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PubMed1994

Perforant path damage results in progressive neuronal death and somal atrophy in layer II of entorhinal cortex and functional impairment with increasing postdamage age.

In vivo model systems that can evaluate neuronal death, survival, and regeneration are critical to revealing basic mechanisms of neuronal response and developing strategies for CNS repair. We propose a distinct experimental model of CNS degeneration following lesions to the perforant path connecting the hippocampus and the entorhinal cortex. Within 2 weeks of a unilateral aspirative perforant path lesion, 30% of the ipsilateral entorhinal cortex layer II (ECL II) projection neurons had died with no change in the contralateral ECL II population. Although there was no loss of ECL II neurons with normal aging, animals that survived for 15 months postlesion experienced an almost 50% loss of ipsilateral neurons compared to unlesioned controls. This progressive neuronal death was bilateral, with the contralateral ECL II experiencing a 30% decline in neuronal number relative to unlesioned controls. The use of unbiased stereology ensured that estimates of total number were not distorted by changes in the reference volume. The documented progressive neuronal death resulted in delayed behavioral impairment in spatial learning and performance (latency nearly 200% of controls). We propose, therefore, that the perforant path model is suitable for experimental investigation of neuronal survival and regeneration following CNS trauma.

Aging↗

PubMed2002

A role of Fos expression in the CA3 region of the hippocampus in spatial memory formation in rats.

Activity-dependent plastic changes in the strength of synaptic connections are considered to underlie learning and memory. Activation of neurons by a variety of stimuli influences the level of expression of the immediate-early gene c-fos, and the heterodimer of the gene product, Fos, regulates transcription of other genes. Therefore, Fos is regarded as a mediator by which brief stimuli trigger long-term changes in the synaptic connections. Here we show that Fos expression in the CA3 region of the hippocampus may be obligatory for spatial memory formation in a radial arm maze test. Fos-positive cells increased in the cerebral cortices and the CA3 region of the dorsal hippocampus during the course of radial arm maze training in rats. Inhibition of Fos expression in this region of the hippocampus, but not the cingulate and motor cortex, by means of antisense oligonucleotide treatment resulted in an impairment of spatial memory formation. Our results support the hypothesis that the inducible transcription factor c-fos is essential for encoding spatial memory.

Animals↗

PubMed2005

Regional acetylcholinesterase activity and its correlation with behavioral performances in 15-month old transgenic mice expressing the human C99 fragment of APP.

In addition to Abeta plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by increased brain levels of APP C-terminal fragments. In the present investigation, the cholinergic innervation in forebrain regions of transgenic mice (Tg13592) expressing the human betaAPP C99 fragment was compared to that of non-transgenic controls by measuring the activity of the non-specific catabolic enzyme, acetylcholinesterase (AChE). The AchE activity of Tg13592 mice was altered in several regions implicated in the functional loop of regulation between septum and hippocampus, vulnerable in Alzheimer pathology and critically involved in cognitive functions. In particular, AChE activity was upregulated in three basal forebrain regions containing cholinergic cell bodies, prelimbic cortex, anterior subiculum, and paraventricular thalamus, but downregulated in lateral septum and reticular thalamus. The increased activity in medial septum and anterior subiculum was linearly correlated with poor performances in a spatial learning task, possibly due to cell stress mechanisms. Because of some similarities in terms of neurochemistry and behavior, this mouse model may be of use for studying prodromal AD.

Acetylcholinesterase↗

PubMed2003

Behavioral analysis of the consequences of chronic blockade of NMDA-type glutamate receptors in the early postnatal period in rats.

Considering data on the possible glutamatergic nature of the pathogenesis of schizophrenia, we attempted to model cognitive derangements in animals by chronic blockade of NMDA glutamate receptors. Wistar rats received daily s.c. injections of the non-competitive NMDA glutamate receptor antagonist MK-801 (0.05 mg/kg) from days 7 to day 49 of postnatal life. One day after the antagonist injections given on days 27 and 28 of life, animals of the experimental group showed decreased levels of spontaneous movement and orientational-investigative activity as compared with controls, where there was no change in the elevated locomotor reaction produced in response to the direct action of MK-801. These animals showed decreases in the level of anxiety (on day 40 of life) and derangement in spatial learning with food reinforcement (days 50-54 of life). It is suggested that early neonatal blockade of NMDA glutamate receptors leads to the development in animals of disturbances to situational perception and assessment of incoming sensory information.

Animals↗

PubMedDate not supplied

Functional significance of long-term potentiation for sequence learning and prediction.

