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PubMedDate not supplied

Increase in syntaxin 1B mRNA in hippocampal and cortical circuits during spatial learning reflects a mechanism of trans-synaptic plasticity involved in establishing a memory trace.

It has long been proposed that the cellular and molecular mechanisms responsible for LTP may well involve the mechanisms that lead to the type of synaptic modification that occurs during learning. However, it is also known that a single memory trace is encoded in spatially distributed networks; implying that alterations of synaptic strength occur at multiple sites along circuits of connected cells. Recent evidence suggests that regulation of the gene encoding syntaxin 1B, a presynaptic protein involved in exocytosis, plays an important role in the mediation of trans-synaptic LTP, a candidate mechanism for the propagation of plasticity in neural circuits during learning. Using in situ hybridization to measure the mRNA levels at different time points after learning a spatial working or reference memory task, we show that expression of the gene encoding this protein in the hippocampal and corticoprefrontal circuits increases linearly with performance at a critical window of learning when rats are reaching between 75% and 100% of their maximal performance. No changes were observed during the early phases of learning or when rats where overtrained. The correlational analysis indicates that coordinated increases in syntaxin 1B expression occurs in hippocampal circuits during working memory and in more widespread hippocampocortical circuits during reference memory. These results suggest that a form of trans-synaptic plasticity mediated in part by regulation of the expression of syntaxin 1B may play an active role in configuring specific spatially distributed circuits during the laying down of memories.

Animals↗
PubMed1994

Non-spatial learning following posterior parietal or hippocampal lesions.

Posterior parietal, hippocampal, or sham-lesioned rats were tested for the acquisition of a non-monotonic serial learning task. The performance of control rats and those with a posterior parietal lesion was similar, while those with hippocampal damage demonstrated a working memory deficit. The results are integrated with contemporary conceptualizations of hippocampal and posterior parietal cortex involvement in learning and memory for non-spatial tasks.

Analysis of Variance↗
PubMed1995

Excitatory amino acid receptors within nucleus accumbens subregions differentially mediate spatial learning in the rat.

The present experiments investigated the effects of excitatory amino acid antagonists, infused into core and shell subregions of the nucleus accumbens, on spatial behavior in the rat. A food-search task was used, in which animals learn a specific pattern of food gathering; duration of each trial (time taken to gather all four pellets) and number of errors (visits to empty holes) were measured. In experiment 1, animals first underwent training, and subsequently were given microinfusions of either D-2-amino-5 phosphonopentanoic acid (AP-5), an N-methyl-d-aspartate (NMDA) antagonist (0, 0.2, 1.0µg/0.5µl), or 6,7-dinitroquinoxaline-2,3-dione (DNQX), an antagonist of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors (0, 0.075, 0.75µg/0.5µl). AP-5-significantly increased trial duration in both core and shell groups, but increased errors only in the core group. DNQX treatment also impaired performance in both groups, but the effect was greater in the core group compared with the shell group. In experiment 2, animals were treated during acquisition. Rats infused with AP-5 (1µg/0.5µl) took significantly longer to finish trials, made more errors and showed a marked learning impairment across days. AP-5 impaired learning in both core and shell groups, but the disruption was significantly greater in the core group. DNQX (0.75µg/0.5µl) also impaired learning when infused into the core during acquisition; however, the pattern of disruption contrasted markedly with that of AP-5. DNQX in the shell had no effect on trial duration during learning. It is hypothesized that both NMDA and non-NMDA receptors in the nucleus accumbens mediate spatial learning and performance, and that NMDA receptors may have a relatively more important role in memory or retrieval mechanisms. Moreover, the core subregion may be preferentially involved in the control of spatial behavior.

Journal Article↗
PubMed1991

Physical activity effects on hippocampal and parietal cortical cholinergic function and spatial learning in F344 rats.

