) during sleep induces significant neurobehavioral deficits in the rat. Since nitric oxide (NO) has been implicated in ischemia-reperfusion-related pathophysiological consequences, the temporal effects of IH (alternating 21% and 10% O(2) every 90 s) and sustained hypoxia (SH; 10% O(2)) during sleep for up to 14 days on the induction of nitric oxide synthase (NOS) isoforms in the brain were examined in the cortex of Sprague-Dawley rats. No significant changes of endothelial NOS (eNOS) and neuronal NOS (nNOS) occurred over time with either IH or SH. Similarly, inducible NOS (iNOS) was not affected by SH. However, increased expression and activity of iNOS were observed on days 1 and 3 of IH (P < 0.01 vs. control; n = 12/group) and were followed by a return to basal levels on days 7 and 14. Furthermore, IH-mediated neurobehavioral deficits in the water maze were significantly attenuated in iNOS knockout mice. We conclude that IH is associated with a time-dependent induction of iNOS and that the increased expression of iNOS may play a critical role in the early pathophysiological events leading to IH-mediated neurobehavioral deficits.

Animals↗
PubMed2006

Intact spatial learning in adult Tg2576 mice.

Tg2576 mice, a transgenic model of amyloid pathology associated with Alzheimer's disease (AD), develop measurable levels of soluble amyloid beta1-40 and 1-42 by 6 months of age and amyloid plaque deposition in cortex, hippocampus and amygdala by 10 months of age. To investigate whether non-hippocampal learning strategies would predominate coincident with the age-related increase in Abeta load in the hippocampal region, we measured learning strategies in the T-maze and a redundant cued version of the water maze. Each of these tasks can be solved using either hippocampal or non-hippocampal learning strategies and has proved sensitive to hippocampal disruption in other settings. The results revealed subtle differences in T-maze and water maze performance in Tg2576 mice compared to controls. Surprisingly, however, Tg2576 mice were not impaired relative to non-transgenic littermates on any measures of hippocampal dependent behavior assessed in these tasks. These data suggest that the medial temporal lobe retains considerable function in 15-month-old Tg2576 mice despite significant Abeta pathology.

Amyloid beta-Peptides↗
PubMed2004

Spermidine/spermine N1-acetyltransferase overexpression in mice induces hypoactivity and spatial learning impairment.

The present work addresses the role of polyamines in learning and general behavior by subjecting transgenic mice overexpressing polyamine catabolic enzyme, spermidine/spermine N(1)-acetyltransferase (SSAT) and their syngenic littermates to neurobehavioral profiling assessment (SHIRPA) and to radial eight-arm maze. The general health and physiological conditions as well as the entire behavioral battery comprising of 34 parameters were recorded. The eight-arm radial maze (8-RAM) task included an initial acquisition task for 9 days followed by a 2-day retention test after a 2-week break. In addition, blood samples were taken for hormone analysis. Transgenic mice, which showed reduced motor activity, aggression and muscle tone, spent more time in the radial maze during initial acquisition and retention tasks as compared with syngenic mice. Moreover, the learning performance of transgenic females was significantly inferior to syngenic females. Interestingly, the levels of several hormones were significantly altered in SSAT transgenic mice; circulating adrenocorticotropic hormone (ACTH) and corticosterone levels were markedly increased while testosterone and thyroidal hormone levels were decreased. These changes may be related to the dramatic increase in brain putrescine levels in SSAT-overexpressing (SSAT-OE) mice, but it is likewise possible that the behavioral changes and learning impairment are attributable to more peripheral mechanisms (such as alterations in steroid hormone metabolism), which in turn, could be a consequence of the disturbed polyamine homeostasis.

Acetyltransferases↗
PubMed2000

Effects of subdural haematoma on sensorimotor functioning and spatial learning in rats.

