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PubMed1997

Acute stress in pregnant rats: effects on growth rate, learning, and memory capabilities of the offspring.

Growth rate of the offspring of female rats stressed by the presence of a cat at the 10th or the 19th gestational day was lower than that of controls whereas footshocks administered at the same periods did not significantly influence growth rate of the young. Whatever the nature of the stress and the time when it was administered to the mother, the death rate of the young rats was much greater than that in controls. When adult, the offspring of stressed mothers exhibited learning and memory impairments in a delayed alternation task as well as in passive avoidance conditioning. Alteration of these cognitive functions is interpreted in terms of subtle dysfunctions in the development of the nervous system through modifications of the hormonal components of the mothers, particularly eventual alterations of the nervous system biochemistry of the offspring.

Animals↗
PubMed1997

Oral administration of propentofylline, a stimulator of nerve growth factor (NGF) synthesis, recovers cholinergic neuronal dysfunction induced by the infusion of anti-NGF antibody into the rat septum.

We have reported that the continuous infusion of anti-nerve growth factor (NGF) monoclonal antibody into the septum of rats produces an impairment of memory and a decrease in choline acetyltransferase (ChAT) and cholinesterase (ChE) activities in the hippocampus. Propentofylline, a xanthine derivative, has potent stimulatory effects on NGF synthesis/secretion in mouse astrocytes in vitro. To investigate the pharmacological effects of propentofylline in vivo, we induced amnesia in rats by infusing anti-NGF antibody into the septum for 16 days. One group of rats was given no further treatment, while the other group was treated with propentofylline orally once a day for 19 days, commencing 3 days before the implantation of the mini-osmotic pump, and continuing throughout the period during which the animals performed the behavioral tasks. In the treated amnesic rats, learning and memory in the 3 tasks and ChAT and ChE activity were reduced compared to values in control rats. The administration of propentofylline recovered the decreased learning capacity and the deficit in cholinergic marker enzyme activity. These results suggest that the use of NGF stimulators may provide a new approach to the treatment of dementia.

Amnesia↗
PubMed1999

Lesions of the medial or lateral perforant path have different effects on hippocampal contributions to place learning and on fear conditioning to context.

The axons of the neurons in the medial and lateral components of the entorhinal cortex (MEC and LEC) form the medial and lateral perforant paths (MPP and LPP) which represent the major source of cortical input to the hippocampus. Anatomical, physiological, and pharmacological studies have shown that MPP and LPP are distinct. Unfortunately, assessment of the functional significance of damage to either of these pathways has not used tasks known to be sensitive to hippocampal function in the rodent. In this study, we performed dissociated lesions of MPP and LPP using a combined physiological and anatomical method. Rats with lesions of either the MPP or the LPP were tested on place learning in the water task and on a discriminative fear conditioning to context task. The results indicated that the MPP, but not LPP, lesions resulted in impaired place learning. The context discrimination data revealed an amygdala-like, reduced fear effect of MPP lesions and an enhanced discriminative fear conditioning to context effect of LPP lesions. Consistent with a two-stage model of spatial learning proposed by Buzsaki (Buzsaki G. Two-stage model of memory trace formation: a role for 'noisy' brain states. Neuroscience 1989;31(3):551-570), the impairment in the water task can be interpreted as reflecting the higher efficiency of the MPP synapses in activating hippocampal neurons. The context discrimination results can be explained by either a dissociation of sensory information that reaches the MEC and LEC, or alternatively, by a dissociation between the limbic nature of the MEC and the sensory nature of the LEC.

Animals↗
PubMed2003

Hippocampal gene expression profiling in spatial discrimination learning.