In the present investigation, the effects of physical activity on hippocampal cholinergic function, parietal cortical cholinergic function, and spatial memory were examined in F344 rats. Single bouts of physical activity elevated hippocampal and cortical high affinity choline uptake, whereas chronic physical activity significantly reduced only hippocampal high affinity choline uptake (HACU) and elevated muscarinic (QNB) receptor density. Three weeks prior to the end of the 14-week chronic treadmill running protocol, a group of chronic-run rats and their non-run controls were tested on a stringent version of Whishaw's place learning-set task. Chronic-run rats exhibited enhanced performance on the spatial task by significantly reduced second trial latencies and elevated first and second trial proximity ratio scores. Chronic-run spatial memory tested rats also showed enhanced hippocampal HACU and muscarinic receptor binding. These data indicate that chronic physical activity improves spatial learning performance. This improvement may be due, in part, to a chronic running-induced enhancement of hippocampal cholinergic functioning.

Animals↗
PubMed1988

Learning in rats with caudate-putamen lesions: unimpaired classical conditioning and beneficial effects of redundant stimulus cues on instrumental and spatial learning deficits.

The effects of caudate-putamen lesions in the rat on conditioning were investigated in three experiments. In Experiment 1, rats with lesions were impaired on a spatial task that required learning to make the correct position response, but no deficit was obtained when the alternatives were differentiated by salient visual cues. Performance remained good even when the visual cues were removed. A classical conditioned suppression paradigm was used in Experiment 2, and caudate-putamen lesions were found not to impair acquisition of suppression or overshadowing. In Experiment 3 we revealed poor instrumental learning in subjects with lesions as retarded acquisition of lever-press responding and depressed variable interval response rates. When a light stimulus was present together with reinforced responses, response rates were depressed in the control group (which suggested an overshadowing phenomenon) but were potentiated in the group with lesions. The results showed that caudate-putamen lesions did not produce a general deficit in association formation. There was disruption of learning about responses but not stimuli and, moreover, it was found that redundant stimulus cues aided response learning. It appears that for normal subjects, the salience or associability of the response cues may largely determine the influence of stimuli presented during instrumental conditioning.

Animals↗
PubMed2001

Of mice and men: virtual Hebb-Williams mazes permit comparison of spatial learning across species.

We developed a computer-generated virtual environment to test humans, for the first time, on the Hebb-Williams mazes. The goal was to provide a standardized test that could be used to directly compare human performance with that of C57BL/6J mice performing in real versions of the mazes. Such a comparison seems crucial if conclusions regarding genetic manipulations of rodents are to be mapped onto human cognitive disorders. The learning curves across species were strikingly similar, lending support to the rodent model of human spatial memory. Humans learned faster than rodents in both the acquisition and the test portions of the protocol, and females of both species were less efficient in solving these problems than males. These results represent the first modern comparison of human and rodent learning that uses the same test of spatial problem solving.

Adult↗
PubMed1993

Comparative effects of excitotoxic lesions of the hippocampus and septum/diagonal band on conditional visual discrimination and spatial learning.

Several experiments compared the effects of excitotoxic lesions of the septal/vertical limb nuclei of the diagonal band of Broca (VDB) complex with those of the hippocampus (sparing the subiculum) on different forms of visual discrimination learning. The septal/VDB lesions, which produced significant reductions in choline acetyltransferase activity in the hippocampus and the cingulate cortex, impaired acquisition of a conditional visual discrimination in an operant chamber, while the hippocampal lesion had no effect, unless there was a delay interposed between the discriminative stimulus and the response. Neither lesion affected simple visual or spatial discrimination or reversal learning, also carried out in operant chambers, but both significantly impaired the acquisition and retention of a spatial navigation task (Morris water maze), with the septal/VDB lesions again producing greater deficits than the hippocampal lesions. Possible explanations for this surprising result are discussed and it is concluded that; (1) additional cholinergic de-afferentation of the cingulate cortex produced by the septal/VDB lesion is of functional significance; (2) this may lead to deficits in conditional rule learning, which can contribute to spatial navigation performance under certain circumstances; and (3) the contribution of septal-hippocampal cholinergic projections to spatial learning is in need of re-appraisal.

