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Spatial learning and memory following fimbria-fornix transection and grafting of fetal septal neurons to the hippocampus.

The ability of intrahippocampal grafts of fetal septal-diagonal band tissue, rich in developing cholinergic neurons, to ameliorate cognitive impairments induced by bilateral fimbria-fornix transections in rats was examined in three experiments using the Morris water-maze to test different aspects of spatial memory. Experiment 1. Rats with fimbriafornix lesions received either septal cell suspension grafts or solid septal grafts; normal rats and rats with lesions alone were used as controls. Sixteen weeks after surgery, the rats' spatial learning and memory were tested in the water-maze using a place test, designed to investigate place navigation performance, in which rats learned to escape from the water by swimming to a platform hidden beneath the water's surface. After 5 days of training, the rats were given a spatial probe test in which the platform was removed from the tank to test spatial reference memory. Experiment 2. The same rats used in Exp. 1 were tested in a delayed-match-to-sample, working memory version of the water-maze task. The platform was located in one of two possible locations during each trial, which was composed of 2 swims. If the rat remembered the location of the platform on the 2nd swim of a trial, it should find the platform more quickly on that swim, and thereby demonstrate working memory. Experiment 3. Prior to receiving fimbria-fornix lesions, normal rats were trained in a modification of the water-maze task using alternating cue navigation and place navigation trials (i.e., with visible or non-visible escape platforms). The retention and reacquisition of the place task and the spatial probe test were examined in repeated tests up to 6 months after the lesion and intrahippocampal grafting of septal cell suspensions. The effects of central muscarinic cholinergic receptor blockade with atropine were also tested. Normal rats performed well in both the place and spatial probe tests. In contrast, rats with fimbria-fornix lesions only were unable to acquire or retain spatial information in any test. Instead, these rats adopted a random, non-spatial search strategy, whereby their latencies to find the platform decreased in the place navigation tasks. Sixty to 80% of the rats with septal suspension or solid grafts had recovered place navigation, i.e., the ability to locate the platform site in the tank, in Exp. 1 and 3, and they showed a significantly improved performance in the working memory test in Exp. 2. Atropine abolished the recovered place navigation in the grafted rats, whereas normal rats were impaired to a lesser extent.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholinesterase↗

[Effects of cerebral GABA level on learning and memory].

In step-down tests, icv GABA 0.1 micrograms (3 min before training) or ip amino-oxyacetic acid 20 mg/kg (1.5 h before training) both significantly impaired memory acquisition in mice. But semicarbazide (ip 110 mg/kg 3.5 h before training), an inhibitor of GABA synthesis, improved the anisodine-induced impairments of learning. The effects of GABA was also enhanced by aminooxyacetic acid. The results suggest that the increase of cerebral GABA contents is unfavourable to learning and memory.

Aminooxyacetic Acid↗

An automated learning and memory model in mice: pharmacological and behavioral evaluation of an autoshaped response.

The purpose of the present experiments was to develop and validate pharmacologically an automated, relatively rapid, and reproducible behavioral model of learning and memory using an autoshaping procedure in mice. Nose-poke responses into a recessed area were differentiated by response-dependent reinforcement during two identical consecutive daily sessions. Performance during the first session was considered to be a measure of acquisition and that during the second session a measure of retention. Sensitivity to procedural manipulation, as well as an index of learning under these conditions, was demonstrated, for example, by a decrease in response rate when nose-poke responses did not produce a reinforcer. The sensitivity of the paradigm to pharmacological intervention was examined after drug administration before the first session. Scopolamine (0.1-10.0 mg/kg) had no effect on acquisition but caused a significant dose-related impairment of retention. Dizocilpine (0.01-1.0 mg/kg) impaired both acquisition and retention performance. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.1-1.0 mg/kg) disrupted behavior in general, but failed to have a selective effect on acquisition or retention. Linopirdine (0.1-1.0 mg/kg) showed only a weak enhancement of acquisition, whereas 4-aminopyridine (4-AP; 0.1-1.0 mg/kg) significantly facilitated acquisition. This paradigm offers the potential for a rapid, objective, and reliable indication of whether a drug will affect the acquisition or retention of a positively reinforced response in mice and could be a useful supplement to existing procedures.