Learning and long-term memory are thought to involve temporally defined changes in gene expression that lead to the strengthening of synaptic connections in selected brain regions. We used cDNA microarrays to study hippocampal gene expression in animals trained in a spatial discrimination-learning paradigm. Our analysis identified 19 genes that showed statistically significant changes in expression when comparing Nai;ve versus Trained animals. We confirmed the changes in expression for the genes encoding the nuclear protein prothymosin(alpha) and the delta-1 opioid receptor (DOR1) by Northern blotting or in situ hybridization. In additional studies, laser-capture microdissection (LCM) allowed us to obtain enriched neuronal populations from the dentate gyrus, CA1, and CA3 subregions of the hippocampus from Nai;ve, Pseudotrained, and spatially Trained animals. Real-time PCR examined the spatial learning specificity of hippocampal modulation of the genes encoding protein kinase B (PKB, also known as Akt), protein kinase C(delta) (PKC(delta)), cell adhesion kinase(beta) (CAK(beta), also known as Pyk2), and receptor protein tyrosine phosphatase(zeta/beta) (RPTP(zeta/beta)). These studies showed subregion specificity of spatial learning-induced changes in gene expression within the hippocampus, a feature that was particular to each gene studied. We suggest that statistically valid gene expression profiles generated with cDNA microarrays may provide important insights as to the cellular and molecular events subserving learning and memory processes in the brain.

Animals↗
PubMed2001

Intrahippocampal injections of somatostatin dissociate acquisition from the flexible use of place responses.

Previous studies showed that injections of somatostatin (SS-14) into the hippocampus facilitate the acquisition of spatial tasks in mice. The present study was aimed at better understanding the learning and memory processes that could be affected by hippocampal SS-14 stimulation. Balb/c mice were submitted to a two-stage learning paradigm. In stage 1, they were trained for acquisition of a spatial discrimination task in a radial maze and, in stage 2, were submitted to a probe test aiming at evaluating their ability to use flexibly their previously acquired knowledge. Injections of vehicle or SS-14 were given during the acquisition phase and/or before the probe test using a 2 x 2 factorial design. Mice receiving SS-14 during acquisition failed to succeed in the probe test despite showing a trend to faster acquisition of the initial spatial discrimination task. By contrast, when given only prior to probe trials, SS-14 did not yield any behavioural effects. Thus, SS-14 interfered with the establishment of a flexible form of memory, not with its expression per se, and therefore dissociated the acquisition of place responses from their flexible use. The theoretical issues raised by the present findings are discussed.

Animals↗
PubMed1994

An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses.

The search for cellular correlates of learning is a major challenge in neurobiology. The hippocampal formation is important for learning spatial relations. A possible long-lasting consequence of such spatial learning is alteration of the size, shape, or number of excitatory synapses. The dendritic spine density is a good index for the number of hippocampal excitatory synapses. By using laser-scanning confocal microscopy, we observed a significantly increased spine density in CA1 basal dendrites of spatially trained rats when compared to nontrained controls. With unchanged dendritic length, the higher spine density reflects an increased number of excitatory synapses per neuron associated with spatial learning.

Animals↗
PubMed2006

Behavioral abnormalities precede neuropathological markers in rats transgenic for Huntington's disease.

Huntington's disease (HD) is caused by an expanded CAG repeat leading to the synthesis of an aberrant protein and to the formation of polyglutamine (polyQ)-containing inclusions and aggregates. Limited information is available concerning the association of neuropathological markers with the development of behavioral markers in HD. Using a previously generated transgenic rat model of HD (tgHD rat), we performed association studies on the time-course of behavioral symptoms (motor function, learning, anxiety) and the appearance of striatal atrophy, 1C2 immunopositive aggregates and polyQ recruitment sites, a precursor to these aggregates. At the age of 1 month, tgHD rats exhibited reduced anxiety and improved motor performance, while at 6 months motor impairments and at 9 months cognitive decline occurred. In contrast, polyQ recruitment sites appeared at around 6-9 months of age, indicating that HD-like behavioral markers preceded the appearance of currently detectable neuropathological markers. Interestingly, numerous punctate sites containing polyQ aggregates were also seen in areas receiving afferents from the densely recruiting regions suggesting either transport of recruitment-competent aggregates to terminal projections where initially 1C2 positive aggregates were formed or different internal properties of neurons in different regions. Furthermore, striatal atrophy was observed at the age of 12 months. Taken together, our findings support the hypothesis of a dynamic process leading to region- and age-specific polyQ recruitment and aggregation. The dissociation of onset between behavioral and neuropathological markers is suggestive of as yet undetected processes, which contribute to the early phenotype of these HD transgenic rats.

