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PubMed1998

Effects of intrahippocampal AP5 treatment on radial-arm maze performance in rats.

The purpose of the present study was to investigate the possible involvement of hippocampal NMDA (N-methyl-d-aspartate) receptors in spatial memory in rats by means of intrahippocampal injection of an NMDA antagonist, AP5 (D,L-2-amino-5-phosphonopentanoic acid). In Expt. 1, spontaneous motor activity (locomotor activity and rearing) was measured in an open-field after bilateral AP5 injection into the hippocampus, and it was shown that AP5 did not affect general activities within the dosage used in the present study. In Expt. 2, radial-maze performance was observed after the intrahippocampal injection of AP5. Rats were required to consume all the pellets which were put on each of the eight arms of the maze without revisiting the arms. AP5 produced dose-dependent impairment on the choice performance in the radial-arm maze, but did not have any effect on their running time. These results suggest that hippocampal NMDA receptors are involved in spatial memory.

2-Amino-5-phosphonovalerate↗
PubMed1999

A cognitive activation study of memory for spatial relationships.

Twelve neurologically normal right-handed subjects were asked to remember the locations of eight representational drawings, presented one at a time, together with two landmarks (white squares), on a computer screen. Subjects were then scanned using positron emission tomography (PET) while performing forced-choice recognition of object location in four conditions, using either the original landmarks or two of the other objects as cues. In two conditions, the absolute location of the objects was unchanged from the time of encoding (fixed-array conditions), whereas in the other two, the location of the objects was shifted, although the spatial relationship among the objects and landmarks was maintained (shifted-array conditions). Subjects were also scanned in a control condition that made the same perceptual and motor demands as the recognition tasks but that had no mnemonic component. Compared to the control condition, all of the recognition tasks activated both the dorsal and ventral visual pathways bilaterally, but with notable asymmetries. In particular, activation in the right, but not left, inferior temporal gyrus (area 37) was observed when both shifted-array conditions were compared to their respective cue-matched fixed-array conditions. The recognition conditions with landmark cues were associated with focal increases in regional cerebral blood flow (rCBF) in the region of the right parahippocampal gyrus. The results support previous reports of involvement of the right mesial temporal region in object-location memory tasks, and suggest that right inferotemporal cortex is involved in extracting the invariant relational features of a visual scene.

Adult↗
PubMed2003

Age-dependent cognitive decline in the APP23 model precedes amyloid deposition.

Heterozygous APP23 mice, expressing human amyloid-precursor protein with the Swedish double mutation and control littermates, were subjected to behavioral and neuromotor tasks at the age of 6-8 weeks, 3 and 6 months. A hidden-platform Morris-type water maze showed an age-dependent decline of spatial memory capacities in the APP23 model. From the age of 3 months onwards, the APP23 mice displayed major learning and memory deficits as demonstrated by severely impaired learning curves during acquisition and impaired probe trial performance. In addition to the cognitive deficit, APP23 mice displayed disturbed activity patterns. Overnight cage-activity recording showed hyperactivity in the transgenics for the three age groups tested. However, a short 2-h recording during dusk phase demonstrated lower activity levels in 6-month-old APP23 mice as compared to controls. Moreover, at this age, APP23 mice differed from control littermates in exploration and activity levels in the open-field paradigm. These findings are reminiscent of disturbances in circadian rhythms and activity observed in Alzheimer patients. Determination of plaque-associated human amyloid-beta 1-42 peptides in brain revealed a fivefold increase in heterozygous APP23 mice at 6 months as compared to younger transgenics. This increase coincided with the first appearance of plaques in hippocampus and neocortex. Spatial memory deficits preceded plaque formation and increase in plaque-associated amyloid-beta 1-42 peptides, but probe trial performance did correlate negatively with soluble amyloid-beta brain concentration in 3-month-old APP23 mutants. Detectable plaque formation is not the (only) causal factor contributing to memory defects in the APP23 model.

Age Factors↗
PubMed1996

Unilateral neonatal hippocampal lesion alters septal innervation and trophism of the entorhinal cortex.

