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PubMed2006

Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories.

Arc/Arg3.1 is robustly induced by plasticity-producing stimulation and specifically targeted to stimulated synaptic areas. To investigate the role of Arc/Arg3.1 in synaptic plasticity and learning and memory, we generated Arc/Arg3.1 knockout mice. These animals fail to form long-lasting memories for implicit and explicit learning tasks, despite intact short-term memory. Moreover, they exhibit a biphasic alteration of hippocampal long-term potentiation in the dentate gyrus and area CA1 with an enhanced early and absent late phase. In addition, long-term depression is significantly impaired. Together, these results demonstrate a critical role for Arc/Arg3.1 in the consolidation of enduring synaptic plasticity and memory storage.

Analysis of Variance↗
PubMed2002

Inhibition of mGluR5 blocks hippocampal LTP in vivo and spatial learning in rats.

Particular subtypes of metabotropic glutamate receptors (mGluRs) have been shown to be specifically involved in certain types of long-term synaptic plasticity and learning. We examined whether inhibition of mGluR5 by the specific noncompetitive antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) has any functional consequences on long-term potentiation in the dentate gyrus in vivo and on learning of a spatial alternation task. Intracerebroventricular application of 13.8 microg MPEP 30 min before tetanization resulted in a rapid decline of potentiation during the first 7 min and a significantly lower potentiation of the MPEP group as compared to controls. The same dose of the antagonist given 30 min before training of a Y-maze spatial alternation task caused a marked impairment of retention tested 24 h later. In contrast, MPEP had virtually no effects on retention if injected immediately after the training session. Our findings suggest an important function of mGluR5 during the initiation of synaptic plasticity and memory formation.

Animals↗
PubMed2004

SNAP-25 in hippocampal CA1 region is involved in memory consolidation.

As a synaptosomal protein, SNAP-25 plays a role in a number of neuronal functions including axonal growth, dendrite formation, fusion of synaptic vesicles with membrane and the expression of long-term potentiation (LTP) in the hippocampus. Using a learning/memory behavior screening, we identified SNAP-25 as one of the differentially expressed genes in the hippocampus upon behavioral training. The inhibition of SNAP-25 with intracerebroventricular antisense oligonucleotide caused a deficit in long- but not short-term memory for step-down inhibitory avoidance. Intra-CA1 infusion of the SNAP-25 antisense oligonucleotide impaired long-term contextual fear memory and spatial memory and interfered with the LTP of synaptic transmission in the CA1 region. The inhibitory effect on LTP was not mediated by a pre-synaptic mechanism because paired pulse facilitation of synaptic transmission was not affected after administration of the antisense oligonucleotide. Together, the results suggest that SNAP-25 in the CA1 region is involved in memory consolidation.

Animals↗
PubMed1990

Intrahippocampal cholinergic grafts in aged rats compensate impairments in a radial maze and in a place learning task.

Age-related cognitive impairments were studied in rats kept in semi-enriched conditions during their whole life, and tested during ontogeny and adult life in various classical spatial tasks. In addition, the effect of intrahippocampal grafts of fetal septal-diagonal band tissue, rich in cholinergic neurons, was studied in some of these subjects. The rats received bilateral cell suspensions when aged 23-24 months. Starting 4 weeks after grafting, they were trained during 5 weeks in an 8-arm maze made of connected plexiglass tunnels. No age-related impairment was detected during the first eight trials, when the maze shape was that of a classical radial maze in which the rats had already been trained when young. The older rats were impaired when the task was made more difficult by rendering two arms parallel to each other. They developed an important neglect of one of the parallel tunnels resulting in a high amount of errors before completion of the task. In addition, the old rats developed a systematic response pattern of visits to adjacent arms in a sequence, which was not observed in the younger subjects. None of these behaviours were observed in the old rats with a septal transplant. Sixteen weeks after grafting, another experiment was conducted in a homing hole board task. Rats were allowed to escape from a large circular arena through one hole out of many, and to reach home via a flexible tube under the table. The escape hole was at a fixed position according to distant room cues, and olfactory cues were made irrelevant by rotating the table between the trials. An additional cue was placed on the escape position. No age-related difference in escape was observed during training. During a probe trial with no hole connected and no proximal cue present, the old untreated rats were less clearly focussed on the training sector than were either the younger or the grafted old subjects. Taken together, these experiments indicate that enriched housing conditions and spatial training during adult life do not protect against all age-related deterioration in spatial ability. However, it might be that the considerable improvement observed in the grafted subjects results from an interaction between the graft treatment and the housing conditions.

