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At least 1,207 records · Page 67Linked to original sources
PubMed2004

Mice with a fra-1 knock-in into the c-fos locus show impaired spatial but regular contextual learning and normal LTP.

The immediate early gene c-fos is part of the AP-1 transcription factor complex, which is involved in molecular mechanisms underlying learning and memory. Mice that lack c-Fos in the brain show impairments in spatial reference and contextual learning, and also exhibit a reduced long-term potentiation of synaptic transmission (LTP) at CA3-to-CA1 synapses. In the present study, we investigated mice in which c-fos was deleted and replaced by fra-1 (c-fos(fra-1) mice) to determine whether other members of the c-fos gene family can substitute for the functions of the c-fos gene. In c-fos(fra-1) mice, both CA3-to-CA1 LTP and contextual learning in a Pavlovian fear conditioning task were similar to wild-type littermates, indicating that Fra-1 expression restored the impairments caused by brain-specific c-Fos depletion. However, c-Fos-mediated learning deficits in a reference memory task of the Morris watermaze were also present in c-fos(fra-1) mice. These findings suggest that different c-Fos target genes are involved in LTP, contextual learning, and spatial reference memory formation.

Animals↗
PubMed2006

A role in learning for SRF: deletion in the adult forebrain disrupts LTD and the formation of an immediate memory of a novel context.

Whereas significant insight exists as to how LTP-related changes can contribute to the formation of long-term memory, little is known about the role of hippocampal LTD-like changes in learning and memory storage. We describe a mouse lacking the transcription factor SRF in the adult forebrain. This mouse could not acquire a hippocampus-based immediate memory for a novel context even across a few minute timespan, which led to a profound but selective deficit in explicit spatial memory. These animals were also impaired in the induction of LTD, including LTD triggered by a cholinergic agonist. Moreover, genes regulating two processes essential for LTD-calcium release from intracellular stores and phosphatase activation-were abnormally expressed in knockouts. These findings suggest that for the hippocampus to form associative spatial memories through LTP-like processes, it must first undergo learning of the context per se through exploration and the learning of familiarity, which requires LTD-like processes.

Animals↗
PubMed2005

Chronic stress impairs acoustic conditioning more than visual conditioning in rats: morphological and behavioural evidence.

Chronic stress affects brain areas involved in learning and emotional responses. These alterations have been related with the development of cognitive deficits in major depression. The aim of this study was to determine the effect of chronic immobilization stress on the auditory and visual mesencephalic regions in the rat brain. We analyzed in Golgi preparations whether stress impairs the neuronal morphology of the inferior (auditory processing) and superior colliculi (visual processing). Afterward, we examined the effect of stress on acoustic and visual conditioning using an avoidance conditioning test. We found that stress induced dendritic atrophy in inferior colliculus neurons and did not affect neuronal morphology in the superior colliculus. Furthermore, stressed rats showed a stronger impairment in acoustic conditioning than in visual conditioning. Fifteen days post-stress the inferior colliculus neurons completely restored their dendritic structure, showing a high level of neural plasticity that is correlated with an improvement in acoustic learning. These results suggest that chronic stress has more deleterious effects in the subcortical auditory system than in the visual system and may affect the aversive system and fear-like behaviors. Our study opens a new approach to understand the pathophysiology of stress and stress-related disorders such as major depression.

Acoustic Stimulation↗
PubMed2001

Involvement of the dorsal anterior cingulate cortex in temporal behavioral sequencing: subregional analysis of the medial prefrontal cortex in rat.