It is generally assumed that central nervous system injury sustained during development produces less severe behavioral deficits than damage in the adult, due to increased plasticity of the immature brain. However, developmental plasticity may also exacerbate deficits, presumably through formation of anomalous connections. Previous studies showed that after unilateral neonatal, but not adult, electrolytic hippocampal lesion spatial memory is severely impaired. To determine whether the memory deficit is correlated with anatomical changes in a major hippocampal afferent system, the septal input, the anterograde tracer Phaeseolus vulgaris leucoagglutinin was injected into the medial septum 2 months after unilateral neonatal hippocampal lesion. The density of septal fiber projections into the entorhinal cortex (EC) was found to be increased. Choline-acetyltransferase activity increased significantly in the EC 2 months postlesion, suggesting that septal cholinergic fibers are sprouting. Finally, nerve growth factor (NGF), which can mediate sprouting, was measured in the EC, NGF protein increased transiently 7 to 12 days postlesion in the ipsilateral EC, suggesting that increased trophic support is associated with growth of septal afferents into the EC. Thus, neonatal hippocampal lesion causes a reorganization of axonal connections associated with elevated NGF in the target region of the increased septal input. Moreover, since previous studies showed that the neonatal lesion is accompanied by a spatial memory deficit, this plasticity may compromise function of the remaining circuitry.

Animals↗
PubMed1998

Sexually dimorphic responses to neonatal basal forebrain lesions in mice: II. Cortical morphology.

Previous studies in the mouse have shown that neonatal lesions to the cholinergic basal forebrain (nBM) areas result in transient cholinergic depletion of neocortex and precipitate altered cortical morphogenesis. Lesion-induced morphological alterations in cortex persist into adulthood and are accompanied by behavioral changes, including spatial memory deficits. The current study investigated whether neonatal nBM lesions affect male and female mice differently in adulthood. Quantitative morphometry of cortical layer width was employed to assess alterations in cytoarchitecture in neonatally nBM-lesioned and littermate control mice of both sexes following behavioral testing. Our results showed significant decreases in cortical layer IV and V widths across somato/motor cortex in neonatally nBM lesioned mice of both sexes. Sexually dimorphic responses were observed in cortical layer II/III and total cortical width, limited to the area containing the "barrel cortex" representation of the whisker hairs. In lesioned females, layer II/III and total cortical width were decreased relative to female controls, and in lesioned males, layer II/III was increased relative to controls, whereas total cortical width was unchanged. In male but not female mice we observed significant correlations between decreased widths in layer IV and V and impaired performance on a spatial memory task. The current data further support a role of developing cholinergic cortical afferents in the modulation of cortical morphogenesis and cortical circuits involved in cognitive behaviors. In addition, our observations provide further evidence for sexually dimorphic development and function in cognitive centers of the rodent brain.

Acetylcholine↗
PubMed1989

The effects of prenatal alcohol exposure on radial arm maze performance in adult rats.

The hippocampal formation is sensitive to the in utero exposure to ethanol. It is one brain area thought to play an important role in spatial memory. We examined radial arm maze performance in rats exposed to ethanol prenatally. Pregnant rats were placed into the following treatment groups: LC, 17% EDC (ethanol-derived calories), 35% EDC, PF 35% or PF 17%. The LC group was fed lab chow and water ad lib, the 17% EDC and 35% EDC groups were fed a liquid diet containing either 3.3% or 6.7% v/v ethanol, respectively. Pair-fed controls were fed the same volume of an isocaloric diet as was consumed by their respective ethanol-treated groups. At birth, litters were culled to six and cross fostered to untreated surrogate mothers. Testing was initiated at 60 days of age and continued until the test criterion was satisfied. One-half of the rats in the 35% EDC group did not reach criterion. The remainder of the 35% EDC group and the 17% EDC rats attained criterion but required twice as many trials as their respective pair-fed controls. These results suggest that in utero administration of ethanol affects spatial memory capacity in rat, an observation consistent with other deficits seen in hippocampus of rats prenatally exposed to ethanol.

