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Protective effect of buckwheat polyphenols against long-lasting impairment of spatial memory associated with hippocampal neuronal damage in rats subjected to repeated cerebral ischemia.

In the present experiment, we studied the action of buckwheat polyphenol (BWP, from Fagopyrum esculentum MOENCH) in a repeated cerebral ischemia model, which induced a strong and long-lasting impairment of spatial memory in 8-arm radial maze with hippocampal CA1 cell death in rats. BWP (600 mg/kg, continuous 21-day p.o.) significantly ameliorated not only the impairment of spatial memory in the 8-arm radial maze, but also necrosis and TUNEL-positive cells in the hippocampal CA1 area subjected to repeated cerebral ischemia (10 min x 2 times occlusion, 1-h interval) in rats. In order to investigate the mechanism of BWP protective action, we measured the release of glutamate and NO(x)(-) (NO(2)(-) + NO(3)(-)) production induced by repeated cerebral ischemia in the rat dorsal hippocampus using microdialysis. A 14-day BWP treatment significantly inhibited the excess release of glutamate after the second occlusion. In addition, the BWP remarkably suppressed a delayed increase in NO(x)(-) (NO(2)(-) + NO(3)(-)) induced by repeated cerebral ischemia in the dorsal hippocampus as determined in vivo by microdialysis. However, the 14-day treatment did not affect hippocampal blood flow in either intact rats or rats subjected to repeated ischemia measured by lasser Doppler flowmeter. These results suggested that BWP might ameliorate spatial memory impairment by inhibiting glutamate release and the delayed generation of NO(x)(-) in rats subjected to repeated cerebral ischemia.

Animals↗

Effects of estrogen and progesterone on spatial memory consolidation in aged females.

Interpretation of data illustrating that estrogen, with or without progestin, is detrimental to memory in post-menopausal women is complicated by the fact that little is known about the effects of progestins on memory. The present study examined if estrogen, alone or with progesterone, affects spatial memory consolidation in ovariectomized aged female mice. Mice received eight training trials in a spatial Morris water maze followed immediately by injection of water-soluble 17beta-estradiol (E(2); 0.2 mg/kg) or vehicle. Mice were re-tested 24 h later. All mice learned to find the platform on Day 1. On Day 2, the performance of control, but not E(2) mice, deteriorated, suggesting that E(2) enhanced memory for the platform location. In a second experiment, mice were injected with E(2) and 10 or 20 mg/kg water-soluble progesterone. The 10 mg/kg dose of progesterone did not affect estrogen's ability to enhance spatial memory consolidation, but 20 mg/kg blocked this effect. These data indicate that estrogen can improve spatial memory consolidation in aged females and that this effect can be attenuated by progesterone.

Analysis of Variance↗

Neural aromatization accelerates the acquisition of spatial memory via an influence on the songbird hippocampus.

Circulating estrogens affect the neural circuits that underlie learning and memory in several vertebrates via an influence on the hippocampus. In the songbird hippocampus local estrogen synthesis due to the abundant expression of aromatase may modulate hippocampal function including spatial memory performance. Here, we examined the effect of estradiol, testosterone, and dihydrotestosterone on the structure and function of the songbird hippocampus. Adult male zebra finches were castrated, implanted with one of these steroids or a blank implant, and trained on a spatial memory task. The rate of acquisition and overall performance on this task was recorded by direct observation. The size and density of cells in the hippocampus and its volume were measured. Estradiol-treated birds learned the task more rapidly than any other group. Although testosterone- and blank-implanted birds did learn the task, we found no evidence of learning in dihydrotestosterone-implanted subjects. Cells in the rostral hippocampus were larger in estradiol- and testosterone-treated birds relative to other groups. A corresponding decrease in the density of cells was apparent in estradiol-implanted subjects relative to all other groups. These data suggest that estradiol may accelerate the acquisition of a spatial memory task and increase the size of neurons in the rostral hippocampus. Since testosterone-mediated changes in acquisition and cell size were similar to those of estradiol, but not dihydrotestosterone, we conclude that neural aromatization of testosterone to estrogen is responsible for effects on the structure and function of the songbird hippocampus.