4-Aminopyridine↗

Memory extinction, learning anew, and learning the new: dissociations in the molecular machinery of learning in cortex.

The rat insular cortex (IC) subserves the memory of conditioned taste aversion (CTA), in which a taste is associated with malaise. When the conditioned taste is unfamiliar, formation of long-term CTA memory depends on muscarinic and beta-adrenergic receptors, mitogen-activated protein kinase (MAPK), and protein synthesis. We show that extinction of CTA memory is also dependent on protein synthesis and beta-adrenergic receptors in the IC, but independent of muscarinic receptors and MAPK. This resembles the molecular signature of the formation of long-term memory of CTA to a familiar taste. Thus, memory extinction shares molecular mechanisms with learning, but the mechanisms of learning anew differ from those of learning the new.

Adrenergic beta-Antagonists↗

Genetic neuroscience of mammalian learning and memory.

Our primary research interest is to understand the molecular and cellular mechanisms on neuronal circuitry underlying the acquisition, consolidation and retrieval of hippocampus-dependent memory in rodents. We study these problems by producing genetically engineered (i.e. spatially targeted and/or temporally restricted) mice and analysing these mice by multifaceted methods including molecular and cellular biology, in vitro and in vivo physiology and behavioural studies. We attempt to identify deficits at each of the multiple levels of complexity in specific brain areas or cell types and deduce those deficits that underlie specific learning or memory. We will review our recent studies on the acquisition, consolidation and recall of memories that have been conducted with mouse strains in which genetic manipulations were targeted to specific types of cells in the hippocampus or forebrain of young adult mice.

Animals↗

The use of alert behaving mice in the study of learning and memory processes.

The availability of transgenic mice that mimic human neurodegenerative processes has made it necessary to develop new recording and stimulating techniques capable of being applied in this species. We have studied here the motor learning and memory capabilities of wild-type and transgenic mice with deficits in cognitive functions, using classical conditioning procedures. We have developed an electrical shock/SHOCK paradigm corresponding to a trace classical conditioning; that is, a learning task involving the cerebral cortex, including the hippocampus. The conditioning procedure is a modification of the air-puff/AIR-PUFF conditioning (Gruart et al., J. Neurophysiol. 74:226, 1995). Animals were implanted with stimulating electrodes in the supraorbitary branch of the trigeminal nerve and with recording electrodes in the orbicularis oculi muscle. Computer programs were developed to quantify the appearance and evolution of eyelid conditioned responses. According to the present results, the classical conditioning of eyelid responses appears to be a suitable (associative) learning procedure to study learning capabilities in genetically-modified mice.

Age Factors↗

Different effects of tropisetron and ondansetron in learning and memory paradigms.

The effects of the 5-HT3 receptor antagonists tropisetron (ICS 205-930) and ondansetron on memory and performance impairments induced by scopolamine were tested in a passive avoidance procedure and in the Morris water maze task. Pretreatment with ondansetron (0.01 and 1 microgram/kg i.p.) but not with tropisetron (1, 10, and 30 micrograms/kg i.p.) reversed scopolamine-induced memory deficits in the step-through passive avoidance task. When the effects of these 5-HT3 receptor antagonists on cognition were assessed in the Morris water maze, ondansetron (0.01, 1, and 10 micrograms/kg i.p.) did not antagonize scopolamine-induced spatial navigation deficits. On the contrary, pretreatment with tropisetron (10 and 30 micrograms/kg, and to some extent also with 1 microgram/kg i.p.) counteracted the learning and memory impairment due to scopolamine treatment. The findings suggest that it could be worthwhile to investigate whether or not different subtypes of the 5-HT3 receptor may underlie the different effects on cognition displayed by compounds that belong to the same pharmacological class.

Animals↗

Tissue inhibitor of metalloproteinases-1 (TIMP-1) modulates neuronal death, axonal plasticity, and learning and memory.