Animals↗
PubMed1997

Spatial learning by rats across visually disconnected environments.

Two spatial tasks were designed to test specific properties of spatial representation in rats. In the first task, rats were trained to locate an escape hole at a fixed position in a visually homogeneous arena. This arena was connected with a periphery where a full view of the room environment existed. Therefore, rats were dependent on their memory trace of the previous position in the periphery to discriminate a position within the central region. Under these experimental conditions, the test animals showed a significant discrimination of the training position without a specific local view. In the second task, rats were trained in a radial maze consisting of tunnels that were transparent at their distal ends only. Because the central part of the maze was non-transparent, rats had to plan and execute appropriate trajectories without specific visual feedback from the environment. This situation was intended to encourage the reliance on prospective memory of the non-visited arms in selecting the following move. Our results show that acquisition performance was only slightly decreased compared to that shown in a completely transparent maze and considerably higher than in a translucent maze or in darkness. These two series of experiments indicate (1) that rats can learn about the relative position of different places with no common visual panorama, and (2) that they are able to plan and execute a sequence of visits to several places without direct visual feed-back about their relative position.

Animals↗
PubMed1994

Impaired spatial learning by vasoactive intestinal peptide in Morris water maze task in the rat.

Intracerebroventricular administration of vasoactive intestinal peptide (VIP) disturbed the learning by rats of the location of a platform submerged in a water pool. When the platform was removed from the pool, VIP injection produced marked impairment of the ability to find a previously learned location in the pool. This spatial memory impairment caused by VIP was restored by peripheral pre-administration of cerulein.

Animals↗
PubMed1984

Developments of a water-maze procedure for studying spatial learning in the rat.

Developments of an open-field water-maze procedure in which rats learn to escape from opaque water onto a hidden platform are described. These include a procedure (A) for automatically tracking the spatial location of a hooded rat without the use of attached light-emitting diodes; (B) for studying different aspects of spatial memory (e.g. working memory); and (C) for studying non-spatial discrimination learning. The speed with which rats learn these tasks suggests that they may lend themselves to a variety of behavioural investigations, including pharmacological work and studies of cerebral function.

Animals↗
PubMed1996

The systemic administration of tacrine or selegiline facilitate spatial learning in aged fisher 344 rats.

When compared to young Fisher 344 rats, aged Fisher 344 rats were impaired in their acquisition of the water maze task as indicated by longer escape latencies and distances to find a hidden platform. In a free swim trial which was performed after the training period, young rats had a better spatial bias, since they spent more time swimming in the previous training quadrant. Tacrine 3 mg/kg, an anticholinesterase, and selegiline 0.25 mg/kg, a MAO-B inhibitor, partially reversed the acquisition deficit in aged rats when administered on their own, and drug-treated aged rats swam more in the previous training quadrant than vehicle-treated aged rats during the free swim trial. Aged rats also swam slower than young rats. Tacrine, but not selegiline, increased swimming speed in aged rats. Taken as a whole, these data support the proposal that tacrine may be effective at alleviating age-related learning impairment and confirm the role of cholinergic dysfunction in the spatial learning deficit in aged rats.

Aging↗
PubMed2001

Spatial learning deficits without hippocampal neuronal loss in a model of early-onset epilepsy.