Analysis of Variance↗

Spatial memory and learning deficits after experimental pneumococcal meningitis in mice.

Survivors of bacterial meningitis frequently suffer from long-term sequelae, particularly from learning and memory deficits. For this reason, spatial memory and learning was studied in a mouse model of ceftriaxone-treated Streptococcus pneumoniae meningitis. Persistent deficits of spatial learning despite normal motor function were observed in mice infected with 10(4) colony-forming units (CFU) in 25 microl of saline into the right forebrain in comparison to mice treated with an equal amount of saline. Survivors of meningitis performed significantly worse in memorizing a hidden platform in a Morris water maze. After 2 weeks, the difference between post-meningitis and control mice diminished. Yet, when the platform was moved after 180 days, learning of the new location was still strongly impaired in mice surviving meningitis.

Animals↗

Allocentric versus egocentric spatial memory after unilateral temporal lobectomy in humans.

Thirty patients who had undergone either a right or left unilateral temporal lobectomy (14 RTL; 16 LTL) and 16 control participants were tested on a computerized human analogue of the Morris Water Maze. The procedure was designed to compare allocentric and egocentric spatial memory. In the allocentric condition, participants searched for a target location on the screen, guided by object cues. Between trials, participants had to walk around the screen, which disrupted egocentric memory representation. In the egocentric condition, participants remained in the same position, but the object cues were shifted between searches to prevent them from using allocentric memory. Only the RTL group was impaired on the allocentric condition, and neither the LTL nor RTL group was impaired on additional tests of spatial working memory or spatial manipulation. The results support the notion that the right anterior temporal lobe stores long-term allocentric spatial memories.

Adult↗

When is the perirhinal cortex necessary for the performance of spatial memory tasks?

The perirhinal cortex and hippocampus have close anatomical links and it has, therefore, been proposed that they have important, coordinated roles in memory. This review examines the relative role of these structures in spatial memory tasks that are known to be hippocampal-dependent. The published lesion data gives a mixed picture, as only some studies detect spatial deficits after perirhinal cortex lesions. The possible reasons for these inconsistencies are reviewed, along with electrophysiological data that indicate how perirhinal cortex lesions may alter neuronal activity in the hippocampus. Overall, the disruptive effects of perirhinal lesions on spatial memory performance are, when they occur, typically transient and never as severe as those seen after hippocampal lesions. It is argued that parallel cortical routes provide key, sensory data to the hippocampus such that in the absence of the perirhinal cortex alternative information is available. The deficits associated with perirhinal damage may then reflect difficulties that arise when task performance requires the use of ambiguous distal cues, for example, those containing overlapping visual features.

Electrophysiology↗

Chronic stress enhances spatial memory in ovariectomized female rats despite CA3 dendritic retraction: possible involvement of CA1 neurons.

Emerging data report sex differences in how the brain responds to chronic stress. Here, we investigated the effects of chronic restraint stress (6 h/day/21 days) on hippocampal morphology and function in ovariectomized female rats. Chronic restraint stress caused CA3 apical dendritic retraction in short- and long-shafted neurons, while it reduced basal dendritic arbors in long-shafted neurons only. Chronic restraint did not affect CA1 dendritic arborization, although it increased the proportion of CA1 spine heads compared with controls. Both stressed and control animals performed well on the Y-maze, a spatial memory task. However, chronic stress enhanced Y-maze performance compared with controls, which may reflect facilitated spatial memory or reduced habituation. Y-maze performance correlated with CA1 spine head proportion. This relationship suggests that spatial ability in females may be more tightly coupled with CA1 morphology, which may override the influence of CA3 dendritic retraction. Thus, this research provides additional evidence that CA3 morphology does not always parallel spatial memory.

Animals↗

Aging and the physiology of spatial memory.