Animals↗
PubMed2000

Differences in visual attention and task interference between males and females reflect differences in brain laterality.

Two cognitive tasks (a letter memory task and a spatial memory task) designed to selectively activate the left or right hemisphere were combined with attentional probe tasks to measure how hemispheric activation affects attention to left and right hemifields. The probe task in Experiment 1 required the identification of digits in the left and right hemifield. During the letter task, male subjects identified more probes from the left hemifield than from the right. Their accuracy varied little across the two hemifields during the dots task. Experiment 2 tested whether this pattern is due to either spatial attention or interference in character processing. Instead of identifying digits, the probe task required subjects to respond to a black square that appeared in the periphery of the screen. For male subjects, the pattern was opposite of that from Experiment 1. During the letter task they responded faster to the probe in the right hemifield than in the left. Their response times were equivalent across the two hemifields during the dots task.These results indicate two separate effects of laterality in male subjects. The activation of one hemisphere produced more attention to the contralateral hemifield in Experiment 2, and the letter memory task interfered with the processing of other characters in the right visual field more than those in the left visual field in Experiment 1. Neither of these effects appeared in female subjects, corroborating earlier claims that female brains are less lateralized than male brains.

Adult↗
PubMed1989

The effects of undernutrition during early life on spatial learning.

Recent research has shown that a lengthy period of undernutrition during early postnatal life can cause alterations in the morphological structure of the dentate gyrus. As this region is involved in the control of spatial memory, we decided to investigate whether undernourished rats also showed any deficits in this aspect of behaviour. Rats were undernourished from about birth until either 30 or 60 days of age and then nutritionally rehabilitated for a lengthy period before testing. There were significant differences in the body weight of control and undernourished rats in each experiment. The testing procedure involved rats being placed in a large pool of opaque water. They were required to swim to find a hidden platform located just below the water surface onto which they could escape. Each rat had to perform this test 20 times over a period of 3 days. The time taken and the total distance swum by each rat during each trial was measured. In Experiment 1, rats were familiarised with the water before testing took place, whereas in Experiment 2 they were not. There were no significant differences in the latency to find the platform or the distance swum between well-fed control and previously undernourished rats in either experiment. In conclusion, in our experiments we could not demonstrate that undernutrition during early life caused any deficits in spatial memory performance.

Animals↗
PubMed2003

Postnatal hypobaric hypoxia in rats impairs water maze learning and the morphology of neurones and macroglia in cortex and hippocampus.

Newborn rats were exposed to intermittent hypobaric hypoxia from birth until the age of 19 days. Spatial memory was tested in a Morris water maze from postnatal day (P) 23 to P32 and from P100 to P109. From P24 to P27 and on days P100 and P101, the escape latencies of hypoxic animals were longer than those of controls. At P24, the number of neuronal bodies increased in cortical layer II of the somatosensory, motor, and auditory areas, and in layer V of the motor area, but the number of neuronal bodies throughout the whole cortical thickness was unchanged. Decreases in the immunostaining density for neurofilaments (anti-NF 160), astrocytes (anti-GFAP), and oligodendrocytes (RIP) were found in the hippocampus, and the typical parallel organisation of neuronal and macroglial processes was lost. Decreases in immunostaining for neurofilaments and oligodendrocytes were also found in the somatosensory cortex and motor cortex. In adult hypoxic rats, at P114-P240, the number of neuronal bodies and the immunostaining density for neurofilaments, astrocytes, and oligodendrocytes in the examined areas were similar to adult controls; however, in the hippocampus we found hypertrophy of fine astrocytic processes and a decreased number of oligodendrocytic processes. We conclude that the neonatal brain damage induced by hypobaric hypoxia impairs spatial memory in infant as well as adult rats. Hypobaric hypoxia delays the maturation of neurones and substantially affects macroglia in the cortex and hippocampus.

Animals↗
PubMed1995

Developmentally expressed Ca(2+)-sensitive adenylyl cyclase activity is disrupted in the brains of type I adenylyl cyclase mutant mice.

