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Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis.

Neurogenesis occurs within the adult dentate gyrus of the hippocampal formation and it has been proposed that the newly born neurons, recruited into the preexistent neuronal circuits, might be involved in hippocampal-dependent learning processes. Age-dependent spatial memory impairments have been related to an alteration in hippocampal plasticity. The aim of the current study was to examine whether cognitive functions in aged rats are quantitatively correlated with hippocampal neurogenesis. To this end, we took advantage of the existence of spontaneous individual differences observed in aged subjects in a hippocampal-dependent task, the water maze. We expected that the spatial memory capabilities of aged rats would be related to the levels of hippocampal neurogenesis. Old rats were trained in the water maze, and, 3 weeks after training, rats were injected with 5-bromo-2'-deoxyuridine (BrdUrd, 50 or 150 mg/kg) to label dividing cells. Cell proliferation was examined one day after the last BrdUrd injection, whereas cell survival and differentiation were determined 3 weeks later. It is shown that a quantitative relationship exists between learning and the number of newly generated neurons. Animals with preserved spatial memory, i.e., the aged-unimpaired rats, exhibited a higher level of cell proliferation and a higher number of new neurons in comparison with rats with spatial memory impairments, i.e., the aged-impaired rats. In conclusion, the extent of memory dysfunction in aged rats is quantitatively related to the hippocampal neurogenesis. These data reinforce the assumption that neurogenesis is involved in memory processes and aged-related cognitive alterations.

Aging↗

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

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

Animals↗

Apolipoprotein-E deficiency results in an altered stress responsiveness in addition to an impaired spatial memory in young mice.

It has been suggested that Alzheimer's disease (AD) is associated with an altered neurotrophic function of apolipoprotein-E (ApoE) and abnormal neuroendocrine activities. In the present study we investigated stress responsiveness of ApoE-deficient mice. Firstly, two sessions of restraint were introduced, 20 min per day for two (session 1) and three (session 2) consecutive days. In session 1, there was no difference between genotypes in open-field activity in response to restraint stress. In session 2, spatial memory was assessed in a Morris Water Maze 'Place Learning Set' task immediately following stress. Restraint stress caused a significant impairment of spatial memory in wild-type mice. The non-restraint ApoE-deficient mice showed a severe impairment of spatial memory similar to that of the restrained wild-type mice. Restraint stress had no obvious effect on spatial memory in ApoE-deficient mice until the third day of testing, when there was a decrease in reference memory compared with their non-restraint controls. In addition, the first session of restraint stress had an inhibitory effect on food intake in wild-type but not ApoE-deficient mice, and a longer-lasting effect on body weight in the wild-type than ApoE-deficient mice. ApoE-deficient mice showed a weaker corticosterone response to the initial restraint stress and a slower descending rate in serum corticosterone level during a 30-min post-stress period than their wild-type controls. However, higher baseline levels and stronger corticosterone responses were observed in ApoE-deficient mice than in wild-type mice when exposed to repeated restraint stress. The expression of ApoE mRNA was upregulated in the hypothalamus in wild-type mice exposed to repeated restraint stress. Taken together, these results demonstrate that ApoE deficiency causes a memory impairment and an altered stress responsiveness in mice.

Analysis of Variance↗

Adult age differences in spatial memory: effects of structural context and practice.

We examined the effect of structural context on memory for spatial location in young and elderly women in two studies. Subjects studied and later reconstructed an array of visually identical objects that were positioned in a three-dimensional Plexiglas matrix. For half the subjects, small household objects were interspersed in the array to serve as spatial landmark cues during encoding and replacement. All subjects received two study and replacement trials. The results indicated that (a) older women remembered fewer locations than younger women but benefited more from landmark cues to location, (b) performance improved on the second replacement trial for the young but not for the older women, and (c) both age groups appeared to use similar processing strategies that were based on the vertical dimension of space. These results suggest that structural context enhances older adults' retention of three-dimensional spatial information. The implications of these data for the conceptual distinction between structural and organizational aspects of spatial context are discussed.

Adult↗

Visual spatial memory is enhanced in female rats (but inhibited in males) by dietary soy phytoestrogens.

