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Aged rats need a preserved complement of perforated axospinous synapses per hippocampal neuron to maintain good spatial memory.

Spatial working memory, which crucially depends on the structural integrity of the hippocampal formation and its afferent connections, is impaired in the most, but not all, of aged rats. This study was designed to verify whether aged animals that do not exhibit the spatial memory deficit are the ones in which the hippocampal synaptic connectivity remains preserved with advancing chronological age. Young adult rats with good spatial memory, aged rats with impaired spatial memory and equally aged rats with intact spatial memory were compared. The number of synapses per neuron was estimated in the hippocampal dentate gyrus. The most important results were obtained when axospinous synapses were divided into perforated and non-perforated ones according to the appearance of their postsynaptic density. A significant decrease in the number of perforated synapses was found in memory-impaired aged rats as compared to either young adults or aged animals without memory deficits. The number of non-perforated synapses per neuron was diminished in memory-deficient aged rats relative to young adults, but not to memory-intact aged rats. However, it was only the loss of perforated synapses which correlated with the degree of spatial memory impairment. Thus, aged rats need a preserved complement of hippocampal perforated synapses to maintain good spatial memory.

Aging↗

Dissociation of spatial reference memory, spatial working memory, and hippocampal mossy fiber distribution in two rat strains differing in emotionality.

Rats of the inbred strains DA/Han and BDE/Han were compared on two complex spatial learning tasks, a spatial reference memory task in a 16-unit multiple T-maze and a spatial working memory task in an eight-arm radial-maze. In addition, sizes of hippocampal mossy fiber terminal fields were measured. BDE rats showed marked superiority in multiple T-maze learning whereas DA rats outperformed BDE rats on the radial-maze task. DA rats had significantly larger intra- and infrapyramidal mossy fiber terminal fields (IIP-MF). This is consistent with findings from other studies suggesting that large IIP-MF are related to excellent spatial radial-maze learning, but it also indicates that size of IIP-MF is correlated with processing of a specific type of spatial information rather than with overall spatial abilities. BDE rats had more extended suprapyramidal mossy fiber projections (SP-MF) and a larger hilus. Rats of both strains differed in exploratory behaviour and emotionality: DA rats revealed little freezing and had a high rearing activity, whereas BDE rats showed frequent freezing and reared rarely. Results suggest that IIP-MF are involved with flexible expression of memory, updating environmental information and parallel processing whereas SP-MF might be linked to processing of familiar information. Presumably, emotional factors contribute to performance differences.

Animals↗

Development of spatial memory and spatial orientation in preschoolers and primary school children.

The present study addresses the question of what kind of information children use when orientating in new environments, if given proximal and distal landmarks, and how spatial memory develops in the investigated age groups. Ten 5-year-old, ten 7-year-old and ten 10-year-old children were presented with the 'Kiel Locomotor Maze', containing features of the Radial Arm Maze and the Morris Water Maze, in order to assess spatial memory and orientation. Children had to learn to approach baited locations only. Task difficulty was equated with respect to the children's age. Training was given until the children reached criterion. During testing, the maze configuration and response requirements were systematically altered, including response rotation, cue rotation, cue deletion and response rotation with cue deletion in order to assess the spatial strategies used by the children. During training and testing, working-memory errors (WM), reference-memory errors (RM) and working-reference memory errors (WR) were recorded. As expected, no difference between age groups appeared during training, thus confirming comparable task difficulty across age groups. During testing, age groups differed significantly with regard to the orientation strategy used. The 5-year-olds were bound to a cue strategy, orientating towards local, proximal cues. The 10-year-olds mastered all tasks, thus displaying a place strategy, being able to use distal cues for orientation, and were even able to do so after being rotated 180 degrees. The 7-year-olds proved to be at an age of transition: five of them were bound to a cue strategy, five children were able to adopt a place strategy. The differences in the orientation strategies used by children of different age groups was reflected by the sum of errors they made, also by RM. WM were found to be rare, especially in older children. We conclude that preschoolers use a cue strategy, that the development of place strategies occurs during primary school age and seems to be complete by the age of 10 years.

Age Factors↗

The cannabinoid receptor agonist WIN 55,212-2 facilitates the extinction of contextual fear memory and spatial memory in rats.