The type I Ca(2+)-sensitive adenylyl cyclase has been implicated in several forms of synaptic plasticity in vertebrates. Mutant mice in which this enzyme was inactivated by targeted mutagenesis show deficient spatial memory and altered long term potentiation (Wu, Z. L., Thomas, S. A., Villacres, E. C., Xia, Z., Simmons, M. L., Chavkin, C., Palmiter, R. D., and Storm, D. R. (1995) Proc. Natl Acad Sci. U. S. A. 92, 220-224). Long term potentiation in the CA1 region of the rat hippocampus develops during the first 2 weeks after birth and reaches maximal expression at postnatal day 15 with a gradual decline at later stages of development. Here we report that Ca(2+)-stimulated adenylyl cyclase activity in rat hippocampus, cerebellum, and cortex increases significantly between postnatal days 1-16. This increase appears to be due to enhanced expression of type I adenylyl cyclase rather than type VIII adenylyl cyclase, the other adenylyl cyclase that is directly stimulated by Ca2+ and calmodulin. Type I adenylyl cyclase mRNA in the hippocampus increased 7-fold during this developmental period. The developmental expression of Ca(2+)-stimulated adenylyl cyclase activity in mouse brain was attenuated in mutant mice lacking type I adenylyl cyclase. Changes in expression of the type I adenylyl cyclase during the period of long term potentiation development are consistent with the hypothesis that this enzyme is important for neuroplasticity and spatial memory in vertebrates.

Adenylyl Cyclases↗
PubMed1985

Memory for two types of spatial location: effects of instructions, age, and format.

Three experiments, with old persons (59-80 years) and college students (17-30 years) in Experiments 1 and 2 and with college students (17-24 years) in Experiment 3, investigated the differences between two types of spatial location memory: memory for the location of individual items in an array and memory for occupied, as opposed to unoccupied, locations in an array. Young persons performed better than old persons on both measures of location memory. However, an effect of instructions (intentional vs. incidental for spatial location) was consistently obtained for memory for occupied, as opposed to unoccupied, locations, whereas no effect of instructions was obtained for memory for individual item locations. In addition, item location memory was superior for objects as opposed to matched words (Experiment 2), whereas occupied location memory was not affected by presentation format (Experiments 2 and 3). These differences indicate that spatial memory is a complex process whose properties are affected by variations in stimulus characteristics and task demands. It was concluded that the distinction of Hasher and Zacks (1979) between automatic and effortful processes is not adequate for understanding spatial memory. A recognition of the complex nature of spatial processing suggests a resolution of discrepancies in the literature based upon differences in stimulus characteristics, task demands, and the effectiveness of task-appropriate mnemonic strategies.

Adolescent↗
PubMed1993

Development of hippocampal specialisation in a food-storing bird.

Previous studies demonstrated that amongst food-storing passerine birds the hippocampal region (dorso-medial cortex) is enlarged relative to the rest of the telencephalon. It has been hypothesised that this hippocampal specialisation is related to the spatial memory requirements of retrieving large numbers of stored items. Here we compare the development of the hippocampus in a food-storing and a non-storing corvid, the adults of which differ in relative hippocampal volume. The volume, cell density and number of cells in the hippocampal region of nestling (5-25 days post hatching) and adult (> 320 days old) magpies Pica pica (food-storing) and jackdaws Corvus monedula (non-storing) were measured. In both species the volume of the hippocampus increases with the volume of the rest of the telencephalon during the nestling growth phase. The relative volume of the hippocampus in 5- to 25-day-old nestlings of the two species does not differ significantly. In the food-storing magpie, the relative volume of the adult hippocampus is significantly larger than that of nestlings, whilst in the jackdaw, adults and nestlings do not differ. The density of neurons declines with increasing age and this effect is more marked in jackdaws than in magpies. Neuron number did not change significantly with age, but is significantly greater in adult magpies than in adult jackdaws. These results are discussed in relation to the possibility that changes in hippocampal volume and cell number are related to the use of spatial memory in retrieving stored food.