The tissue inhibitor of metalloproteinases-1 (TIMP-1) belongs to a family of multifunctional proteins that inhibit matrix metalloproteinases (MMPs), but also regulate cell growth, proliferation, migration and apoptosis in non-nervous tissues. We had previously reported that kainate (KA)-mediated excitotoxic seizures induce the expression of TIMP-1 in resistant neurons and reactive astrocytes of the rat CNS, but the functional implications of these changes had not been elucidated. In the present work we used a targeted gene null mutation in mice to investigate in vivo the involvement of TIMP-1 in neuronal death and axonal sprouting following KA. We found no differences in seizure behaviour between the wild-type (WT) and the TIMP-1 knock-out (KO) mice, without any compensation by other TIMPs, at least at the mRNA level. However, the TIMP-1 KO mice were resistant to excitotoxicity and did not undergo the typical mossy fibre sprouting observed in WT mice. The lack of TIMP-1 paradoxically hampered the increase in the activity of MMPs observed in the seizing WT mice. In addition, we demonstrate that learning and memory are impaired in untreated KO mice. In conclusion, this study provides the first in vivo evidence for the implication of TIMP-1 in neuronal death and axonal sprouting in a pathological situation, but also suggests the involvement of TIMP-1 in the synaptic mechanisms underlying learning and memory in physiological conditions. More generally, these data support the idea that the control of proteolysis is instrumental for pathological and physiological processes in the brain.

Animals↗

[Effects of excessive zinc in fodder on brain development and abilities of learning and memory and their mechanisms in young rats].

OBJECTIVE: To study the effects of excessive zinc in fodder on brain development and abilities of learning and memory and to explore their mechanisms in young rats. METHODS: Animal models with excessive zinc were established in young Wistar rats during their lactation period. Rats were divided into five groups, Groups ZE1 and ZE2 were fed with excessive zinc, Group AL was freely fed with Flanagna fomula fodder added with zinc sulfate, Group PF was matched pair of Group ZE2 and Group ZE2R was fed with fodder same as Group AL after weaning. Ultrastructure was observed with electron microscopy, their free amino acids, nitrous oxide and somatostatin were measured with neurobiochemical methods, and their abilities to learn and memorize were examined. RESULTS: Weight of cerebrum and hippocampus in the rats reduced and zinc levels in their serum and hippocampus raised with the increase of zinc content in their fodder. Acute avoidance response (AAR) and movement in the young rats fed with excessive zinc in Groups ZE1 and ZE2 were obviously lower than in Groups AL and PF. AAR was significantly lower in Group ZE2R than that in Groups AL and PF, but significantly higher than that in Group ZE2. There was no significant difference in AAR between Groups PF and AL, but more movement was observed in them. Nitrous oxide in hippocampus raised and somatostatin decreased in Group ZE2, and total amount of excitatory and inhibitory amino acids in brain tissues raised, especially for glutamic acid. Neurones, gliocytes and organella in the CA1 region of hippocampus in the Group ZE2 showed degeneration, necrosis and rupture of synaptic bolus to varied extent. CONCLUSION: Excessive zinc in fodder could significantly affect brain development and functions in young rats with multiple mechanisms.

Animals↗

Spatial learning and memory is preserved in rats after early development in a microgravity environment.

This study evaluated the cognitive mapping abilities of rats that spent part of their early development in a microgravity environment. Litters of male and female Sprague-Dawley rat pups were launched into space aboard the National Aeronautics and Space Administration space shuttle Columbia on postnatal day 8 or 14 and remained in space for 16 days. These animals were designated as FLT groups. Two age-matched control groups remained on Earth: those in standard vivarium housing (VIV) and those in housing identical to that aboard the shuttle (AGC). On return to Earth, animals were tested in three different tasks that measure spatial learning ability, the Morris water maze (MWM), and a modified version of the radial arm maze (RAM). Animals were also tested in an open field apparatus to measure general activity and exploratory activity. Performance and search strategies were evaluated in each of these tasks using an automated tracking system. Despite the dramatic differences in early experience, there were remarkably few differences between the FLT groups and their Earth-bound controls in these tasks. FLT animals learned the MWM and RAM as quickly as did controls. Evaluation of search patterns suggested subtle differences in patterns of exploration and in the strategies used to solve the tasks during the first few days of testing, but these differences normalized rapidly. Together, these data suggest that development in an environment without gravity has minimal long-term impact on spatial learning and memory abilities. Any differences due to development in microgravity are quickly reversed after return to earth normal gravity.