RATIONALE: Previous studies demonstrated that pharmacological blockade of CB1 cannabinoid receptors decreases the extinction of conditioned fear and spatial memory in rodents. However, the effects of CB1 cannabinoid receptor activation in this response remain unclear. OBJECTIVES: To evaluate the effects of the cannabinoid agonist WIN 55,212-2 (WIN) and the cannabinoid antagonist SR 147778 (SR) on the extinction of contextual fear memory in rats 24 h or 30 days after fear conditioning. METHODS: For fear conditioning, rats were placed in the conditioning chamber for 3 min and received a 1-s electric foot shock (1.5 mA). Retrieval testing consisted of a 3-min exposure to the conditioning chamber and extinction training consisted of successive 9-min exposures at 24-h intervals. Rats were also evaluated in the open field and water maze reversal task. RESULTS: The administration of SR (1.0 mg/kg, i.p.) and WIN (0.25 mg/kg, i.p.) before extinction training disrupted and facilitated, respectively, the extinction of 24 h contextual fear memory. These effects were not related to any disturbance in memory retrieval, unconditioned freezing expression, or locomotor activity. WIN (0.25 mg/kg, i.p.) also facilitated the extinction of 30-day-old contextual fear memory, while the prior administration of SR (0.2 mg/kg, i.p.) antagonized this response. The facilitative effect of WIN on memory extinction does not seem to be specific for contextual fear memory because it was also observed in the water maze reversal task. CONCLUSIONS: These results suggest cannabinoid receptor agonists as potential drugs to treat anxiety disorders related to the retrieval of aversive memories.

Animals↗

Lateral ventricle injection of the protein synthesis inhibitor anisomycin impairs long-term memory in a spatial memory task.

Although protein synthesis inhibition has been shown to affect long-term memory in a wide variety of animal species, cases have been reported in which protein synthesis inhibition failed to affect memory consolidation [S. Wittstock, R. Menzel, Color learning and memory in honey bees are not affected by protein synthesis inhibition, Behav. Neural Biol., 62 (1994) 224-229.]. Most findings argue that the critical time for protein synthesis is during or immediately after training. However, other reports show a second time window, hours after training, where protein synthesis inhibition can cause amnesia [F.M. Freeman, S.P.R. Rose, A.B. Scholey, Two time windows of anisomycin-induced amnesia for passive avoidance training in the day-old chick, Neurobiol. Learn. Mem., 63 (1995) 291-295.][G. Grecksch, H. Matthies, Two sensitive periods for the amnesic effect of anisomycin, Pharmacol. Biochem. Behav., 12 (1980) 663-665.]. In this study, we addressed two questions: (1) Is protein synthesis essential for spatial memory? and (2) At what injection time window(s) will protein synthesis inhibition cause spatial memory amnesia? We report that bilateral intraventricular microinjection of anisomycin (Ani) impairs consolidation of long-term memory, in the hippocampal-dependent Morris water maze spatial memory task. Memory was impaired in a dose-dependent manner without affecting short-term memory. Spatial memory was affected only if Ani was injected 20 min before performing the task and not in any other time window before or after the behavioral test. The inhibition did not affect pre-existing memories or the capability to memorize once the effect of the inhibition diminished.

Animals↗

Spatial memory following prenatal alcohol exposure: more than a material specific memory deficit.

Spatial memory deficits have been reported following prenatal alcohol exposure and animal studies have demonstrated hippocampal vulnerability to alcohol. This study examined spatial memory in children diagnosed with fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE) and matched controls. Spatial memory was examined with location recall measures. Since visual perceptual skills and nonspecific memory impairment could impact spatial memory, tasks assessing perception and verbal memory were administered. Analyses revealed group differences on perceptual and verbal and spatial memory tasks. There was no significant difference in spatial memory once perceptual and verbal memory task performance was taken into account, suggesting that differences in spatial memory were not solely attributable to a material specific memory deficit.

Adolescent↗

Selective verbal and spatial memory impairment after 5-HT1A and 5-HT2A receptor blockade in healthy volunteers pre-treated with an SSRI.

Serotonergic neurotransmission has been implicated in memory impairment. It is unclear however if memory performance is mediated through general 5-HT availability, through specific 5-HT receptors or both. The aim of the present study was to assess the contribution of 5-HT reuptake inhibition and specific blockade of 5-HT(1A) and 5-HT(2A) receptors to memory impairment. The study was conducted according to a randomized, double-blind, placebo-controlled, four-way cross-over design including 16 healthy volunteers. The treatment consisted of oral administration of escitalopram 20 mg + placebo, escitalopram 20 mg + ketanserin 50 mg, escitalopram 20 mg + pindolol 10 mg and placebo on 4 separate days with a washout period of minimum 7 days. Different memory tasks were performed including verbal memory, spatial working memory and reversal learning. Escitalopram showed an impairing effect on immediate verbal recall which nearly reached statistical significance. No effects of escitalopram were found on other types of memory. In combination with pindolol, immediate verbal recall was significantly impaired. Escitalopram in combination with ketanserin impaired spatial working memory significantly. No effects were found on reversal learning. Selective impairment of immediate verbal recall after a 5-HT(1A) partial agonist and selective impairment of spatial working memory performance after 5-HT(2A) receptor antagonist, both in combination with a selective serotonergic reuptake inhibitor (escitalopram), suggests that 5-HT(1A) and 5-HT(2A) receptors are distinctly involved in verbal and spatial memory.