Acetylcholinesterase↗
PubMed2001

Anticonvulsant action and long-term effects of gabapentin in the immature brain.

The anticonvulsant action and the long-term effects on learning, memory and behavior of the new generation antiepileptic drug gabapentin (GBP) were investigated in immature animals. Kainic acid (KA) was administered to rats on postnatal day (P) 35. Animals were treated with GBP or saline from P36 to P75 and spontaneous seizure frequency was monitored. After tapering the drug, the rats were tested in the water maze and open field test. Brains were then analyzed for histological lesions. Animals treated with GBP following KA-induced status epilepticus had a reduced incidence of spontaneous recurrent seizures, a better pathology score, and less aggressiveness compared to saline-treated controls. Effectiveness of GBP on seizure threshold was tested using flurothyl inhalation in 10 separate age groups of animals ranging from the newborn period to adulthood. Furthermore, GBP plasma concentration peaks were determined in all age groups. At all ages, GBP pre-treated animals demonstrated a higher seizure threshold. Plasma GBP concentrations did not significantly change with age. These data suggest that acute administration of a single therapeutic dose of GBP increases the seizure threshold at all ages studied, while chronic treatment following the status reduces spontaneous seizure frequency and cell damage and has no long-term adverse consequences on cognitive processes during development.

Acetates↗
PubMed2002

Seizure-induced damage in the developing human: relevance of experimental models.

A considerable amount of money and effort is spent every year investigating the effects of seizure on the developing rodent brain. A critical question is the relevance of these studies to children. The goal of this chapter is to review the relationship between seizures during early development and cognitive impairment in children and rodents. While the majority of children with epilepsy have normal cognitive development, a small group of children with frequent, recurrent seizures show progressive cognitive impairment. Likewise, in rodent models recurrent seizures during early development are associated with cognitive impairment and histological changes including mossy fiber sprouting and reduced neurogenesis. Status epilepticus is associated with a lower morbidity and mortality rate in children than in adults. Status epilepticus in rodent models is associated with less cell loss and cognitive impairment than in adults. While rodent studies can offer a great deal of insight into mechanisms of seizure-induced brain damage, they also have significant limitations. No animal models have yet been developed that mimic human epileptic syndromes, such as infantile spasms, Lennox-Gastaut syndrome, or the severe myoclonic epilepsies. In addition, rodent studies supply only crude measures of learning and memory. Disturbances of language or higher cortical functions such as visual or auditory processing cannot be tested in animal models.

Animals↗
PubMed2002

Place and matching-to-place spatial learning affected by rat inbreeding (Dark-Agouti, Fischer 344) and albinism (Wistar, Sprague-Dawley) but not domestication (wild rat vs. Long-Evans, Fischer-Norway).

Domestication has been shown to produce a shift in both morphological and behavioral characteristics of animals. While changes in body weight, brain size, reproductive rates, and temperament are well documented, the effects of domestication on learning and memory are not as clearly understood. This issue is of particular importance to the use of rodent models in learning and memory where the domestication of Rattus norvegicus for research has resulted in the availability of numerous strains. To investigate cognitive effects resulting frm domestication, we examined the spatial performance of a number of rat strains: wild, Long-Evans, Fischer-Norway, Dark-Agouti, Wistar, Fischer 344, Sprague-Dawley. The wild rats served as a baseline for comparing inbred and outbred domestic strains and pigmented and albino domestic strains. Place (a measure of nonspatial and procedural learning), matching-to-place (spatial working memory), and probe (retention) performance were measured in the Morris swimming pool task. The task is an ideal means for comparing different rat strains because place learning has not been selected for in the domestication of Rattus norvegicus and because the task is ethologically relevant. The results indicated that wild rats and Long-Evans rats did not differ on any measure, with Fischer-Norway rats being only slightly inferior. Larger impairments were found in Wistar > Fischer 344 > Dark-Agouti > Sprague-Dawley strains. Impairments were more obvious on place acquisition but also occurred in matching-to-place performance. Platform crosses, but not quadrant preference was found to be correlated with place learning. In general, although nonspatial and spatial deficits were associated with both inbreeding and albinism, impaired spatial performance is not a necessary result of domestication.

Animals↗
PubMedDate not supplied

Effects of sodium arsenite exposure on development and behavior in the rat.