We recently demonstrated that rats with dorsal anterior cingulate (ACd) cortical lesions were disrupted in the acquisition of a temporal Go/No-Go alternation task, suggesting either an involvement of this medial prefrontal subregion in sequencing temporally ordered behaviors or alternatively in more general response selection processes 'Gisquet-Verrier et al., Psychobiology 28 (2000) 248'. In the present study, the effects of ACd lesions were investigated in two different training situations. Both tasks involved response selection but only one of the two tasks required behavioral sequencing. In experiment 1, rats with ACd lesions were normally able to select Go and No-Go responses, when selection processes were based on a tone/light conditional rule that does not require temporal patterning. In experiment 2, ACd-lesioned rats were disrupted during the acquisition of a spatial alternation task that relies on temporal patterning. These results provide further evidence of ACd involvement in behavioral sequencing, regardless of the nature (spatial or non-spatial) of chained responses. A comparison of ACd lesions-induced effects with those obtained with lesions to the adjacent prelimbic-infralimbic area 'Delatour & Gisquet-Verrier, Behav. Neurosci. 110 (1996) 1282; Delatour & Gisquet-Verrier, Behav. Neurosci. 113 (1999) 941' reveals a double dissociation of these two regions that reflects a functional regionalization of the medial prefrontal cortex in the rat.

Animals↗
PubMed1998

Protective effects of fetal neocortical transplants on cognitive function and neuron size in rats with congenital micrencephaly.

The rat with micrencephaly, produced by prenatal exposure to methylazoxymethanol, provides a useful model to study neurobehavioral abnormalities associated with congenital brain defects. The micrencephalic animals have a life-long learning impairment. As they age, their already impaired learning competence deteriorates further. To determine whether the aging-associated functional deterioration could be ameliorated by a neural transplant, micrencephalic rats bearing solid transplants of normal fetal neocortical tissue since infancy were evaluated on a visual pattern discrimination learning at 15 months and a spatial navigation test at 24 months of age. The transplant-bearing rats learned both tasks significantly better than the micrencephalic rats without transplants. Morphometric analyses revealed that cortical pyramidal neurons were larger in the transplant-bearing rats than in micrencephalic rats without transplants. The life-long presence of a transplant appeared to have protected the micrencephalic brain against aging-associated deterioration. This is the first demonstration that a neural transplant, placed in a congenitally defective infant brain, can ameliorate aging-associated cognitive deficits.

Animals↗
PubMed1997

Candidates for cognitive enhancer extracted from medicinal plants: paeoniflorin and tetramethylpyrazine.

A traditional Chinese medicine, Shimotsu-to, consisting of four herbs: Japanese angelica root, cnidium rhizome, peony root and rehmannia root, has been reported to improve spatial working memory in rats. The present results indicate that Paeoniflorin and tetramethylpyrazine (TMP) extracted from peony root and cnidium rhizome, respectively, are candidates for cognitive enhancer.

Aging↗
PubMed2000

Continuous place avoidance task reveals differences in spatial navigation in male and female rats.

A new place navigation test was used to estimate the spatial orientation abilities of male and female rats. Animals had to avoid a room frame defined area on a rotating arena, entering of which was punished by mild footshock, i.e. rats had to avoid the same place in the room but different parts of the floor, which was rotated through the punished zone. Because of the rotation of the arena (one revolution per min), animals could not rely on intramaze cues and only extramaze landmarks could be used for accurate navigation. During 8 consecutive days rats were exposed to daily 40-min sessions, consisting of 20-min acquisition and 20-min extinction (shock discontinued). The position of the punished sector centered around one of the four mutually perpendicular azimuths was daily changed in a predetermined sequence. The results showed no male female differences during acquisition and better performance of males during extinction. The performance of females was not affected by estral cycle-related hormonal changes. The findings are discussed in the light of controversial results of research into sex differences in spatial abilities.

Animals↗
PubMed1999

Neuroprotective effects of brain-derived neurotrophic factor in seizures during development.