Animals↗
PubMed2005

Functional interaction between the associative parietal cortex and hippocampal place cell firing in the rat.

The hippocampus and associative parietal cortex (APC) both contribute to spatial memory but the nature of their functional interaction remains unknown. To address this issue, we investigated the effects of APC lesions on hippocampal place cell firing in freely moving rats. Place cells were recorded from APC-lesioned and control rats as they performed a pellet-chasing task in a circular arena containing three object cues. During successive recording sessions, cue manipulations including object rotation in the absence of the rat and object removal in the presence of the rat were made to examine the control exerted by the objects or by non-visual intramaze cues on place field location, respectively. Object rotations resulted in equivalent field rotation for all cells in control rats. In contrast, a fraction of place fields in APC-lesioned rats did not rotate but remained stable relative to the room. Object removal produced different effects in APC-lesioned and control rats. In control rats, most place fields remained stable relative to the previous object rotation session, indicating that they were anchored to olfactory and/or idiothetic cues. In APC-lesioned rats, a majority of place fields shifted back to their initial, standard location, thus suggesting that they relied on uncontrolled background cues to maintain place field stability. These results provide strong evidence that the hippocampus and the APC cooperate in the formation of spatial memory and suggest that the APC is involved in elaboration of a hippocampal map based on proximal landmarks.

Action Potentials↗
PubMed1994

Scene schemata in memory for spatial relations.

Two schema-based hypotheses were developed and tested regarding recall for the following five types of spatial relations: scene-expected relations, two types of scene-unexpected relations, and two types of scene-irrelevant relations. In two experiments, subjects read relations that were described in passages and then recalled the passages. An attention hypothesis states that the amount of attention directed to a relation increases as the relation increasingly deviates from the schema. This hypothesis predicts high recall for unexpected relations, intermediate recall for irrelevant relations, and low recall for expected relations. A retrieval hypothesis states that a schema guides the search for schema-related information. This hypothesis predicts high recall for expected relations, intermediate recall for one type of scene-unexpected relation and one type of scene-irrelevant relation, and low recall for the remaining types of relations that are unexpected and irrelevant. The results of Experiment 1 supported certain predictions of both hypotheses, and the results of Experiment 2 supported the retrieval hypothesis.

Adult↗
PubMed2003

Theta- and movement velocity-related firing of hippocampal neurons is disrupted by lesions centered on the perirhinal cortex.

The hippocampus is critically involved in spatial memory and navigation. It has previously been proposed that, as part of this process, the hippocampus might have access to self-motion information. The possibility that some of this information may originate from the perirhinal cortex, a region involved in high-order multimodal processing, was tested in the present study by recording the responses of hippocampal complex-spike (place cells) and theta cells (putative interneurons) to movement velocity and to the movement-related theta rhythm EEG while rats with bilateral ibotenic acid lesions centered on the perirhinal cortex (n = 5), or control surgeries (n = 5), foraged in a rectangular environment. Perirhinal cortex lesions altered several characteristics of place and theta cell firing. First, the proportion of theta cells recorded was significantly lower in perirhinal lesion animals (8/39 units) compared to controls (22/53 units). Second, the firing of place cells recorded from lesion animals was phase-shifted so as to occur significantly earlier during the theta rhythm cycle than in place cells from controls (mean difference = 48.73 degrees). Third, the firing rates of a significantly lower proportion of place cells from lesion animals were modulated by the movement velocity of the animal compared to place cells from controls. These results indicate that the perirhinal cortex contributes to the responses of hippocampal CA1 place cells by providing information about self-movement and by controlling the timing of firing of these cells. This information may normally be utilized by the hippocampus during spatial memory and navigation processes.

Action Potentials↗
PubMed2000

Nicotine for Alzheimer's disease.