Studies were undertaken to examine the effects recurrent early-life seizures have on the ability of rats to acquire spatial memories in adulthood. A minute quantity of tetanus toxin was injected unilaterally into the hippocampus on postnatal day 10. Within 48 h, rats developed recurrent seizures that persisted for 1 week. Between postnatal days 57 and 61, rats were trained in a Morris water maze. Toxin-injected rats were markedly deficient in learning this task. While these rats showed gradual improvement in escape latencies over 20 trials, their performance always lagged behind that of controls. Poor performance could not be explained by motor impairments or motivational difficulties since swimming speed was similar for the groups. Only eight of 16 toxin-injected animals showed focal interictal spikes in the hippocampus during electroencephalographic recordings. This suggests that learning deficiencies and chronic epilepsy may be independent products of recurrent early-life seizures. A quantitative analysis of hippocampus revealed a significant decrease in neuronal density in stratum pyramidale of experimental rats. However, the differences were largely explained by a concomitant increase in the area of stratum pyramidale. Studies of glial fibrillary acidic protein expression and spread of horseradish peroxidase-conjugated tetanus toxin in the hippocampus suggest that the dispersion of cell bodies in stratum pyramidale can neither be explained by a reactive gliosis nor the direct action of the toxin itself. Taken together, we suggest that recurrent seizures beginning in early life can lead to a significant deficiency in spatial learning without ongoing hippocampal synchronized network discharging or a substantial loss of hippocampal pyramidal cells.

Action Potentials↗
PubMed2000

Nonreceptor tyrosine protein kinase pp60c-src in spatial learning: synapse-specific changes in its gene expression, tyrosine phosphorylation, and protein-protein interactions.

c-src is a nonreceptor tyrosine protein kinase that is highly concentrated in synaptic regions, including synaptic vesicles and growth cones. Here, we report that the mRNA signal of pp60c-src is widely distributed in the rat brain with particularly high concentrations in the hippocampus. After spatial maze learning, up-regulation of c-src mRNA was observed in the CA3 region of the hippocampus, which was accompanied by increases in pp60c-src protein in hippocampal synaptosomal preparations. Training also triggered an increase in c-src protein tyrosine kinase activity that was correlated with its tyrosine dephosphorylation in the synaptic membrane fraction. After training, pp60c-src from hippocampus showed enhanced interactions with synaptic proteins such as synapsin I, synaptophysin, and the type 2 N-methyl-d-aspartate receptor, as well as the cytoskeletal protein actin. The association of pp60c-src with insulin receptor in the synaptic membrane fraction, however, was temporally decreased after training. Furthermore, in vitro results showed that Ca(2+) and protein kinase C might be involved in the regulation of protein-protein interactions of pp60c-src. These results suggest, therefore, that pp60c-src participates in the regulation of hippocampal synaptic activity during learning and memory.

Animals↗
PubMed1986

Scopolamine-induced deficits in acquisition of a complex spatial learning.

The role of scopolamine was studied in a complex spatial orientation task. The procedure involved an increasing difficulty of the task: at the pretraining stage a cue (box) was placed at the reinforcement spot and the animal could give a correct response by adopting either a cue-strategy or an orientation response (i.e., go to the arm on the right of a visual landmark). In the subsequent spatial training, the box was removed, so that the orientation response was the only correct one. Results show that scopolamine-injected animals are able to use a cue-strategy but are unable to acquire a spatial orientation strategy: this more complex task asks for more time and for more sustained attention. When the response is already partly acquired, scopolamine has less effect. The cholinergic system would thus be involved in the quality or even the complexity of the response rather than in the retention itself. Though a state-dependent effect may not be excluded, it by itself cannot explain the observed differences. Finally, an impairment of the maintenance of attention could be responsible for the deficits observed in the acquisition of the complex task.

Animals↗
PubMed1989

Early rearing environment and dorsal hippocampal ibotenic acid lesions: long-term influences on spatial learning and alternation in the rat.