Animals↗

Attenuated hippocampus-dependent learning and memory decline in transgenic TgAPPswe Fischer-344 rats.

Alzheimer's disease (AD) is characterized by increased beta amyloid (Abeta) levels, extracellular Abeta deposits in senile plaques, neurofibrillary tangles, and neuronal loss. However, the physiological role of normal levels of Abeta and its parent protein, the amyloid precursor protein (APP) are unknown. Here we report that low-level transgenic (Tg) expression of the Swedish APP mutant gene (APPswe) in Fischer-344 rats results in attenuated age-dependent cognitive performance decline in 2 hippocampus-dependent learning and memory tasks compared with age-matched nontransgenic Fischer-344 controls. TgAPPswe rats exhibit mild increases in brain APP mRNA (56.8%), Abeta-42 (21%), and Abeta-40 (6.1%) peptide levels at 12 mo of age, with no extracellular Abeta deposits or senile plaques at 6, 12, and 18 mo of age, whereas 3- to 6-fold increases in Abeta levels are detected in plaque-positive human AD patients and transgenic mouse models. The data support the hypothesis that a threshold paradigm underlies Abeta-related pathology, below which APP expression may play a physiological role in specific hippocampus-dependent tasks, most likely related to its neurotrophic role.

Aging↗

GM1 ganglioside improves spatial learning and memory of aged rats.

GM1 ganglioside, 30 mg/kg, i.p., was administered to cognitively impaired aged rats for 30 days, and spatial learning and memory evaluated in a Morris water maze paradigm. During treatment with GM1, aged animals improved both the acquisition and retention of place navigation, as reflected by reduced escape latencies and swim distances to a hidden platform, and persistently performed better than the aged control animals. Furthermore, the GM1-treated animals showed improved spatial acuity in a spatial probe test when the hidden platform was removed. The improved performance in place navigation was not lost if GM1 treatment was discontinued and the animals tested up to 15 days later. GM1 treatment had no effect on the performance of young rats in the water maze. These results indicate that memory deficits associated with aging can be attenuated by treatment with GM1 ganglioside.

Aging↗

Constraints on priming in spatial memory: naturally learned versus experimentally learned environments.

In four experiments, we explored constraints on priming in spatial memory. In Experiments 1 and 2, subjects who were familiar with the locations of buildings on the Vanderbilt campus participated in a recognition test. The subjects' task was to decide whether or not named buildings were on the campus. Foils in this recognition test were realistic but fictional names of buildings. In principle, the subjects could have performed this task without using spatial knowledge; in fact, they must not have used spatial knowledge, because there was no evidence of priming in recognition as a function of the spatial relations between buildings on the campus. This result differs from those obtained in earlier experiments that have examined memory of spatial layouts learned in laboratory settings. In Experiment 3, the fictional foils were replaced by names of buildings in an area of the campus separated geographically from the main campus. Evidently, this change induced subjects to retrieve spatial knowledge, because the spatial priming effect materialized. A fourth experiment replicated the above findings in a single experiment and demonstrated that spatial priming could be obtained when the configuration of buildings was learned experimentally. These results are explained by appealing to the "decontextualization" that takes place in memory over time.

Adult↗

Cortico-hippocampal interaction and adaptive stimulus representation: a neurocomputational theory of associative learning and memory.