BACKGROUND: In learning and memory tasks, requiring visual spatial memory (VSM), males exhibit superior performance to females (a difference attributed to the hormonal influence of estrogen). This study examined the influence of phytoestrogens (estrogen-like plant compounds) on VSM, utilizing radial arm-maze methods to examine varying aspects of memory. Additionally, brain phytoestrogen, calbindin (CALB), and cyclooxygenase-2 (COX-2) levels were determined. RESULTS: Female rats receiving lifelong exposure to a high-phytoestrogen containing diet (Phyto-600) acquired the maze faster than females fed a phytoestrogen-free diet (Phyto-free); in males the opposite diet effect was identified. In a separate experiment, at 80 days-of-age, animals fed the Phyto-600 diet lifelong either remained on the Phyto-600 or were changed to the Phyto-free diet until 120 days-of-age. Following the diet change Phyto-600 females outperformed females switched to the Phyto-free diet, while in males the opposite diet effect was identified.Furthermore, males fed the Phyto-600 diet had significantly higher phytoestrogen concentrations in a number of brain regions (frontal cortex, amygdala & cerebellum); in frontal cortex, expression of CALB (a neuroprotective calcium-binding protein) decreased while COX-2 (an inducible inflammatory factor prevalent in Alzheimer's disease) increased. CONCLUSIONS: Results suggest that dietary phytoestrogens significantly sex-reversed the normal sexually dimorphic expression of VSM. Specifically, in tasks requiring the use of reference, but not working, memory, VSM was enhanced in females fed the Phyto-600 diet, whereas, in males VSM was inhibited by the same diet. These findings suggest that dietary soy derived phytoestrogens can influence learning and memory and alter the expression of proteins involved in neural protection and inflammation in rats.

Animals↗

Manipulation of prenatal hormones and dietary phytoestrogens during adulthood alter the sexually dimorphic expression of visual spatial memory.

BACKGROUND: In learning and memory tasks, requiring visual spatial memory (VSM), males exhibit higher performance levels compared to females (a difference attributed to sex steroid hormonal influences). Based upon the results from our companion investigation, this study examined the influence of prenatal sex steroid hormone manipulations on VSM in adulthood, as assessed in the radial arm maze. Additionally, the influence of dietary soy phytoestrogens (i.e., the presence of high or low estrogen-like compounds present in the animal's diet) on VSM was examined in combination with the prenatal hormonal manipulations. RESULTS: Radial arm maze performance on a phytoestrogen-rich diet: 1) females treated prenatally with testosterone were masculinized and acquired/performed in a manner similar to control or oil-treated males and 2) males treated prenatally with an androgen receptor blocker (flutamide) were feminized and acquired/performed in a fashion typical of control or flutamide-treated females. When a diet change was initiated in adulthood, control phytoestrogen-rich fed females outperformed control females switched to a phytoestrogen-free diet. Whereas, in control males the opposite diet effect was identified. Furthermore, flutamide-treated males fed a phytoestrogen-rich diet outperformed flutamide-treated males switched to a phytoestrogen-free diet. CONCLUSIONS: These results suggest that prenatal hormonal manipulations significantly sex-reverse the normal sexually dimorphic expression of VSM. Specifically, VSM was enhanced in females treated with testosterone and inhibited in males treated with flutamide. Finally, dietary soy phytoestrogens set a bias on learning and memory in these hormonally manipulated animals in a predictable manner and these data confirm and extend the findings in our companion paper.

Androgen Antagonists↗

Disturbance effect of music on processing of verbal and spatial memories.

The purpose of the present study was to examine the disturbance effect of music on performances of memory tasks. Subjects performed a verbal memory task and a spatial memory task in 4 sound conditions, including the presence of vocal music, instrumental music, a natural sound (murmurings of a stream), and no music. 47 undergraduate volunteers were randomly assigned to perform tasks under each condition. Perceived disturbance was highest under the vocal music condition regardless of the type of task. A disturbance in performance by music was observed only with the verbal memory task under the vocal and the instrumental music conditions. These findings were discussed from the perspectives of the working memory hypothesis and the changing state model.

Adolescent↗

Long-term effects of low-level sarin inhalation exposure on the spatial memory of rats in a T-maze.

1. To study the influence of low-level sarin exposure on cognitive functions, male albino Wistar rats were exposed to three various low concentrations of sarin (LEVEL 1-3) for 60 minutes in the inhalation chamber. Testing of cognitive functions was carried out using the T-maze evaluating learning and spatial memory. The behavior of sarin-exposed rats in the T-maze was tested several times within five weeks following sarin inhalation exposure to look for any cognitive impairments. The alteration of cognition was evaluated by using a method studying memory elicitation in response to appetitive motivation in a multiple T-maze. 2. Statistically significant, short-term deficiency in the T-maze performance was observed in rats exposed to symptomatic (LEVEL 3) as well as clinically asymptomatic concentration (LEVEL 2) of sarin. The repeated exposure of rats to clinically asymptomatic dose of sarin (LEVEL 2R) did not change the effect of low-level sarin exposure on spatial memory compared to the single exposure to the same dose of sarin. 3. Thus, sarin is able to influence the cognitive functions (e.g. spatial memory) even at low doses that do not cause clinically manifested intoxication following the inhalation exposure. Nevetheless, the alteration of spatial memory lasts for a short time only, in contrast with the severe sarin poisoning.