Administration, Oral↗

Interference in immediate spatial memory: shifts of spatial attention or central-executive involvement?

Interference in serial spatial memory was investigated in six experiments. Experiment 1 replicated Experiment 2 by Smyth and Scholey (1994) in showing that listening to tones that originated from different directions interfered with spatial memory. Experiment 2 showed, however, that the effect of mere listening was not observed when this was the only interference condition experienced by the subject. In Experiment 3, a binary pitch discrimination task performed on spatially separated tones impaired recall performance to the same extent as did left-right decisions. The same disrupting effect was also observed when the tones were presented from the same direction in the pitch discrimination task (Experiment 4) as well as in a binary loudness discrimination task (Experiment 5). Finally, repeating heard words did not interfere, whereas pitch discrimination performed on these same words disrupted recall (Experiment 6). It is argued that the disrupting effects reflect not a specifically spatial interference, but a central executive involvement in the rehearsal process in serial spatial memory.

Attention↗

A molar entropy model of age differences in spatial memory.

Two very-short-term-memory, spatial scanning aging experiments were conducted involving a graphics character as a target stimulus. On the probe portion of a trial, the stimulus was presented in the same position as it was on the target portion of the trial (i.e., a same trial) 50% of the time. However, on the remaining 50% of the trials, the probe stimulus was shifted (or transposed) 1, 2, or 3 positions to the right or left of the original presentation (target) position. In Experiment 1, exposure duration was manipulated. In Experiment 2, the number of potential target display positions was manipulated. For both experiments, older adults showed larger transposition distance effects than younger adults for errors. In the past (e.g., P.A. Allen, 1990, 1991), this effect has been attributed to higher levels of internal noise (entropy) in older than younger adults. This research provides converging operations to this contention by using statistical physics methods to rigorously compute the entropy in a molar neural network across age groups. After successfully fitting the statistical mechanics model to the data, the model is proved to have external validity by fitting a simplified version of it to an earlier spatial memory aging experiment reported by P. R. Bruce and J. F. Herman (1986). The results of both traditional reaction time and error rate analyses, as well as the entropy modeling analyses, indicated that older adults exhibited higher levels of entropy than did the younger adults and that this effect appeared to be generalized across processing stage.

Adolescent↗

Estradiol enhances learning and memory in a spatial memory task and effects levels of monoaminergic neurotransmitters.

The effects of chronic estrogen treatment on radial arm maze performance and on levels of central monoaminergic and amino acid neurotransmitters were examined in ovariectomized (Ovx) rats. In an eight arms baited paradigm, choice accuracy was enhanced following 12 days but not 3 days of treatment. In addition, performance during acquisition of the eight arms baited maze task was better in estrogen-treated Ovx rats than in Ovx rats. Performance of treated rats was also enhanced in win-shift trials conducted 12 days postestrogen treatment. Working, reference, and working-reference memory was examined when four of the eight arms were baited, and only working memory was improved by estrogen and only after long-term treatment. Activity of Ovx rats on an open field, crossings and rearings, was increased at 5 but not at 35 days following estrogen treatment. In medial prefrontal cortex, levels of NE, DA, and 5-HT were decreased but glutamate and GABA levels were not affected following chronic estrogen treatment. Basal forebrain nuclei also showed changes in monoamines following estrogen. Hippocampal subfields showed no effects of estrogen treatment on monoaminergic or amino acid transmitters. Levels of GABA were increased in the vertical diagonal bands following chronic estrogen. Results show that estrogen enhances learning/memory on a task utilizing spatial memory. Effects in Ovx rats appear to require the chronic (several days) presence of estrogen. Changes in activity of both monoaminergic and amino acid transmitters in the frontal cortex and basal forebrain may contribute to enhancing effects of estrogen on learning/memory.

Animals↗

Antipsychotic and anticholinergic effects on two types of spatial memory in schizophrenia.