Behavioural responses in a set of spatial and cue tasks were assessed in adult rats that had been given ibotenic acid lesions of the dorsal hippocampus at weaning. The lesions or sham operations were immediately followed by one month of differential rearing, either in enriched, social or isolated housing environments. The differential rearing was followed by standard (social) housing conditions until behavioural testing began at 4 months of age. Compared to sham-operated rats, the rats with early cytotoxic lesions showed substantial impairments on learning and efficient strategy formation in radial arm maze, retention of a spatial location, but not of a cue-marked location, in a + maze and spontaneous alternation. Differential rearing had some long-term effects depending on the task. Sham-operated rats which had been housed in isolation used a pattern of strategies in the radial arm maze that resembled the pattern used by rats with lesions. Early enrichment, on the other hand, alleviated lesion deficits only in a spontaneous alternation task in a T-maze where the variety and salience of proximal cues were maximised. Enrichment increased lesion deficits in the radial maze task, where distal cues only could guide performance. The results suggest that the hippocampus may play an important role in the use of contextual information and that behavioural recovery after early hippocampal damage--limited to situations in which featural information is highly salient--may be permanently induced by rearing in environments, as in enriched ones, where rats can attend to and manipulate environmental cues.

Animals↗
PubMed1995

Dentate gyrus destruction and spatial learning impairment after corticosteroid removal in young and middle-aged rats.

We investigated the functional and behavioral implications of chronic corticosteroid removal in young and middle-aged rats. Prepubertal and 13-month-old rats were adrenalectomized (ADX) or sham operated (SHAM). The young ADX rats were divided further into three groups: ADX with no hormone replacement, ADX given corticosterone chronically, (chCORT), and ADX given corticosterone acutely at the time of Morris water maze testing (acCORT). All rats were run on the Morris water maze 12 weeks after surgery. They were then sacrificed and the brains were removed for histological analysis. The results showed that prolonged corticosteroid absence caused major damage to the dentate gyrus and learning impairment on the Morris water maze. The chCORT rats had little dentate gyrus cell loss and were as efficient as the controls in Morris water maze performance, whereas the acCORT rats had dentate gyrus cell loss and were impaired in the spatial acquisition task. Furthermore, exogenously administered corticosterone had an interactive effect on ADX rats. Water maze performance was improved in dentate gyrus damaged rats (acCORT) compared to ADX rats not given corticosterone, whereas ADX rats with very little dentate gyrus damage (chCORT) did not exhibit better water maze performance relative to controls. Middle-aged ADX rats lost cells only in the dorsal blade of the dentate gyrus but they did not show a learning impairment in the Morris water maze relative to the middle-aged controls. These results indicate that corticosteroids are trophic for the dentate gyrus, that mature granule cells are less affected by adrenalectomy, that corticosteroid absence is responsible for some water maze impairment in ADX rats, but that in addition to corticosteroid absence, a substantial amount of dentate gyrus damage is necessary to impair spatial learning.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Effect of sex and age on brain monoamines and spatial learning in rats.

The concentrations of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and their metabolites were measured in the prefrontal cortex, caudate-putamen, and hippocampus in young (3 months) and aged (27-31 months) Wistar rats of both sexes. Age-related changes were found in prefrontal NA and HVA/DA ratio, striatal DA and DOPAC/DA ratio, and striatal and hippocampal 5-HT and 5-HIAA/5-HT ratio. Age and sex dependent changes were found in striatal DA and DOPAC/DA ratio, and hippocampal MHPG-SO4/NA ratio. The aged rats were tested in spatial discrimination and reversal tasks in a T maze. The effects of alpha 2-agonist medetomidine (3 micrograms/kg) on the task performance were assessed in relation to individual variation in monoamine metabolism. Medetomidine impaired spatial discrimination learning of the aged rats by interacting with the hippocampal 5-HT turnover. Medetomidine improved reversal learning through an interaction with the striatal DA turnover and reduced the number of perseverative errors after reversal, mainly due to its interaction with the prefrontal NA turnover. It is concluded that the memory enhancing effect of drugs acting through the brain monoamine systems is highly dependent on the stage of degeneration of these systems that show considerable individual variation in aged animals.

Adrenergic alpha-Agonists↗