Aging↗
PubMed1997

Spatial memory in transgenic mice with impaired glucocorticoid receptor function.

Spatial learning and memory function of transgenic mice with impaired glucocorticoid receptor function was assessed in the Morris water maze and the radial arm maze. Transgenic mice took longer to find a submerged and a visual platform in the water maze task than did mice from the parent strain (B6C/3F1), although performance was improved in the visible platform condition relative to the submerged platform task. In the radial arm maze, transgenic mice made significantly more errors than B6C/3F1 mice. In both tasks, the behavioural strategies adopted by transgenic mice were non-optimal for correct performance. It is suggested that the impaired performance displayed by transgenic mice in both tests is largely attributable to these altered behavioural strategies.

Animals↗
PubMed2002

The effects of extrinsic context on nicotine discrimination.

There is evidence from memory studies that context acquired in parallel with the encoded material will facilitate retrieval. However, relatively little is known of how context affects drug discrimination behaviour in humans. The present study employs conventional drug discrimination procedures to investigate the effects of music, as an external cue, on nicotine drug discrimination. Subjects were trained to discriminate a low dose of nicotine (1 mg) from placebo while listening to two different types of music [elated (EL) and depressant (DE): thought to induce happy and sad mood respectively]. Half of the subjects received EL music with nicotine and DE with placebo and the other half vice versa. At the end of training, subjects who reached the criterion (80% of trials identified correctly) entered the generalization phase and were required to discriminate different doses of nicotine (0, 0.25, 0.5 and 1 mg) by indicating how similar each sample was to the training dose. Generalization took place in the presence of either EL or DE music. Nicotine-appropriate responding during generalization was linearly related to dose, with subjects being able to distinguish 0.5mg of nicotine from placebo. Nicotine-appropriate responding at generalization was higher when the context (type of music) was the same as the one employed during discrimination training when nicotine was administered (i.e. a context-dependent generalization effect was present). In addition, it was shown that the context-dependent effect was due to the properties of the EL music. These data provide the first evidence that extrinsic context can facilitate nicotine discrimination in humans. In addition, the findings suggest that this facilitatory effect is not a general effect but is sensitive to specific attributes of the context.

Adult↗
PubMed1995

Acute ethanol impairs spatial memory but not stimulus/response memory in the rat.

The present studies investigate how acutely administered ethanol (ETOH) affects the use of spatial memory. Previous electrophysiological results have shown that acutely administered ETOH alters the firing of hippocampal neurons and that prenatal or chronic exposure to ETOH produces deficits on spatial learning tasks, tasks dependent on the hippocampus. In contrast, it has also been demonstrated that acutely administered ETOH does not impair spatial localization. In the current studies, rats were trained to perform a spatial or stimulus/response task under saline. After training, rats were injected with ETOH, and the use of spatial or stimulus/response memory was tested. Acutely administered ETOH impaired the use of spatial memory, but not the use of stimulus/response memory. Because the use of spatial memory requires an intact hippocampus, the present studies suggest that acutely administered ETOH selectively impairs behaviors dependent on the hippocampus.

Animals↗
PubMedDate not supplied

Alterations in brain function after loss of docosahexaenoate due to dietary restriction of n-3 fatty acids.

The concentration of the major polyunsaturated fatty acid (PUFA) in brain, docosahexaenoate, may be markedly reduced by two or more generations of dietary restriction of sources of n-3 fatty acids in the diet. Such a deficiency was induced through the feeding of safflower oil as the principal source of essential fatty acids. The reference point for this diet was an n-3 adequate diet to which alpha-linoleate and docosahexaenoate were added through the addition of a small quantity of flax seed or algael oils, respectively. The loss of brain DHA was associated with poorer performance in spatial tasks and an olfactory-cued reversal learning task. No difference could be observed in the hippocampal gross morphology. This study demonstrates the importance of providing a source of n-3 fatty acids during mammalian growth and development.