Spatial memory is of interest in schizophrenia because of widespread impairments in adaptive functioning, including independent living skills. Short-term spatial memory is impaired in this disease, whereas spatial reference memory, a longer-term spatial memory, has not been evaluated. Animal studies have demonstrated that anticholinergics impair short-term spatial memory but not spatial reference memory. The effects of haloperidol and risperidone on these two types of spatial memory were evaluated in a double-blind randomized comparison in inpatients with schizophrenia. It was predicted that risperidone would have a greater beneficial effect on spatial working memory than haloperidol. Computerized measures of spatial working memory and spatial reference memory were developed based on animal assessment of these functions. Subjects with schizophrenia were assessed during a medication-free period and again following 4 weeks of fixed-dose treatment. Risperidone, compared to haloperidol, improved spatial working memory performance, an effect that became nonsignificant when benztropine co-treatment was controlled. There were no treatment effects on spatial reference memory performance. Consistent with animal studies, benztropine impaired spatial working memory but not spatial reference memory. The relative benefits of risperidone on spatial working memory performance were largely explained by differential benztropine treatment for the haloperidol-treated subjects.

Adult↗

Lateralization of spatial-memory processes: evidence on spatial span, maze learning, and memory for object locations.

Spatial memory is one of the most important cognitive functions in daily life, enabling us to locate objects in our environment or to learn a route or a path. In the present study, we elaborated on the hypothesis that human spatial memory consists of multiple sub-processes, relying on different brain structures. Therefore, 50 patients with an ischemic stroke and 40 healthy participants underwent tests measuring spatial span and maze learning. By means of a computer paradigm the following aspects of memory for object locations were assessed: (1) object location binding; (2) positional memory; (3) a combination of these two aspects. The results clearly showed a double dissociation: the group of patients with an infarct in the left hemisphere (LH) was impaired on object location binding, whereas the group with an infarct in the right hemisphere (RH) was impaired on positional memory. Lesions in the RH resulted also in impairments on maze learning. Moreover, patients with lesions in the posterior part of the parietal or the occipital lobe performed especially worse on spatial-memory tasks. These findings extend the theoretical framework of categorical versus coordinate spatial processing in the human brain and corroborate previous findings on selective aspects of memory for object locations.

Adult↗

Intact LTP and fear memory but impaired spatial memory in mice lacking Ca(v)2.3 (alpha(IE)) channel.

To investigate the functional roles of the Ca(v)2.3 (alpha(1E)) channel in hippocampal CA1 pyramidal neurons, we studied in vitro synaptic properties and in vivo behaviors of the Ca(v)2.3 gene deficient mice. The Ca(v)2.3 channel mRNA was identified in the hippocampal formation of the wild-type mouse by in situ hybridization. The basic excitatory synaptic transmission and long-term potentiation by theta-burst stimulation were intact in CA1 region of Ca(v)2.3-/- mice. We performed two forms of behavioral tests to examine the hippocampus-dependent function, i.e., emotional and spatial learning tests. The Ca(v)2.3-/- mice were able to establish and maintain fear memories. Although general improvement in the performance of Morris water maze test was seen in Ca(v)2.3-/- mice, they displayed an obvious impairment in the probe test. These results suggest that the Ca(v)2.3 channel plays some role in formation of the accurate spatial memory but not of the fear memory.

Animals↗

Spatial memory, habituation, and reactions to spatial and nonspatial changes in rats with selective lesions of the hippocampus, the entorhinal cortex or the subiculum.

Various spatial memory deficits have been described in rats with damage to the hippocampal formation (including the subiculum and the entorhinal cortex) and particularly in rats with selective lesions of the hippocampus proper. So far, the involvement of the entorhinal cortex in spatial memory is still controversial and the role of the subiculum is poorly documented. The aim of the present study was to compare the behavioural effects of selective lesions of the hippocampus, the entorhinal cortex or the subiculum in (a) a water-maze task using testing procedures sensitive to the disruption of reference or working memory and (b) in an object exploration task designed to evaluate habituation and subsequently reactions to changes of the spatial layout of objects (spatial change) or to the substitution of a familiar object by a new one (nonspatial change). Our results showed several similarities between the behavioural consequences of damage to each of the three structures. A few differences were also noted. Hippocampal rats were impaired in all spatial tasks, but they reacted like controls to a nonspatial change. The rats sustaining lesions of the entorhinal cortex or the subiculum were not impaired in the reference-memory procedure of the water-maze task and showed a deficit in reacting to a nonspatial change. Overall, our results confirm the central role of the hippocampus in spatial memory and also suggest a role for the entorhinal cortex and the subiculum in processing spatial informations. In addition, they indicate that the entorhinal cortex and the subiculum may have a hippocampal-independent role in memory.

Animals↗

Prefrontal cortex hemispheric specialization for categorical and coordinate visual spatial memory.