Computational models of the hippocampal region link psychological theories of associative learning with their underlying physiological and anatomical substrates. Our approach to theory development began with a broad description of the computations that depend on the hippocampal region in classical conditioning (Gluck and Myers, 1993 and Gluck and Myers, 2001). In this initial model, the hippocampal region was treated as an Information-processing system that transformed stimulus representations, compressing (making more similar) representations of inputs that co-occur or are otherwise redundant, while differentiating (or making less similar) representations of inputs that predict different future events. This model led to novel predictions for the behavioral consequences of hippocampal-region lesions in rodents and of brain damage in humans who have amnesia or are in the earliest stages of Alzheimer's disease. Many of these predictions have, since been confirmed by our lab and others. Functional brain imaging studies have provided further supporting evidence. In more recent computational modeling, we have shown how some aspects of this proposed information-processing function could emerge from known anatomical and physiological characteristics of the hippocampal region, including the entorhinal cortex and the septo-hippocampal cholinergic system. The modeling to date lays the groundwork for future directions that increase the depth of detail of the biological modeling, as well as the breadth of behavioral phenomena addressed. In particular, we are working now to reconcile these kinds of incremental associative learning models with other models of the hippocampal region that account for the rapid formation of declarative memories.

Animals↗

Hippocampus and olfactory discrimination learning: effects of entorhinal cortex lesions on olfactory learning and memory in a successive-cue, go-no-go task.

Three experiments assessed the effect of entorhinal cortex lesions on olfactory learning and memory using a successive-cue olfactory discrimination paradigm. In contrast to the results of other studies that used a simultaneous-cue paradigm, lesions of the entorhinal cortex facilitated rats' acquisition of individual odor discrimination problems, with no impairment in memory for the individual odors across both short (24-hr) and long (65-day) retention intervals and despite limited training. When considered together with previous observations of facilitation or impairment in learning after damage to the hippocampal system, the present data suggest that the hippocampus is preferentially involved in encoding relations among multiple stimuli. By this account, facilitation of performance is due to an interaction between hippocampal system dysfunction and task conditions that hinder direct comparisons among cues.

Animals↗

Measures of working memory, sequence learning, and speech recognition in the elderly.

This study describes the measurement of 2 cognitive functions, working-memory capacity and sequence learning, in 2 groups of listeners: young adults with normal hearing and elderly adults with impaired hearing. The measurement of these 2 cognitive abilities with a unique, nonverbal technique capable of auditory, visual, and auditory-visual stimulation, patterned after the Simon memory game, is described. The use of simple, easily understood items in the test sequences enabled the measurement of these cognitive abilities in older listeners with no apparent impact of age-related hearing loss on the cognitive measures. Age-related cognitive deficits were observed for all 3 modes of stimulation and in both working-memory capacity and sequence-learning ability. The age-related deficits appeared to be greatest, however, for the sequence-learning task. Although it was hypothesized that there might be an association between an individual's performance on these cognitive tasks and his or her performance on various measures of speech recognition, such an association generally was not observed.

Adult↗

Memory and learning in pediatric bipolar disorder.

OBJECTIVE: To test the hypothesis that patients with pediatric bipolar disorder (PBPD) would demonstrate impairment relative to diagnosis-free controls of comparable age, gender, and IQ on measures of memory functioning. METHOD: The authors administered a battery of verbal and visuospatial memory tests to 35 outpatients with PBPD and 20 healthy controls who participated as volunteers in this study. Groups did not differ on age, gender, or IQ. RESULTS: Consistent with findings in adults with BPD, patients with PBPD performed more poorly than controls on measures of verbal learning/memory and delayed facial recognition memory. Impaired memory was particularly evident in patients with comorbid PBPD/attention-deficit/hyperactivity disorder or acute mood symptoms. CONCLUSIONS: These findings suggest that deficits in verbal learning and memory, as well as some aspects of visuospatial memory, characterize patients with narrow phenotype PBPD. Further research is needed, however, to clarify the roles of comorbid attention-deficit/hyperactivity disorder and acute mood state in the emergence of these deficits. Given the apparent continuity in memory dysfunction between adult BPD and narrow phenotype PBPD, research aimed at elucidating underlying neural mechanisms for this set of deficits is warranted.

Bipolar Disorder↗