Although the immature brain is highly susceptible to seizures, it is more resistant to seizure-induced neuronal loss than the adult brain. The developing brain contains high levels of neurotrophins which are involved in growth, differentiation and survival of neurons. To test the hypothesis that neurotrophins may protect the developing brain from seizure-induced neuronal loss, brain-derived neurotrophic factor up-regulation was blocked by intracerebroventricular infusion of an 18mer antisense oligodeoxynucleotide sequence to brain-derived neurotrophic factor in 19-day-old rats using micro-osmotic pumps. Control rats were infused with sense or missense oligodeoxynucleotide. Status epilepticus was induced by intraperitoneal administration of kainic acid 24 h after the start of oligodeoxynucleotide infusion. Seizure duration was significantly increased in the antisense oligodeoxynucleotide plus kainic acid group compared to groups that received kainic acid alone or kainic acid plus sense or missense oligodeoxynucleotide. There was no difference between groups in the latency to forelimb clonus. A twofold increase in brain-derived neurotrophic factor levels was observed in the hippocampus 20 h following kainic acid-induced seizures. This kainic acid-induced increase was absent in animals receiving infusion of antisense oligodeoxynucleotide to brain-derived neurotrophic factor at time of seizure induction. Hippocampi of rats in this group (antisense oligodeoxynucleotide plus kainic acid) showed a loss of CA1 and CA3 pyramidal cells and hilar interneurons. This neuronal loss was not dependent upon seizure duration since animals injected with diazepam to control seizure activity in the antisense plus kainic acid group also showed similar neuronal loss. Administration of kainic acid or infusion of antisense alone did not produce any cell loss in these regions. Induction of seizures at postnatal day 20, in the presence or absence of antisense oligonucleotide, did not produce an impairment in learning and memory when tested 15 days later in the Morris water maze. The hippocampi of these animals did not show any synaptic reorganization as assessed by growth-associated protein-43 immunostaining and Timm staining. Our findings confirm prior studies demonstrating that seizures in the immature brain are associated with little, if any, cell loss. However, when seizure-induced increase in brain-derived neurotrophic factor is blocked, seizures do result in neuronal loss in the developing brain. Thus, brain-derived neurotrophic factor appears to provide protection against kainic acid seizure-induced neuronal damage in the developing brain.

Animals↗
PubMed1999

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

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

Amygdala↗
PubMed2004

Absence of an interaction between navigational strategies based on local and distal landmarks.

In 3 experiments, rats were required to escape from a Morris pool by swimming to a submerged platform that was located at the apex of a notional, equilateral triangle with 2 different landmarks occupying the corners at the base. Training for 1 group was always conducted in view of the landmarks surrounding the pool and with the triangular array in a fixed orientation. Subjects could therefore identify the direction of the platform from a single landmark within the pool by reference to cues outside the pool or to the other landmark within the pool. Both strategies were used, and the results from additional groups revealed that the first of these strategies did not affect the acquisition of the second one.

Animals↗
PubMed1998

Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein.

Specific patterns of neuronal firing induce changes in synaptic strength that may contribute to learning and memory. If the postsynaptic NMDA (N-methyl-D-aspartate) receptors are blocked, long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission and the learning of spatial information are prevented. The NMDA receptor can bind a protein known as postsynaptic density-95 (PSD-95), which may regulate the localization of and/or signalling by the receptor. In mutant mice lacking PSD-95, the frequency function of NMDA-dependent LTP and LTD is shifted to produce strikingly enhanced LTP at different frequencies of synaptic stimulation. In keeping with neural-network models that incorporate bidirectional learning rules, this frequency shift is accompanied by severely impaired spatial learning. Synaptic NMDA-receptor currents, subunit expression, localization and synaptic morphology are all unaffected in the mutant mice. PSD-95 thus appears to be important in coupling the NMDA receptor to pathways that control bidirectional synaptic plasticity and learning.

Animals↗
PubMed2002

Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.

Neurofibromatosis type I (NF1) is one of the most common single-gene disorders that causes learning deficits in humans. Mice carrying a heterozygous null mutation of the Nfl gene (Nfl(+/-) show important features of the learning deficits associated with NF1 (ref. 2). Although neurofibromin has several known properties and functions, including Ras GTPase-activating protein activity, adenylyl cyclase modulation and microtubule binding, it is unclear which of these are essential for learning in mice and humans. Here we show that the learning deficits of Nf1(+/-) mice can be rescued by genetic and pharmacological manipulations that decrease Ras function. We also show that the Nf1(+/-) mice have increased GABA (gamma-amino butyric acid)-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Our results indicate that the learning deficits associated with NF1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. Our findings have implications for the development of treatments for learning deficits associated with NF1.