BACKGROUND: Nicotine is a cholinergic agonist that acts, not only post-synaptically, but also releases pre-synaptic acetylcholine, and in animal models has been shown to reverse spatial memory decline in rats with lesion in the medial septal nucleus and to show recovery on memory in aged monkeys. Nicotine also has effects on other transmitters like serotonin (5HT), dopamine, or GABA. On the other hand, because nicotine has serious adverse effects, especially concerning cardiovascular risks in elderly people, and also on sleep and behavior, there are several important reasons to conduct a systematic review to assess the clinical efficacy and safety of nicotine in patients with AD. OBJECTIVES: The aim of this review is to determine whether there is evidence of beneficial effect, and to assess its safety profile, when nicotine is used for Alzheimer's disease. SEARCH STRATEGY: The Cochrane Controlled Trials Register (Issue 2, 99) was searched using the terms nicotin* and alzheimer*. Three references to trials were deemed suitable for inclusion but are awaiting consideration while the investigators are contacted. SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with nicotine patches or administration of nicotine intravenously was administered for more than a day and compared to placebo in people with Alzheimer's disease. DATA COLLECTION AND ANALYSIS: As no trials were suitable for inclusion, no data have been extracted or pooled in a meta-analysis. One trial is awaiting consideration, and if included in an update of this review, any available data will be incorporated. MAIN RESULTS: The poor quality of the trials did not allow any synthesis of results across studies. However, the data available in trials considered are compatible with nicotine producing harm, no change or improvement. REVIEWER'S CONCLUSIONS: This review is not able to provide reliable evidence that nicotine is a useful treatment for Alzheimer's disease.

Alzheimer Disease↗
PubMedDate not supplied

Age and experience-dependent representational reorganization during spatial learning.

Previously, we found that aged rats showed a significant enhancement of hippocampal CA1 place cell spatial specificity, as well as a reduction of hilar place cell spatial specificity, during asymptote performance of a spatial memory task. Because such an age effect was not observed when animals performed a nonspatial task, the present study tested the hypothesis that the different patterns of spatial selectivity observed in memory and nonmemory tests reflected a redistribution of spatial representations that occurred in response to changing task demands. In the present experiment, after animals became familiar with the test environment and motor demands of performance on a radial maze, CA1 and hilar place cells were recorded as they learned a spatial memory task. CA1 place cells recorded from unimpaired old, but not impaired old or young, animals became more spatially selective as animals learned the task. Hilar spatial selectivity for both age groups was not significantly related to choice accuracy. These data support the hypothesis that at least a subpopulation of aged rats may benefit from reorganization of spatial representations in such a way that the normal age-related spatial learning deficit is attenuated.

Aging↗
PubMed2005

Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms.

BACKGROUND: Cigarette smoking rates in schizophrenia are higher than in the general population. OBJECTIVES: To determine whether cigarette smoking modifies cognitive deficits in schizophrenia and to establish the role of nicotinic acetylcholine receptors (nAChRs) in mediating cigarette smoking-related cognitive enhancement. DESIGN: Neuropsychological assessments were performed at smoking baseline, after overnight abstinence, and after smoking reinstatement across 3 separate test weeks during which subjects were pretreated in a counterbalanced manner with the nonselective nAChR antagonist mecamylamine hydrochloride (0, 5, or 10 mg/d). PARTICIPANTS: Twenty-five smokers with schizophrenia and 25 control smokers. SETTING: Outpatient mental health center. MAIN OUTCOME MEASURES: Visuospatial working memory (VSWM) and Continuous Performance Test (CPT) scores. RESULTS: In smokers with schizophrenia and control smokers, overnight abstinence led to undetectable plasma nicotine levels and an increase in tobacco craving. While abstinence reduced CPT hit rate in both groups, VSWM was only impaired in smokers with schizophrenia. Smoking reinstatement reversed abstinence-induced cognitive impairment. Enhancement of VSWM and CPT performance by smoking reinstatement in smokers with schizophrenia, but not the subjective effects of smoking, was blocked by mecamylamine treatment. CONCLUSIONS: Cigarette smoking may selectively enhance VSWM and attentional deficits in smokers with schizophrenia, which may depend on nAChR stimulation. These findings may have implications for understanding the high rates of smoking in schizophrenia and for developing pharmacotherapies for cognitive deficits and nicotine dependence in schizophrenia.

Adult↗