During visual spatial perception of multiple items, the left hemisphere has been shown to preferentially process categorical spatial relationships while the right hemisphere has been shown to preferentially process coordinate spatial relationships. We hypothesized that this hemispheric processing distinction would be reflected in the prefrontal cortex during categorical and coordinate visual spatial memory, and tested this hypothesis using functional magnetic resonance imaging (fMRI). During encoding, abstract shapes were presented in the left or right hemifield in addition to a dot at a variable distance from the shape (with some dots on the shape); participants were instructed to remember the position of each dot relative to the shape. During categorical memory retrieval, each shape was presented centrally and participants responded whether the previously corresponding dot was 'on' or 'off' of the shape. During coordinate memory retrieval, each shape was presented centrally and participants responded whether the previously corresponding dot was 'near' or 'far' from the shape (relative to a reference distance). Consistent with our hypothesis, a region in the left prefrontal cortex (BA10) was preferentially associated with categorical visual spatial memory and a region in the right prefrontal cortex (BA9/10) was preferentially associated with coordinate visual spatial memory. These results have direct implications for interpreting previous findings that the left prefrontal cortex is associated with source memory, as this cognitive process is categorical in nature, and the right prefrontal cortex is associated with item memory, as this process depends on the precise spatial relations among item features or components.

Adult↗

Memory reconsolidation: sensitivity of spatial memory to inhibition of protein synthesis in dorsal hippocampus during encoding and retrieval.

Reconsolidation is a putative neuronal process in which the retrieval of a previously consolidated memory returns it to a labile state that is once again subject to stabilization. This study explored the idea that reconsolidation occurs in spatial memory when animals retrieve memory under circumstances in which new memory encoding is likely to occur. Control studies confirmed that intrahippocampal infusions of anisomycin inhibited protein synthesis locally and that the spatial training protocols we used are subject to overnight protein synthesis-dependent consolidation. We then compared the impact of anisomycin in two conditions: when memory retrieval occurred in a reference memory task after performance had reached asymptote over several days; and after a comparable extent of training of a delayed matching-to-place task in which new memory encoding was required each day. Sensitivity to intrahippocampal anisomycin was observed only in the protocol involving new memory encoding at the time of retrieval.

Animals↗

Temporal-spatial memory: retrieval of spatial information does not reduce recency.

Factors influencing the shape of serial position curves in non-verbal serial short-term memory were examined, using a task testing memory for the position of dots. Similar recency slopes were found when both position and order were recalled (Experiment 1A) and when order only was required (Experiment 1B). This observation was confirmed and tested further in conditions requiring the same encoding but different amounts of spatial information at retrieval (Experiment 2). However, Experiment 2 also revealed an effect of spatial information retrieval on the overall level of memory for recency items. Overall, the results indicate that spatial items produce bow-shaped serial positions curves in tasks requiring the maintenance of order information and that recency is affected by the demand on spatial information retrieval in terms of the overall level of performance but not in terms of the recency slope. These findings are contrary to what is found in the literature on serial verbal recall when both item and order information are required.

Adult↗

Attenuating corticosterone levels on the day of memory assessment prevents chronic stress-induced impairments in spatial memory.

This study investigated whether chronic stress-induced spatial memory deficits were caused by changes in the hypothalamic-pituitary-adrenal axis, such as corticosterone (CORT) elevations on the day of memory assessment, rather than the consequence of structural changes in the hippocampus. Male Sprague-Dawley rats were restrained for 6 h/day/21 days, and spatial memory was assessed on the Y-maze on day 22. Ninety minutes before training, rats received a subcutaneous injection of vehicle or metyrapone, a CORT synthesis inhibitor, and then spatial memory was determined 4-h later. The highest dose of metyrapone (75 mg/kg, s.c.) was most effective at preventing stress-induced spatial memory deficits. Chronic stress increased total CORT levels following Y-maze exposure, while acute metyrapone treatment dose-dependently attenuated total and free (unbound) CORT levels in both stress and control conditions. Blood samples taken from a separate subset of chronically stressed rats showed that baseline CORT levels were similar across the restraint period. Finally, chronic stress down-regulated glucocorticoid, but not mineralocorticoid, receptor mRNA expression within the hippocampus (dentate gyrus, CA1, CA2, CA3). These findings suggest that chronic stress-induced spatial memory deficits may be mediated by hypothalamic-pituitary-adrenal axis dysregulation. Specifically, CORT elevations and reductions in hippocampal glucocorticoid receptor expression, at the time of behavioural assessment may be involved, as opposed to a direct effect that is solely dependent upon hippocampal structural changes. These results have significance for treating cognitive decline in conditions associated with elevated glucocorticoids that include subpopulations in ageing, depression, Cushing's disease and Alzheimer's disease.

Aging↗