Animals↗
PubMed2003

Lesions of the mammillothalamic tract impair the acquisition of spatial but not nonspatial contextual conditional discriminations.

This study examined the influence of selective mammillothalamic tract lesions in rats on the acquisition of two kinds of contextual conditional discrimination: one involving two contexts (A and B) that differed in their visuo-spatial properties and another involving two contexts (C and D) that differed in temperature. In contexts A (and C) presentations of a tone were paired with food whereas presentations of a clicker were not; and in contexts B (and D) presentations of the clicker were paired with food whereas those of the tone were not. Mammillothalamic tract lesions disrupted initial acquisition of the conditional discrimination involving visual contexts (A and B), but not the formally equivalent discrimination involving thermal contexts (C and D). These results provide support for the suggestion that mammillothalamic tract lesions disrupt visuo-spatial encoding.

Acoustic Stimulation↗
PubMed2006

beta-Amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or beta-amyloid deposits.

beta-Amyloid (Abeta) polypeptide plays a critical role in the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of Abeta deposits and neurofibrillary tangles, and loss of neurons. Increased genetic production or direct intracerebral administration of Abeta in animal models results in Abeta deposition, gliosis, and impaired cognitive functions. Whether aging renders the brain prone to Abeta and whether inflammation is required for Abeta-induced learning deficits is unclear. We show that intraventricular infusion of Abeta1-42 results in learning deficits in 9-month-old but not 2.5-month-old mice. Deficits that become detectable 12 weeks after the infusion are associated with a slight reduction in Cu,Zn superoxide dismutase activity but do not correlate with Abeta deposition and are not associated with gliosis. In rats, Abeta infusion induced learning deficits that were detectable 6 months after the infusion. Approximately 20% of the Abeta immunoreactivity in rats was associated with astrocytes. NMR spectrum analysis of the animals cerebrospinal fluid revealed a strong reduction trend in several metabolites in Abeta-infused rats, including lactate and myo-inositol, supporting the idea of dysfunctional astrocytes. Even a subtle increase in brain Abeta1-42 concentration may disrupt normal metabolism of astrocytes, resulting in altered neuronal functions and age-related development of learning deficits independent of Abeta deposition and inflammation.

Aging↗
PubMedDate not supplied

A rat neurodevelopmental evaluation of offspring, including evaluation of adult and neonatal thyroid, from mothers treated with ammonium perchlorate in drinking water.

The purpose of this study was to evaluate the potential neurodevelopmental toxicity of perchlorate exposure during gestation and the first 10 days of lactation. Mated Sprague-Dawley rats (25/exposure group) were given continual access to 0, 0.1, 1.0, 3.0, or 10.0 mg/kg-day ammonium perchlorate (AP) in drinking water, starting gestation day 0 (mating) through lactation day 10 (DL 10). One pup/sex/litter/exposure group was assigned to (1) juvenile brain weights, morphometry, and neuropathology; (2) passive avoidance and watermaze testing; (3) motor activity and auditory startle habituation; and (4) adult regional brain weights, morphometry, and neuropathology. AP had no effect on body weights, feed consumption, clinical observations, or sexual maturation of pups at exposures as high as 10.0 mg/kg-day. There were no behavioral effects in the offspring exposed as high as 10.0 mg/kg-day as evaluated by passive avoidance, swimming watermaze, motor activity, and auditory startle. Increases in hypertrophy and hyperplasia of the thyroid follicular epithelium and a decrease in the thyroid follicle size were observed in culled male pups in the 10.0 mg/kg-day group on DL 5. The exposure level for effects on triiodothyroxine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) levels for pups were 0.1, 1.0, and 3.0 mg/kg-day, respectively. There was an apparent increase in the thickness of the corpus callosum of the 10 mg/kg-day group pups on DL 12. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was greater than 10.0 mg/kg-day. Based on the thyroid morphometric and histopathologic findings, the NOAEL for pup toxicity was 0.1 mg/kg-day.