Evidence for age-related changes in spatial memory in rodents and humans is presented, along with data that suggest that the hippocampal formation is necessary for normal performance on spatial tasks in both species. An examination of the electrophysiological characteristics of this structure in rats suggests that the changes that occur with age in the hippocampus are selective, but that at least two primary types of alterations contribute to the spatial cognitive impairment seen in these animals. These include a deficit in the ability to maintain synaptic enhancement and a reduction in the accuracy of information processing ability of single hippocampal neurons.

Aging↗

Cholinergic mediation of spatial memory in the preweanling rat: application of the radial arm maze paradigm.

These experiments assessed spatial memory capabilities in the developing rat by the radial arm maze paradigm. Subjects were trained and tested in the maze beginning at 16 days until they were 25 days of age. Results showed that animals that received training performed significantly better than those naive to the task, and better than chance, which suggests an early capacity for this type of learning. The second experiment investigated the neural mechanism that underlies spatial memory at this age as measured by the radial arm maze. In order to distinguish between the working and the reference memory components of the task, a modification of the basic radial arm maze paradigm was used. Subjects trained from 16 days received drug injections of saline, methylscopolamine, scopolamine, or arecoline prior to testing at age 25 days. Results indicated that central cholinergic antagonism severely impairs working memory while sparing reference memory. This finding is consistent with the existing literature that suggests a role for acetylcholine in adult learning and memory, specifically in working memory. Most important, these experiments document that (a) the radial arm maze paradigm can be used effectively for the developmental study of learning and memory in the rat and (b) cholinergic system(s) mediate working memory at an early age.

Animals↗

The study of spatial memory in adult male rats with injection of testosterone enanthate and flutamide into the basolateral nucleus of the amygdala in Morris water maze.

Extensive evidence suggests that the amygdala is involved in memory. The presence of androgenic and estrogenic receptors in the amygdala may reflect a possible involvement in certain activities of this part of the brain. Since sex steroids are known to play role in the maintenance and modulation of behavior, particularly spatial cognition throughout the life span, it was interesting to explore the role of these receptors in spatial memory. Therefore, an experiment was designed to investigate the effect of testosterone enanthate as an agonist and flutamide as an antagonist of androgenic receptors on spatial memory and learning. Wistar rats were bilaterally cannulated into basolateral nucleus of amygdala. Animals in different groups including vehicle (dimethyl sulfoxide) were proven to be inert for memory and learning. Testosterone enanthate (20, 40, 80 and 120 microg/0.5 microl), and flutamide (2, 5, 10, 20 and 40 microg/0.5 microl) were injected in both cannulae 30 min before each training day. After 4 days of experiments, results indicate a dose-dependent increase in parameters of escape latencies and travel distances to find the invisible platform in the group that received 120 microg/0.5 microl testosterone enanthate as compared to the control and vehicle groups. Flutamide had no effect on spatial memory. Therefore, it appears that androgens may effect memory and learning in amygdala. This is a feature that requires further investigation.

Amygdala↗

Fluvastatin alters psychomotor performance and daily activity but not the spatial memory in rats.

Statins, inhibitors of cholesterol synthesis for treating dyslipidemia and preventing cardiovascular complications, have been shown to alter central nervous system functions. Our aim was to investigate the effects of the fluvastatin, a member of statin family, on psychomotor performance, daily activity and spatial memory. Sprague-Dawley rats were treated with fluvastatin (n = 8) or placebo as a control (n = 11) regardless of sex. Fluvastatin (7.5 mg/kg) was administered orally once a day for four weeks, while the control group was administered only placebo. Psychomotor performance was measured by rotarod tests. No significant difference was observed in the fluvastatin group over the course of weeks, but the control group preferred to stay on the device shorter times (p < 0.05). For the first three weeks of the drug administration there was a statistical difference between the groups, however no difference was found after the 4th week. There was no difference in the Barnes maze spatial memory test between the groups and also within the groups over the course of time. Daily activity tests revealed that stereotypical and vertical movements of the fluvastatin group were significantly less than the control group in all four weeks. Ambulatory movements and the distances taken by the fluvastatin group were decreased significantly over the course of time (p < 0.005 and p < 0.001, respectively), but the control group did not reveal any significant change. Our results suggest that fluvastatin altered psychomotor performance and daily activity in rats, but it did not affect the spatial memory. These behavioral changes might be associated with alterations in the composition of the brain lipids caused by fluvastatin.