Administration, Inhalation↗

Post-ischemic treatment with toki-shakuyaku-san (tang-gui-shao-yao-san) prevents the impairment of spatial memory induced by repeated cerebral ischemia in rats.

Previously we have reported that Toki-shakuyaku-san (TSS) ameliorated the impairment of spatial memory induced by single cerebral ischemia (1 x 10 minutes) and scopolamine, a muscarinic receptor antagonist. In this experiment, we studied the effect of TSS on repeated cerebral ischemia (2 x 10 minutes, 1-hour interval) induced impairment of spatial memory and neuronal injury in rats. The 8-day post-ischemic treatment with TSS (30-300 mg/kg) was administered p.o. once per day. TSS dose-dependently prevented the impairment of spatial memory, neuronal death and TUNEL positive cells induced by repeated cerebral ischemia. In order to determine the mechanism of TSS, we also studied the effect of TSS on GluR2 mRNA, one of the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor subunits. Repeated cerebral ischemia significantly decreased GluR2 flop mRNA at 1 and 3 days after the occlusion. TSS (300 mg/kg) significantly suppressed the decrease in GluR2 flop at 3 days after repeated cerebral ischemia. These results suggested that the TSS has neuroprotective action which may be indirectly mediated by the AMPA receptor, and TSS may be beneficial for the treatment of cerebrovascular dementia.

Animals↗

The time course of spatial memory distortions.

Four experiments investigated the memory distortions for the location of a dot in relation to two horizontally aligned landmarks. In Experiment 1, participants reproduced from memory a dot location with respect to the two landmarks. Their performance showed a systematic pattern of distortion that was consistent across individual participants. The three subsequent experiments investigated the time course of spatial memory distortions. Using a visual discrimination task, we were able to map the emergence of spatial distortions within the first 800 msec of the retention interval. After retention intervals as brief as 50 msec, a distortion was already present. In all but one experiment, the distortion increased with longer retention intervals. This early onset of spatial memory distortions might reflect the almost immediate decay of detailed spatial information and the early influence of an enduring spatial memory representation, which encodes spatial information in terms of the perceived structure of space.

Adult↗

Effects of early and late nocturnal sleep on priming and spatial memory.

A wordstem priming task (nondeclarative memory), and a mental spatial rotation task (declarative memory) were presented to subjects of an experimental "sleep" group (n = 11) and of a "wake" control group (n = 10). Repetition priming effects and recall of spatial memory were tested after 3-hr retention intervals, which followed learning and were placed either in the early or in the late half of the night. Sleep group subjects slept during the retention intervals while subjects of the wake group stayed awake. As expected, early retention sleep was dominated by slow wave sleep (SWS), whereas rapid eye movement (REM) sleep prevailed during late retention sleep. After early retention sleep, recall of spatial memory was superior to that after late retention sleep (p < 0.01), and also to that after retention intervals of wakefulness (p < 0.05). In contrast, priming was more effective after late than early retention sleep (p < 0.05). It appears that early sleep dominated by SWS facilitates consolidation of declarative memory whereas late sleep dominated by REM sleep facilitates consolidation of nondeclarative memory.

Adult↗

Conservation of spatial memory function in the pallial forebrain of reptiles and ray-finned fishes.

The hippocampus of mammals and birds is critical for spatial memory. Neuroanatomical evidence indicates that the medial cortex (MC) of reptiles and the lateral pallium (LP) of ray-finned fishes could be homologous to the hippocampus of mammals and birds. In this work, we studied the effects of lesions to the MC of turtles and to the LP of goldfish in spatial memory. Lesioned animals were trained in place, and cue maze tasks and crucial probe and transfer tests were performed. In experiment 1, MC-lesioned turtles in the place task failed to locate the goal during trials in which new start positions were used, whereas sham animals navigated directly to the goal independently of start location. In contrast, no deficit was observed in cue learning. In experiment 2, LP lesion produced a dramatic impairment in goldfish trained in the place task, whereas medial and dorsal pallium lesions did not decrease accuracy. In addition, none of these pallial lesions produced deficits in cue learning. These results indicate that lesions to the MC of turtles and to the LP of goldfish, like hippocampal lesions in mammals and birds, selectively impair map-like memory representations of the environmental space. Thus, the forebrain structures of reptiles and teleost fish neuroanatomically equivalent to the mammalian and avian hippocampus also share a central role in spatial cognition. Present results suggest that the presence of a hippocampus-dependent spatial memory system is a primitive feature of the vertebrate forebrain that has been conserved through evolution.