Arsenic is an environmental contaminant found in soil, water and air in some zones of the world. It has been widely studied for its effects as a human carcinogenic agent, but few studies have dealt with neurobehavioral effects. In addition, studies of arsenic effects on development have only addressed its effects on embryotoxicity and teratogenicity after a single oral, gavage or intraperitoneal exposure. Among the behavioral alterations reported after intoxication with arsenic are both increased and decreased locomotor activity and learning deficits in a delayed alternation task [Toxicol. Lett. 54 (1990) 345; Bull. Environ. Contam. Toxicol. 50 (1993) 100; Brain Res. Bull. 55 (2001) 301]. To further characterize developmental and behavioral alterations induced by arsenic exposure, Sprague-Dawley rats were exposed to arsenite (36.70 mg arsenic/l in drinking water) from gestation day 15 (GD 15) or postnatal day 1 (PND 1), until approximately 4 months old. The pregnant or lactating dams received either the arsenic solution or regular drinking water and once pups were weaned, they continued receiving the same solution as drinking water. Animals exposed from GD 15 showed increased spontaneous locomotor activity and both exposed groups showed increased number of errors in a delayed alternation task in comparison to the control group. Total arsenic (TA) content in brain was similar for both exposed groups and significantly different from the control group. These results indicate that rats exposed to arsenic during development present deficits in spontaneous locomotor activity and alterations in a spatial learning task.

Animals↗
PubMed1999

In vivo metabolism of nociceptin/orphanin FQ in rat hippocampus.

The in vivo metabolism of the newly identified endogenous ligand for the ORL1 receptor, the opioid-like peptide nociceptin (orphanin FQ) in rat hippocampus was studied using size-exclusion chromatography linked to electrospray ionization mass spectrometry. The results show that nociceptin is metabolized step-wise in vivo into fragments (1-13) and (14-17) as well as (1-9) and (10-13), respectively. Interestingly, the (1-13) and (1-9) fragments have the same C-terminus, Arg-Ala-Lys, suggesting that this is a motif recognized by an enzyme which fragments the peptide in two consecutive steps. Injection of the (1-13) fragment into rat hippocampus had no effect on spatial learning or motor function under conditions where nociceptin is active, showing that this metabolic conversion reduces affinity for the ORL-1-receptor.

Amino Acid Sequence↗
PubMed2002

Impaired spatial performance in rats with retrosplenial lesions: importance of the spatial problem and the rat strain in identifying lesion effects in a swimming pool.

Behavioral, electrophysiological, and anatomical evidence suggests that retrosplenial (RS) cortex (areas RSA and RSG) plays a role in spatial navigation. This conclusion has been questioned in recent work, suggesting that it is damage to the underlying cingulum bundle (CG) (areas CG and IG), and not RS, that disrupts spatial place learning (Aggleton et al., 2000). We revisited this issue by comparing Long-Evans rats, the strain used in studies that report RS deficits, to Dark Agouti rats, the strain in which no RS deficit has been reported. Rat groups with RS, RS + CG, or no lesion were tested on a place task in a swimming pool, a test of nonspatial and spatial learning, and a matching-to-place task, a relatively selective test of spatial learning. Long-Evans rats given RS and RS + CG lesions, either before or after training on the two tasks, were impaired on both tasks, a deficit not attributable to impaired visual acuity. Control Dark Agouti rats and RS Dark Agouti rats, although not different on the place task, were both significantly impaired relative to Long-Evans rats. The RS Dark Agouti group, however, was also impaired on the matching-to-place task. Thus, we show that RS cortex is part of an extended neural circuit involved in spatial behavior in both Long-Evans and Dark Agouti rats, but its role in the place task may be masked by an innate nonspatial deficit in Dark Agouti rats. The results are discussed in relation to the importance of assessing spatial learning with appropriate spatial tests, the problems of interpretation posed by rat strain differences, and the role of retrosplenial cortex in spatial behavior.

Analysis of Variance↗
PubMed1984

Chronically elevating plasma Mg2+ improves hippocampal frequency potentiation and reversal learning in aged and young rats.

One prediction of the hypothesis that the capacity for hippocampal frequency potentiation is relevant to behavioral plasticity is tested in this study, by chronically elevating magnesium in intact aged and young rats. Elevated extracellular Mg2+ specifically improves frequency potentiation in hippocampal slices, and chronic alterations in plasma Mg2+ can increase brain Mg2+ in intact animals. Aged and young rats on a diet that elevated plasma Mg2+ exhibited stronger frequency potentiation under urethane anesthesia, and showed improved maze reversal learning.