Animals↗
PubMed1995

Acidic fibroblast growth factor protects memory and immunoreactivity impairment in senescence accelerated mice.

Subcutaneous injection of aFGF once per a week into senescence accelerated mice (SAM)P8 was begun at 3 weeks after birth and continued for 10 months. Saline was injected as a control. Learning and memory and cellular immunological functions in the aFGF (F) group were enhanced significantly and while those of the saline (S) group deteriorated. The number of cholinergic neurons was decreased slightly and choline acetyltransferase activity in individual neurons in the medial septum which send monosynaptic terminals to the hippocampus was significantly decreased in the S group, but were more spared in the F group. The MAO-B activity was significantly lower in the F group than in the S group. The respective densities of muscarinic and NMDA receptors and the aFGF receptor, i.e. FGFR-1 in the hippocampus were also significantly higher in the F group than in the S group. The delayed type hypersensitivity reactions (DTH) in the footpad caused by challenge with trinitrophenyl or sheep red blood cells as measured at the end of the 2nd and 7th months, indicated the T cell immune response. Both types of DTHs were reduced in the 7th month as compared with the 2nd month in the S group. However, aFGF administration protected against this reduction in response with age. These results show that aFGF provides protection against impairment of not only learning and memory but also the DTH immunoreactivity in SAMP8, indicating thereby a close relationship between learning-memory and T cell immune function.

Aging↗
PubMedDate not supplied

[The effect of emotional stress on the behavioral and endocrine indices of rats selected for their contrasting capacities for active avoidance].

Female rats of two strains selected for high (Koltushi high avoidance, KHA) and low (Koltushi low avoidance, KLA) acquisition of active avoidance of shock in a two-way shuttle-box were exposed to emotional stress accompanied by pain and without it. Emotional stress with pain (electrical paw stimulation) had no effects on behavioural and endocrine responses. It was found out that behaviour of KHA rats with their active behavioural strategy was not affected by the emotional stress without pain. In contrast, KLA rats demonstrated enhanced locomotion and exploratory activity, decreased grooming and anxiety. There were no changes in endocrine stress responses. Our findings suggest putative beneficial effect of emotional stress on the animals with passive behavioural strategy.

Animals↗
PubMed1999

A partial agonist at strychnine-insensitive glycine sites facilitates spatial learning in aged rats.

1-Aminocyclopropanecarboxylic acid (ACPC) is a high affinity ligand at strychnine-insensitive glycine sites of the N-methyl-D-aspartate (NMDA) channels and exhibits partial agonist properties in both biochemical and electrophysiological measures. While ACPC was reported active in animal models used to evaluate potential antidepressants and anxiolytics, its effects on learning and memory are unknown. In the present study we investigated the effects of ACPC on spatial learning in the Morris water maze. On a schedule of 12 learning trials, one trial per day, mature male Wistar rats (3 months of age) rapidly acquired the task. Electroconvulsive shocks applied after each of the learning trials markedly inhibited the consolidation of spatial memory. Administration of either a muscarinic agonist, arecoline (1 mg/kg) or ACPC (250 or 400 mg/kg) 20 min before each of the learning trials did not affect the acquisition of spatial learning. Aged (16 months old) male Wistar rats demonstrated difficulties in the acquisition of spatial learning task. In these subjects, ACPC administered 20 min before each of the learning trials at a dose of 400, but not 250 mg/kg, facilitated the acquisition of spatial memory as indicated on trials 3-5. ACPC did not affect the strength of spatial memory as assessed at the end of conditioning, by measuring swimming behavior of rats in the pool with platform removed. It is suggested that ACPC may alleviate learning deficits observed in the elderly.

Age Factors↗
PubMed1991

Effects of MK-801 on learning and memory as assessed using a novel water maze.