Animals↗

Spatial memory deficits in patients with lesions affecting the medial temporal neocortex.

Lesion studies in monkeys suggest that neocortical subregions of the medial temporal lobe (MTL) carry memory functions independent of the hippocampal formation. The present study investigates possible differential contributions of MTL subregions to spatial memory in humans. Eye movements toward remembered spatial cues (memory-guided saccades) with unpredictably varied memorization delays of up to 30 seconds were recorded in patients with postsurgical lesions of the right MTL, either restricted to the hippocampal formation (n = 3) or including the adjacent neocortex (n = 5) and in 10 controls. Although saccadic targeting errors of patients with selective hippocampal lesions did not differ from controls, saccadic targeting errors of patients with additional neocortical involvement showed a significant and contralaterally pronounced increase at memorization delays above 20 seconds. We conclude that the human medial temporal neocortex carries spatial memory functions independent of the hippocampal formation and distinct from spatial short-term memory.

Adult↗

Spatial memory impairments following damage to the mediodorsal nucleus of the thalamus in rhesus monkeys.

The present study assessed whether the mediodorsal nucleus (MD) of the primate thalamus subserves some of the same learning and memory functions mediated by its prefrontal cortical projection areas. Behavioral effects of MD lesions were evaluated in 14 young adult rhesus monkeys, using tests known to be sensitive to damage in different regions of the prefrontal cortex. Performance on a spatial delayed alternation task was significantly (P less than 0.01) impaired by MD lesions, and this impairment was significantly correlated (rs = 0.52) with damage to the posterior half of the mediodorsal nucleus. Such damage was also correlated significantly (rs = 0.51) with performance on another spatial memory task, delayed response; monkeys that sustained the largest lesions of the posterior mediodorsal nucleus were significantly (P less than 0.05) impaired on this task relative to operated animals suffering the least posterior MD damage. In contrast to their performance on spatial memory tasks, operated animals were not impaired on tests of object reversal or visual pattern discrimination. These results indicate that lesions of the mediodorsal nucleus can elicit a specific syndrome of spatial memory loss qualitatively similar to that observed after damage to the dorsolateral prefrontal cortex.

Animals↗

Spatial memory disturbance after focal cerebral ischemia in rats.

We investigated the impairment of retention of spatial memory in rats with chronic focal cerebral ischemia, and examined the correlation between this impairment and pathological outcomes. A preoperative acquisition trial of the Morris water-maze task was performed twice a day for 14 successive days, and then the middle cerebral artery (MCA) was occluded. A retention trial was performed 8 weeks after MCA occlusion. Escape latency and swimming path length to the platform were significantly increased in MCA-occluded rats compared with those of sham-operated rats, and these deficits significantly correlated with massive shrinkage of the brain. Retention latency of a passive avoidance task, which was trained preoperatively, was also significantly shortened in MCA-occluded rats compared with that in sham-operated rats. These results suggest that chronic focal cerebral ischemia causes prolonged spatial memory disturbance in rats and is associated with pathological changes, and that this rat model may be useful for assessing not only anterograde but also retrograde amnesia caused by focal cerebral ischemia.

Animals↗

Hippocampal CA1 kindling but not long-term potentiation disrupts spatial memory performance.