Age Factors↗
PubMed2006

Posterior parahippocampal gyrus lesions in the human impair egocentric learning in a virtual environment.

Functional imaging studies have shown that the posterior parahippocampal gyrus (PHG) is involved in allocentric (world-centered) object and scene recognition. However, the putative role of the posterior PHG in egocentric (body-centered) spatial memory has received only limited systematic investigation. Thirty-one subjects with pharmacoresistant medial temporal lobe epilepsy (TLE) and temporal lobe removal were compared with 19 matched healthy control subjects on a virtual reality task affording the navigation in a virtual maze (egocentric memory). Lesions of the hippocampus and PHG of TLE subjects were determined by three-dimensional magnetic resonance imaging volumetric assessment. The results indicate that TLE subjects with right-sided posterior PHG lesions were impaired on virtual maze acquisition when compared with controls and TLE subjects with anterior PHG lesions. Larger posterior PHG lesions were significantly related to stronger impairments in virtual maze performance. Our results point to a role of the right-sided posterior PHG for the representation and storage of egocentric information. Moreover, access to both allocentric and egocentric streams of spatial information may enable the posterior PHG to construct a global and comprehensive representation of spatial environments.

Adult↗
PubMed1995

Effect of delta 9-tetrahydrocannabinol on short-term memory in the rat.

We have reported that marihuana and its principal psycoactive compound, delta 9-tetrahydrocannabinol (delta 9-THC) produce alterations in several cerebral areas after acute treatment. Based on the involvement of 5-hydroxytryptamine (5-HT) on memory and learning and the reported effects of delta 9-THC on short-term memory, we designed an experiment to evaluate the memory performance and its possible relationship with serotonergic alterations after delta 9-THC administration. Male Wistar rats received an acute oral dose of THC (5 mg/kg). Short-Term memory was tested on a radial 8-arm maze with a 5 s delay, after 35 days of training. The animals were food deprived and adjusted for growth. 5-HT and its metabolite, 5-HIAA, levels were measured in cerebral cortex, dorsal hippocampus, ventral hippocampus, rostral neoestriatum and amygdala basal nucleus, by HPLC-ED. The experiment indicates an impairment of short-term memory in the radial maze test after delta 9-THC administration. The control group performed the test without errors, while the treated group made a significant number of errors (Z = 0.019, Mann-Whitney test). This behavioral effect did not seem to be related to serotonergic alterations, as the 5-HT turnover rate was not different between treated and control animals.

Administration, Oral↗
PubMed2006

Reduced reactivity to novelty, impaired social behavior, and enhanced basal synaptic excitatory activity in perforant path projections to the dentate gyrus in young adult mice deficient in the neural cell adhesion molecule CHL1.

The neural cell adhesion molecule CHL1 is implicated in neural development in the mouse and has been related to psychiatric disorders in humans. Here we report that mice constitutively deficient for CHL1 display reduced reactivity to environmental stimuli and reduced expression of social behaviors, whereas cognitive, motor and olfactory functions are normal. Basal synaptic transmission and plasticity in seven major excitatory connections in the hippocampus were analyzed to test whether dysfunctions in this brain region, which controls complex behaviors, correlate with the behavioral alterations of CHL1 deficient mice. We found that basal synaptic transmission in lateral and medial perforant path projections to the dentate gyrus is elevated in CHL1-deficient mice. Taking in consideration the function of these synapses in processing information from cortical areas, we hypothesize that constitutive ablation of CHL1 leads to reduced capability to react to external stimuli due to dysfunctions in the dentate gyrus.

Animals↗
PubMed2002

Effect of intraperitoneal mRNA antisense-oligodeoxynucleotides to cholecystokinin on anxiety-like and learning behaviors in rats: association with pre-experimental stress.