The effects of the NMDA receptor antagonist MK-801 [(+)-10,11-dihydro-5-methyl-5H-dibenzo [a,d]-cyclohepten-5,10 imine hydrogen maleate] on learning and memory were assessed using a water maze. The maze was a traditional type of maze with alleys and choices between various paths, but set inside a pool of water to a height of 25 cm. Different mazes could be configured by altering the arrangement of open vs. closed doors. Both the time required to reach an out-of-the-water exit platform and the errors made during the swim from start to finish were recorded. Learning was assessed during the first 10 to 20 trials in a new maze configuration, while memory was tested after the maze was well learned. Three experiments, some with several phases, were performed. These experiments compared the effects of 0.1 mg/kg of either (+)-MK-801, or (-)-MK-801 vs. saline on learning new maze configurations as well as swimming well-learned mazes. Neither of the MK-801 isomers impaired performance of a previously learned maze. (+)-MK-801 clearly slowed learning of new mazes as measured by both maze completion time and errors committed, while (-)-MK-801 had a significant but smaller effect on learning. Rats given (+)- or (-)-MK-801 (0.1 mg/kg) for 16 days while learning one maze and then challenged to learn a new maze without drug administration performed no differently on the new maze than controls, suggesting that the acute effect of MK-801 on learning is not long lasting.

Animals↗
PubMed1995

Ameliorating effects of histidine on learning deficits in an elevated plus-maze test in mice and the contribution of cholinergic neuronal systems.

We investigated the effects of histidine on scopolamine-induced learning deficits in the elevated plus-maze test in mice. In this test, transfer latency, the time mice took to move from the open arm to the enclosed arm, was used as an index of learning and memory. Intraperitoneal administration of scopolamine (0.5 mg/kg) prolonged the transfer latency on day 2 as compared with that in the saline-treated group. Histidine loading (500, 800 and 1600 mg/kg) reversed the prolongation of the transfer latency induced by scopolamine. This ameliorating effect of histidine was abolished by alpha-fluoromethylhistidine, an inhibitor of histidine decarboxylase, suggesting that histidine itself has no such ameliorating effect. Moreover, the ameliorating effect of histidine was antagonized by a histamine H1-receptor antagonist, pyrilamine, but not by zolantidine, a histamine H2-receptor antagonist. Thus, histamine, a decarboxylated product of histidine, elicited an ameliorating effect on scopolamine-induced learning deficit via histamine H1 receptors in mice. In the biochemical study, histidine significantly decreased acetylcholine (ACh) levels in the cerebral cortex and diencephalon of mice, and also significantly decreased them in the midbrain at a dose of 500 mg/kg. Histidine significantly increased and decreased levels of metabolites of noradrenaline and serotonin, respectively, in the brains of mice. Levels of dopamine and its metabolites were not very affected by histidine in the brains of mice. These findings clearly indicate that there is a close relationship between histaminergic and cholinergic system in the brain, and that histamine may play certain important roles in learning and memory.

Acetylcholine↗
PubMed2002

Effects of fimbria-fornix lesion and amyloid pathology on spatial learning and memory in transgenic APP+PS1 mice.

Transgenic mice carrying mutated human amyloid precursor protein (APPswe) and presenilin (PS1, A246E) genes develop first amyloid plaques around 9 months of age, but up to 18 months of age, amyloid depositions in these mice were largely restricted to the hippocampus, subiculum, and neocortex. To assess the behavioral consequences of amyloid accumulation in the hippocampal formation, we compared the effects of APP+PS1 (AP) genotype and fimbria-fornix (FFX) transection, either alone or combined, on various spatial learning and memory tasks. Both FFX-lesioned and AP mice were impaired in spatial navigation in the water maze, a typical hippocampal dependent task. Conversely, neither group of mice was impaired in a win-stay version of the radial arm maze (RAM) or position discrimination in the T-maze, tasks that do not depend on the hippocampus. FFX-lesioned mice were impaired in the win-shift version of the RAM, and in spontaneous and rewarded alternation in the T-maze, while AP mice performed equal to non-transgenic controls in all these working memory tasks, except long-term retention of the RAM task. AP mice thus appear to have a selective deficit in hippocampal dependent long-term memory, as do Alzheimer patients at early stage of the disease.

Amygdala↗