Administration, Oral↗
PubMed2004

Long-term impairment of acquisition of a spatial memory task following isoflurane-nitrous oxide anesthesia in rats.

BACKGROUND: The authors demonstrated previously that isoflurane-nitrous oxide anesthesia attenuates performance improvement on an already-learned spatial memory task and that the effect persists for weeks. This experiment was designed to test the hypothesis that learning of new information is particularly susceptible to prolonged disruption after general anesthesia. METHODS: Six- (n = 5) and 20- (n = 5) month-old male Fischer 344 rats were anesthetized for 2 h with 1.2% isoflurane, 70% nitrous oxide, and 30% oxygen. Age-matched control rats received 30% oxygen and 70% nitrogen (n = 5 per group). Rats breathed spontaneously, and anesthetic and oxygen concentrations were measured. Spatial learning was assessed daily for 21 days on a 12-arm radial maze (RAM) beginning 48 h after anesthesia. In a post hoc experiment to examine locomotion, swim speed was assessed in a separate group of identically treated rats (n = 3 per group) for 4 days beginning 48 h after anesthesia. RESULTS: Aged rats were slower to complete the maze, made fewer correct choices before first error, and made more errors at baseline than young rats (P < 0.05). Anesthesia worsened maze performance in both age groups, as evidenced by increased time to complete the maze and a decreased number of correct choices before first error (P < 0.05), but there were no statistically significant differences in total number of errors. Interestingly, there were no age-by-anesthesia interactions. Aged rats swam slower than adult rats (P < 0.001), but there were no differences between the control and anesthesia groups. CONCLUSIONS: Isoflurane-nitrous oxide anesthesia is associated with a persistent deficit in RAM performance that is not explained by impaired locomotion. This impairment occurs in adult and aged rats, indicating that it is not an age-specific phenomenon. Thus, RAM performance is altered after general anesthesia for longer than predicted by the pharmacology of the drugs used, which, by inference, suggests a long-term deficit in learning/memory.

Aging↗
PubMedDate not supplied

Differential effects of damage within the hippocampal region on memory for a natural, nonspatial Odor-Odor Association.

Debate continues on whether the role of rodent hippocampus in memory is limited to the spatial domain. Recently, this controversy has been addressed with studies on the social transmission of food preference, an odor-odor association task with no spatial requirements. Multiple reports have concluded that damage to the hippocampal region impairs memory in this task, but there remain questions about the extent of damage essential to produce an impairment. Furthermore, a recent study () found no effect of hippocampal lesions on memory in this task. We tested animals with complete lesions of the hippocampus (H) lesions of the hippocampus plus subiculum (HS), and lesions of the adjacent, anatomically related cortices of the parahippocampal region (PHR). H lesions produced an impairment on spatial delayed alternation, but not on memory for the social transmission of food preference, whereas HS and PHR lesions produced severe and equivalent impairments on memory for the socially acquired food preference. We discuss possible explanations for the discrepancy with the results of and conclude that the hippocampus and subiculum together play a critical role in the formation of this form of nonspatial, relational memory.

Animals↗
PubMed2005

REM restriction persistently alters strategy used to solve a spatial task.

We tested the hypothesis that rapid eye movement (REM) sleep is important for complex associative learning by restricting rats from entering REM sleep for 4 h either immediately after training on an eight-box spatial task (0-4 REMr) or 4 h following training (4-8 REMr). Both groups of REM-restricted rats eventually reached the same overall performance level as did nonrestricted controls, but 0-4 REMr animals were delayed in their improvement in the first few days and lagged behind controls in the middle portion of the training period. More importantly, performance gains of 0-4 REMr rats depended more on simple local cues throughout the 15-d study since, unlike control and 4-8 REMr animals, their error rate increased after daily disruption of the relationship between local (intramaze) cues and the food reward. Thus, although overall performance was only subtly and transiently impaired, due to the ability to use alternate, nonspatial behavioral strategies, complex associative (spatial) learning was persistently impaired by restricting REM for a short critical period each day.

Animals↗