RATIONALE: Cholecystokinin and its analogs generate anxiety in humans and measurable anxiety-like behaviors in rats. Cholecystokinin receptor blockers have been reported to have variable effects in the treatment of anxiety disorders. We demonstrated that intracerebroventricular administration of Cholecystokinin-antisense oligodeoxynucleotides (ASODN) for 3 days significantly diminished anxiety-like behavior in rats. OBJECTIVE: This study was designed to examine the effects of peripheral (intraperitoneal) administration of Cholecystokinin-ASODN on anxiety-like and learning behaviors in rats, in general and in a pre-experiment stress paradigm. METHODS: In the first study Cholecystokinin-ASODN was injected intraperitoneally to rats five times at 24-h intervals. Control groups received injections of either a scrambled oligodeoxynucleotide (ScrODN) or vehicle. On the sixth day, the rats were assessed in the elevated plus-maze paradigm and in the Morris water maze. In the second study, rats were pre-exposed to a cat for 10 min as a model for psychological stress, and then treated with intraperitoneal Cholecystokinin-ASODN and tested in both paradigms. RESULTS: The results show that for intact rats, intraperitoneal Cholecystokinin-ASODN significantly increased anxiety-like behavior and impaired retention performance in the Morris water maze, compared to both control groups. In stressed rats, Cholecystokinin-ASODN reduced anxiety-like behaviors in the plus-maze and improved performance in the water maze compared with controls. CONCLUSIONS: These results indicate that the anxiolytic effect of intraperitoneal Cholecystokinin-ASODN may be dependent on the baseline endogenous level of stress (i.e., on the Cholecystokinin levels). Basal endogenous levels of Cholecystokinin, as well as exogenous dosage of Cholecystokinin agonists and/or anxiolytic agents, appear to play an important role in the expression and/or control of anxiety-related behaviors in rats.

Animals↗
PubMed2002

Niche-related learning in laboratory paradigms: the case of maze behavior in Norway rats.

The general hypothesis underlying this paper is that behavior in traditional paradigms of laboratory learning is based on niche-related mechanisms. The specific hypothesis is that the behavior of Norway rats in laboratory mazes is based on niche-related mechanisms related to trail following and navigating. I evaluate seven types of evidence for this hypothesis: (a) resemblance of maze behavior to behavior in unconstrained settings; (b) importance of experimenter tuning of apparatus and procedures; (c) overdetermination of laboratory behavior; (d) reverse-engineering of niche-related mechanisms from laboratory data; (e) prediction of laboratory results from ecological data; (f) contribution of specific relative to general mechanisms; and (g) phylogenetic conservation and ecologically-based convergence and divergence of maze mechanisms. I conclude there is strong evidence for the hypothesis that behavior of rats in laboratory mazes is based on niche-related mechanisms. I suggest that a niche-related approach to laboratory learning paradigms has conceptual generality and the potential to facilitate connections with the study of neurophysiology, genetics, and evolution.

Animals↗
PubMed2001

Lipopolysaccharide causes deficits in spatial learning in the watermaze but not in BDNF expression in the rat dentate gyrus.

We investigated the effects of a single injection and a daily injection of lipopolysaccharide (LPS) on spatial learning and brain-derived neurotrophic factor (BDNF) expression in the rat dentate gyrus. LPS is derived from the cell wall of Gram-negative bacteria and is a potent endotoxin that causes the release of cytokines such as interleukin-1 and tumour necrosis factor. LPS is thought to activate both the neuroimmune and neuroendocrine systems; it also blocks long-term potentiation in the hippocampus. Here, we examined the effects of LPS on a form of hippocampal-dependent learning-spatial learning in the water maze. Rats were injected with LPS intraperitoneally (100 microg/kg) and trained in the water maze. The first group of rats were injected on day 1 of training, 4 h prior to learning the water maze task. Groups 2 and 3 were injected daily, again 4 h prior to the water-maze task; group 2 with LPS and group 3 with saline. A number of behavioural variables were recorded by a computerised tracking system for each trial. The behavioural results showed a single injection of LPS (group 1) impaired escape latency in both the acquisition and retention phases of the study, whereas a daily injection of LPS did not significantly impair acquisition or retention. BDNF expression was analysed in the dentate gyrus of all animals. No significant differences in BDNF expression were found between the three groups.

Animals↗
PubMed2001

Age-related differences in hippocampal extracellular fluid glucose concentration during behavioral testing and following systemic glucose administration.

Recent evidence indicates that the level of glucose in the brain's extracellular fluid (ECF) is not constant, as traditionally thought, but fluctuates. We determined the effect of aging on hippocampal ECF glucose before, during, and after spatial memory testing. Fischer-344 rats (24 months old) showed a greater decrease in ECF glucose than 3-month-old rats (48% vs 12%); the decrease seen in 24-month-old rats persisted for much longer following testing. These changes were associated with an age-related deficit in spontaneous alternation performance. Following systemic glucose administration, the decrease in ECF glucose was reversed in both aged and young rats, and performance in aged versus young rats following glucose administration did not differ. These findings suggest that increased susceptibility to depletion of ECF glucose in aged rats may contribute to age-related deficits in learning and memory and that administration of glucose may enhance memory by providing additional glucose to the brain at times of increased cognitive demand.

Aging↗