Animals↗

[Spatial memory and hippocampus in aves].

The avian hippocampus, that locates in the posterior part of dorsomedial telencephalon, is considered to be a mammalian hippocampus homologue. The studies of connection, distribution of transmitters, and development of the avian hippocampus all support the homology. Food storing birds have large capacity of spatial memory and have a big hippocampus in comparison to non-storing species. The food-storing birds do not have good memory in general but have good memory specialized to the spatial tasks. The correlation between the volume of the hippocampus and behavior other than food storing but needs spatial memory is also suggested. The hippocampal damages cause deficits in spatial learning especially those using a maze but do not impair non-spatial learning tasks. These studies suggest that the avian hippocampus share a similar function with the mammalian hippocampus, especially that of rodents.

Animals↗

Pharmacological evidence of the role of dorsal striatum in spatial memory consolidation in mice.

This study investigated the role of dorsal striatum in spatial memory in mice. The mice were tested for their ability to detect a spatial displacement 24 hr after training. In order to manipulate the dorsal striatum, focal administrations of the N-methyl-D-aspartate (NMDA) antagonist D-2-amino-5 phosphonopentanoic acid (AP-5) were performed immediately after training. AP-5 impaired the mice's ability to detect the spatial change only if their initial position was constant during training and testing. These findings demonstrate that NMDA receptor blockade within the dorsal striatum impairs spatial memory consolidation in a task in which no explicit reward or procedural learning is involved. The results are discussed with reference to a possible selective involvement of this structure in processing spatial information acquired through an egocentric, but not an allocentric, frame of reference.

2-Amino-5-phosphonovalerate↗

Sex, age, and training modulate spatial memory in the rhesus monkey (Macaca mulatta).

The authors tested 90 rhesus monkeys (Macaca mulatta) on a task of spatial memory, the spatial Delayed Recognition Span Test. The results showed that performance declined significantly with age, males had greater scores than females, and the rate of apparent decline with age was greater in males than in females. Both working and reference memory declined with age, but only working memory showed sex differences. The authors compared these data with that of 22 monkeys who were trained on a simpler version of the task before formal testing. Training had no effect on males but dramatically improved working memory in young females. The results confirm a male advantage in spatial working memory at a young age and confirm a greater decline with age in males than in females. It is important to note that prior training completely reverses the deficits of young females.

Age Factors↗

Spatial memory following temporal lobe resection.

The present study sought a clearer understanding of spatial memory function consequent to temporal lobe resection, and, in particular, of spatial memory function with respect to two- as well as three-dimensional frames of reference. Relative to a group of 15 control participants, a group of 15 epilepsy patients with right temporal resections demonstrated deficits of memory for locations in a two-dimensional display. A group of 13 epilepsy patients with left temporal resections did not demonstrate such deficits. The right and the left resection groups both demonstrated deficits of memory for item-location relationships in a two-dimensional display. The right but not the left resection group demonstrated deficits of memory for item-location relationships in a three-dimensional display. The differing results that were observed for item-location relationships in two- and three-dimensional displays were attributed to differences in the way item information is bound with location information concerning two- and three-dimensional domains.

Adult↗

Spatial memory deficit and neurodegeneration induced by the direct injection of okadaic acid into the hippocampus in rats.

We investigated the effects of okadaic acid (OA), a specific inhibitor of protein phosphatases 1 and 2A, on spatial memory and neuronal survival in rats. Rats were initially trained on a spatial memory task in an eight arm radial maze. Spatial reference and working memory was impaired 1 day after the unilateral microinjection of OA into the dorsal hippocampus. The impairment was transient, and had disappeared by the following day. In contrast, neurodegeneration induced by OA was persistent and extended to the contralateral side 13 days after the injection. These results suggest that OA causes spatial memory impairment and neurodegeneration when injected directly into the hippocampus. Our findings also indicate dissociation between memory impairment and neurodegeneration induced by OA.

Animals↗

Involvement of bcl-family expression in the spatial memory impairment induced by repeated ischemia.

In the present study, we examined the effects of repeated ischemia (10 min x 2, 1 hr interval) on spatial memory in rats in an 8-arm radial maze test compared with single ischemia (10 min x 1). Repeated ischemia produced more severe impairment of spatial memory and stronger TUNEL-positive immunoreactivity in the hippocampal CA1 region than single ischemia at 7 days after reperfusion. Moreover, repeated ischemia altered bcl-family expression, which is related to apoptosis, while this was not affected by single ischemia. These results suggest that spatial memory impairment at 7 days after repeated ischemia may be related to apoptosis in hippocampal CA1 cells.

Acetylcholine↗