Twenty per cent of all strokes are haemorrhagic in character and are associated with severe disturbances in sensorimotor behaviour and cognition. Although spontaneous recovery of pre-stroke functioning occurs in some cases, the process is demanding, slow, and often incomplete. A first step in the preclinical testing of new putative, neuroprotective and recovery-supporting therapeutics is to validate animal models of brain injury. In a series of four experiments we evaluated the behavioural impairments and the time course of recovery of functional deficits in rats with an experimentally induced subdural haematoma. We found that unilateral subdural haematoma resulted in dysfunction in both simple reflexive (experiment 1) and skilled sensorimotor behaviour (experiment 2). Reflexive behaviour did not recover, or recovered only marginally, and neither did the deficits in skilled forepaw use. Bilateral subdural haematoma impaired the learning and memory performance of adult (experiment 3) and old rats (experiment 4) in the Morris water escape task. Considering the diversity of the deficits found in our experiments, we conclude that different models are needed to cover the broad range of deficits seen in stroke patients.

Age Factors↗
PubMed2000

Chlordiazepoxide-induced spatial learning deficits: dose-dependent differences following prenatal malnutrition.

The sensitivity of prenatally protein-malnourished rats to the amnestic properties of the benzodiazepine (BZ) receptor agonist, chlordiazepoxide (CDP), was studied in the male offspring of rats provided with a protein-deficient diet (6% casein) for 5 weeks prior to mating and throughout pregnancy. Rats were tested during acquisition of the submerged platform version of the Morris water maze task using three systemic doses of CDP (3.2, 5.6, and 7.5 mg/kg i.p.) at two ages (day 30 and day 90). At 30 days, prenatally malnourished rats showed less sensitivity to the amnestic effect of the 5.6-mg/kg dose when compared with well-nourished controls by displaying shorter swim paths during acquisition and a more selective search of the target quadrant upon removal of the platform (probe trial). At 90 days, prenatally malnourished rats again showed less sensitivity to CDP at a dose of 5.6 mg/kg, but more sensitivity to the 3.2-mg/kg dose (indicated on the probe trial). No obvious relationship was identified between the nutritional group differences in behavioral sensitivity to CDP at 90 days and their BZ receptor density in the hippocampus or medial septum. It can be concluded that prenatal malnutrition alters the amnestic response to CDP in a dose-dependent and developmentally specific manner, thus providing further support for functional changes within the GABAergic system subsequent to malnutrition.

Animals↗
PubMed2001

Molecular changes in glutamatergic synapses induced by Pb2+: association with deficits of LTP and spatial learning.

What are the molecular bases for the neurotoxicity that occurs after developmental exposure to low levels of Pb2+, and are these effects persistent and detrimental in adults? Our inability to understand specific mechanisms behind Pb2+ neurotoxicity has long been one of many problem areas of this preventable childhood disease. The sensitivity of the developing brain to Pb2+-induced neurotoxicity is an outcome of the many unique characteristics that comprise the developing central nervous system. The developing brain can be exposed to significant concentrations of Pb2+ during vulnerable periods of development such as synapse formation, gene and protein expression, and other diverse molecular changes associated with these processes. Recently, changes in NMDA receptor subunits were identified in animals that showed cognitive deficits induced by exposure to Pb2+. This molecular association is important because it provides new evidence in the characterization of developmental Pb2+ neurotoxicity that supports physiological findings of impairments in synaptic plasticity and behavior. This review updates information from molecular studies that can be directly associated with impairments of behavior and synaptic plasticity, and outlines the functional consequences of molecular differences in Pb2+-exposed animals that illuminate potential mechanisms of Pb2+-induced neurotoxicity.

Animals↗
PubMed1989

Microinjections of leupeptin in the frontal cortex or dorsal hippocampus block spatial learning in the rat.

Adult male Long-Evans hooded rats were given bilateral microinjections of 18 mM leupeptin or saline through cannulae implanted with tips aimed at the frontal cortex or CA1 or CA3 hippocampal cell fields. Five minutes following injections animals were allowed to complete an eight-arm radial maze. The acquisition criterion required that the animal make 7 correct choices of the first 8, and 8 correct choices of the first 10, for five consecutive sessions. Leupeptin slowed acquisition of the eight-arm radial maze task when injected into the CA1 and CA3 hippocampal fields or the frontal cortex, but did not influence spontaneous activity. These results suggest that earlier reports of the amnestic effect of leupeptin when administered into the lateral cerebral ventricle may have been due to effects within the cortex and hippocampus. The present experiment represents the first attempt to identify behaviorally those brain areas in which leupeptin acts to alter learning.

Animals↗