Population coding, where neurons with broad and overlapping firing rate tuning curves collectively encode information about a stimulus, is a common feature of sensory systems. We use decoding methods and measured properties of NMDA-mediated LTP induction to study the impact of long-term potentiation of synapses between the neurons of such a coding array. We find that, due to a temporal asymmetry in the induction of NMDA-mediated LTP, firing patterns in a neuronal array that initially represent the current value of a sensory input will, after training, provide an experienced-based prediction of that input instead. We compute how this prediction arises from and depends on the training experience. We also show how the encoded prediction can be used to generate learned motor sequences, such as the movement of a limb. This involves a novel form of memory recall that is driven by the motor response so that it automatically generates new information at a rate approximate for the task being performed.

Excitatory Amino Acid Agonists↗

PubMed1987

Dietary restriction benefits learning and motor performance of aged mice.

Female C3B10RF1 mice maintained on either a control (approximately 95 kcal/week) or restricted (approximately 55 kcal/week) diet since weaning were tested in a behavioral battery at 11 to 15 or 31 to 35 months of age (middle-aged vs. aged). Age-related declines observed among control groups in tests of motor coordination (rotorod) and learning (complex maze) were prevented by the restriction regime. In addition, diet restriction increased locomotor activity in a runwheel cage among mice of both ages but did not affect exploratory activity in a novel arena.

Aging↗

PubMed1998

[Behavioral-teratological effects of caffeine on mice].

Pregnant ICR mice were exposed to caffeine at levels of 0, 4, 20 and 100 mg/kg during pregnancy. The behavioral-teratological tests indicated that the retardation of development, the obstruction of early reflexes and sensation and decline of learning ability existed in the offsprings of 20 and 100 mg/kg groups. The number of the dead fetus increased in the group of 100 mg/kg coffeine treated mice. No morphological changes were found.

Animals↗

PubMedDate not supplied

Lack of the metabotropic glutamate receptor subtype 7 selectively modulates Theta rhythm and working memory.

Metabotropic glutamate receptors (mGluRs) are known to play a role in synaptic plasticity and learning. We have previously shown that mGluR7 deletion in mice produces a selective working memory (WM) impairment, while other types of memory such as reference memory remain unaffected. Since WM has been associated with Theta activity (6-12 Hz) in EEGs, and since EEG abnormalities have been observed in these mice before, we studied the effect of mGluR7 gene ablation on EEG activity in the hippocampus, in particular in the Theta range, during performance of a WM task. In an eight-arm maze with four arms baited, mGluR7 knock-out (KO) and wild-type mice committed the same number of reference memory errors, whereas KOs committed more WM errors. While performing the task, KO mice showed substantially higher Theta amplitudes, and the ratio of Theta to overall EEG power was much increased. No change was seen in the Delta (0-5 Hz), or Gamma (30-40 Hz) EEG bands compared with controls. When recording EEGs during periods of rest in the home cages, no difference was seen between groups. These findings suggest that mGluR7 is important for modulation and control of Theta activity. Since only WM was affected, and only the Theta range of EEG activity was altered, these results show a correlation between Theta rhythm and WM performance, and therefore support the concept that Theta activity in the hippocampus is involved in WM storage.

Analysis of Variance↗

PubMed2000

Individual differences in spatial learning from computer-simulated environments.

A multivariate study examined relationships between the following factors: paper-and-pencil assessments of verbal and spatial ability, ability to form an accurate spatial representation of a large real-world environment, gender, computer attitudes and experience, proficiency with the navigational interface of a virtual environment (VE), and the ability to acquire and transfer spatial knowledge from a VE. Psychometrically assessed spatial ability and proficiency with the navigational interface were found to make substantial contributions to individual differences in the ability to acquire spatial information from a VE. Gender influenced many VE-related tasks, primarily through its relationship with interface proficiency and spatial ability. Measures of spatial knowledge of a VE maze were highly predictive of subsequent performance in a similar real-world maze, suggesting that VEs can be useful for training people about real-world spaces.

Adult↗

PubMed1981

The behaviour of immature and mature rats exposed prenatally to anti-ganglioside antibodies.

Three behavioural experiments were carried out in rats born to mothers injected with anti-ganglioside antibodies between days 16 and 19 of their pregnancies. Immature animals were slower to habituate to an open-field arena and took longer to learn sequence maze when no cues were provided than did offspring of mothers who had received normal serum. The latter difference disappeared when the way through the maze was cued. In a third experiment mature rats, exposed prenatally to the antibody, showed superior adaptation on a visual discrimination task compared to their controls. It was concluded that antiganglioside modifies sensory rather than motor mechanisms in the rat.

Age Factors↗

PubMed2002

Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear.

We identified the Grp gene, encoding gastrin-releasing peptide, as being highly expressed both in the lateral nucleus of the amygdala, the nucleus where associations for Pavlovian learned fear are formed, and in the regions that convey fearful auditory information to the lateral nucleus. Moreover, we found that GRP receptor (GRPR) is expressed in GABAergic interneurons of the lateral nucleus. GRP excites these interneurons and increases their inhibition of principal neurons. GRPR-deficient mice showed decreased inhibition of principal neurons by the interneurons, enhanced long-term potentiation (LTP), and greater and more persistent long-term fear memory. By contrast, these mice performed normally in hippocampus-dependent Morris maze. These experiments provide genetic evidence that GRP and its neural circuitry operate as a negative feedback regulating fear and establish a causal relationship between Grpr gene expression, LTP, and amygdala-dependent memory for fear.

Amygdala↗

PubMedDate not supplied

Age differences in spatial memory in a virtual environment navigation task.

The use of virtual environment (VE) technology to assess spatial navigation in humans has become increasingly common and provides an opportunity to quantify age-related deficits in human spatial navigation and promote a comparative approach to the neuroscience of cognitive aging. The purpose of the present study was to assess age differences in navigational behavior in a VE and to examine the relationship between this navigational measure and other more traditional measures of cognitive aging. Following pre-training, participants were confronted with a VE spatial learning task and completed a battery of cognitive tests. The VE consisted of a richly textured series of interconnected hallways, some leading to dead ends and others leading to a designated goal location in the environment. Compared to younger participants, older volunteers took longer to solve each trial, traversed a longer distance, and made significantly more spatial memory errors. After 5 learning trials, 86% of young and 24% of elderly volunteers were able to locate the goal without error. Performance on the VE navigation task was positively correlated with measures of mental rotation and verbal and visual memory.

Adult↗

PubMed1999

Memory impairment after soman intoxication in rat: correlation with central neuropathology. Improvement with anticholinergic and antiglutamatergic therapeutics.

The effects of soman, a potent irreversible inhibitor of acetylcholinesterase, on central neuropathology in rats were studied in relation with subsequent spatial memory impairments. In a first step, it was found that, without treatment, neuropathology and learning impairment were observed only in rats which experienced convulsions. Then, treatment consisting of atropine sulfate, and/or TCP and/or NBQX was administered to intoxicated animals at infraanticonvulsant doses to obtain a graded subsequent neuropathology and to appreciate an eventual relation between neuropathology and spatial memory impairment. Thus, a correlation between neuropathology in the hippocampal CA1 region and spatial learning performance was found, the degradation of performance of rat being directly related to the amplitude of their neural damage. A threshold was emphasized : below a certain degree of neural loss, no memory impairment was found. Only treatment with tritherapy (atropine + TCP + NBQX) was able to improve the different parameters of spatial learning, despite no effect on the convulsions of the animals.

Animals↗

PubMed2004

The effects of estrogens on learning in rats with chronic brain cholinergic deficiency in a Morris water test. Identification of the "passive swimming" component.

Chronic decreases in brain cholinergic functions due to intraventricular administration of the neurotoxin AF64A were accompanied by increases in the latent period of locating an invisible platform during training of rats in a Morris water test, as compared with control sham-operated animals. Recordings of the animals' movement trajectories using a video camera along with an original computer program (Behavioral Vision) showed that administration of 17beta-estradiol and its synthetic analog J-861 (0.2 mg/kg p.o. daily for seven days before and 10 days after single intraventricular injections of AF64A) improved learning. The directivity of platform search trajectories was assessed quantitatively using a new parameter--trajectory straightness. Introduction of the "passive swimming" parameter allowed periods of immobility in water to be identified within the total latent period in animals after administration of AF64A; 17beta-estradiol but not J-861 "eliminated" these periods. The new parameters (especially trajectory straightness) allowed the ability to learn to be discriminated from decreases in mobility, including mobility losses due to study agents, in the Morris water test.

Adrenal Glands↗

PubMed1995

Displacement of corticotropin releasing factor from its binding protein as a possible treatment for Alzheimer's disease.

In Alzheimer's disease (AD) there are dramatic reductions in the content of corticotropin releasing factor (CRF), reciprocal increases in CRF receptors, and morphological abnormalities in CRF neurons in affected brain areas. Cognitive impairment in AD patients is associated with a lower cerebrospinal fluid concentration of CRF, which is known to induce increases in learning and memory in rodents. This suggests that CRF deficits contribute to cognitive impairment. The identification in post-mortem brain of CRF-binding protein (CRF-BP), a high-affinity binding protein that inactivates CRF, and the differential distribution of CRF-BP and CRF receptors, provides the potential for improving learning and memory without stress effects of CRF receptor agonists. Here we show that ligands that dissociate CRF from CRF-BP increase brain levels of 'free CRF' in AD to control levels and show cognition-enhancing properties in models of learning and memory in animals without the characteristic stress effects of CRF receptor agonists.

Adult↗

PubMed2001

Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory.

Activation of central glucocorticoid receptors caused by the stress that is associated with a learning task facilitates storage of the acquired information. The molecular mechanism underlying this phenomenon is entirely unknown. Glucocorticoid receptors can influence transcription both through DNA binding-dependent and -independent mechanisms. To assess the importance of these two modes of action for spatial memory, we here used male mutant mice in which homodimerization and DNA binding of the glucocorticoid receptor is largely prevented (GR(dim/dim)) while protein-protein interactions still can take place. These mice showed a selective impairment of spatial memory in the water maze. Locomotion and anxiety-related parameters measured in an open field and a light/dark preference task were comparable for mutant and control mice. Mutant mice released more corticosterone than control mice under basal resting conditions and in response to swimming, which could have influenced memory processes of the mice. However, mimicking the task-related increase in corticosterone by supplementary injection of corticosterone (250 microg/kg, i.p.) in adrenalectomized mice, resulting in equal plasma corticosterone concentrations in both genotypes, improved spatial memory of control mice but had no effect on mutant mice. These findings suggest that task-related facilitating effects of corticosterone on spatial memory indeed depend on DNA binding of the glucocorticoid receptor rather than on protein-protein interactions of the receptor with other transcription factors. Although it cannot be excluded that both processes are involved in a coordinated way, interrupting the DNA-binding capacity of the receptor is sufficient to induce impairment.

Animals↗

PubMed1996

Role of nitric oxide and cyclic GMP in the dizocilpine-induced impairment of spontaneous alternation behavior in mice.

The activation of N-methyl-D-aspartate receptors induces the synthesis of nitric oxide, which activates soluble guanylate cyclase and leads to the formation of cyclic GMP in the brain. The inhibition of nitric oxide production, as well as the blockade of N-methyl-D-aspartate receptors, has been reported to prevent the induction of hippocampal long-term potentiation and learning and memory formation in vivo, although the effects of inhibitors of nitric oxide synthase are still controversial. We investigated the putative role of nitric oxide and cyclic GMP in dizocilpine-induced memory impairment in mice. The nitric oxide synthase inhibitors, NG-nitro-L-arginine methyl ester and 7-nitro indazole, as well as dizocilpine, a non-competitive N-methyl-D-aspartate receptor antagonist, dose-dependently impaired spatial working memory in mice, assessed by their spontaneous alternation behavior in a Y-maze. The inhibitory effects of both NG-nitro-L-arginine methyl ester and dizocilpine on their behavior were completely reversed by 8-bromo-cyclic GMP. Cyclic GMP levels in the cerebellum were reduced by treatment with dizocilpine. NG-Nitro-L-arginine methyl ester and 7-nitro indazole reduced cyclic GMP levels in the cerebral cortex/hippocampus and cerebellum, and the suppressive effect of NG-nitro-L-arginine methyl ester on cyclic GMP levels in the cerebral cortex/hippocampus was reversed by co-treatment with L-arginine. Cyclic AMP levels in the brain were not affected by treatment with either dizocilpine, NG-nitro-L-arginine methyl ester, or 7-nitro indazole. Neither NG-nitro-L-arginine methyl ester nor L-arginine had any effect on monoamine and acetylcholine metabolism in the brain. These results suggest that the reduction in nitric oxide/cyclic GMP production in the brain may be responsible for dizocilpine-induced impairment of spontaneous alternation behavior in a Y-maze.

Animals↗

PubMed1999

The effects of paradoxical sleep deprivation and valine on spatial learning and brain 5-HT metabolism.

We have previously reported that rapid eye movement sleep deprivation (REMSD), induced by the flower pot technique, causes a deficit in reference spatial memory and increases rates of serotonin (5-HT) metabolism in the brain. In this study we used increased concentrations of dietary valine to inhibit tryptophan (TRP) transport across the blood-brain barrier in an attempt to modify the REMSD-induced increase of 5-HT metabolism. Rats were fed either a control diet or the same diet supplemented to 2% by weight valine, and were allocated to one of three experimental groups: cage control (CC), stress tank control (TC), or REMSD. Reference and working spatial memory of all rats was tested in a Morris water maze on Days 2, 3, and 4. REMSD produced a significant decrement in reference memory on Days 2 and 4, independent of dietary condition. The valine diet had a detrimental effect on the reference memory of TC rats on Day 2 but not Day 4. Measurements made on Day 4 indicated that the valine diet decreased brain TRP only in the CC rats. In contrast, the valine diet did not prevent increases in brain TRP or 5-HT metabolism in REMSD rats, and increased hypothalamic and brain stem TRP concentrations and the hippocampal 5-HIAA/5-HT ratio in TC rats. These results indicate that dietary valine does not prevent REMSD-induced changes in spatial memory or serotonin metabolism, although it does reduce brain TRP in nonstressed rats.

Animals↗