Long-term synaptic enhancement in the hippocampus has been suggested to cause deficits in spatial performance. Synaptic enhancement has been reported after hippocampal kindling that induced repeated electrographic seizures or afterdischarges (ADs) and after long-term potentiation (LTP) defined as synaptic enhancement without ADs. We studied whether repeated stimulations that gave LTP or ADs resulted in spatial performance deficits on the radial arm maze (RAM) and investigated the minimal number of ADs required for such deficits. Three experimental groups were run as follows: (1) 5 hippocampal ADs in 1 d (5-AD group), (2) 10 hippocampal ADs in 2 d (10-AD group), and (3) 12 -frequency primed-burst stimulations (PBSs) in 2 d in order to induce LTP without ADs (LTP group). Each experimental group was run together with a control group during the same time period. Rats were first trained in a spatial task on a radial arm maze with four of the eight arms baited, then given control or experimental treatment, and maze performance was tested in the first week (1-4 d) and fourth week (22-25 d) after treatment. Basal dendritic population excitatory postsynaptic potentials (pEPSPs) and medial perforant path (MPP)-evoked dentate gyrus population spike and polysynaptic CA1 excitation were recorded before and after experimental and control treatment. Spatial memory errors, in particular reference memory errors, were significantly higher in the 10-AD kindled group than any other group on the first and fourth week after treatment. Spatial memory errors were not significantly different in the 5-AD and LTP groups as compared with any control groups at any time. Basal dendritic pEPSP in CA1 was enhanced for about 1 wk after 12 PBSs, 10 ADs, or 5 ADs, while the dentate gyrus population spike and CA1 polysynaptic excitation evoked by MPP was increased for up to 4 wk after 10 ADs, but not 12 PBSs. Thus, distributed alteration of multiple synaptic transmission in the entorhinal-hippocampal circuit, but not LTP at the basal dendritic synapses in CA1, may disrupt spatial performance after 10 hippocampal ADs.

Animals↗

Low doses of delta-9 tetrahydrocannabinol (THC) have divergent effects on short-term spatial memory in young, healthy adults.

Evidence suggests that manipulating spatial information within working memory depends upon a circuitry organized around the prefrontal cortex (PFC) and the activity of the catecholamine systems. Other evidence attests to the effects of Delta-9 tetrahydrocannabinol (THC) on short-term spatial memory function, most probably involving CB(1) receptor activity within hippocampal circuitries. At the current time, there have been no systematic studies of the effects of THC on spatial working memory in human subjects using tasks known to depend upon frontotemporal neural circuitries. We examined the effects of a single sublingual 5 mg dose of THC on a test of spatial working memory (requiring active manipulation of remembered spatial information for the management of future behavior) and a test of spatial span (requiring only the reproduction of sequences of previously presented spatial cues). In all, 19 healthy adults were administered 5 mg THC and placebo in a double-blind, placebo-controlled, within-subject, crossover design. Male participants performed more accurately than female participants. THC significantly enhanced spatial working memory performance of female participants. By contrast, male and female participants produced more intrusion errors during performance of the Spatial Span task. These results suggest that THC has relatively complex effects on spatial memory in human subjects, perhaps reflecting altered CB(1) receptor activity within frontotemporal circuits or altered activity of mesocortical dopaminergic pathways in PFC areas associated with spatial memory.

Adult↗

The effects of nicotine and sucrose on spatial memory and attention.

Both nicotine and sucrose can enhance performance on cognitive tasks. However, little is known about whether nicotine and sucrose could act jointly to augment mental performance. To investigate if there is an interaction between nicotine and sucrose on cognitive behavior, performance on a continuous performance task (CPT) and a spatial memory task was examined in 14 healthy smokers after they had drunk 8 oz of either a sucrose- or aspartame-containing beverage, and then chewed a piece of gum containing either 2 mg nicotine or no nicotine. To assess changes in mood as a function of nicotine and sucrose intake, the profile of mood states (POMS) test was administered three times during each test session. Participants made significantly more correct responses and significantly fewer incorrect responses on the CPT when they received nicotine than when they received the placebo gum. Closer analysis of the data revealed that there was an interaction between sucrose consumption and nicotine intake. Nicotine increased hits and decreased misses when participants were given the sucrose-containing beverage, but not when they were given the aspartame-containing beverage. Neither nicotine nor sucrose affected spatial memory or mood across experimental sessions. However, when data were analyzed for just the first session, participants who drank the sucrose-containing beverage performed significantly better on the spatial memory task than those who drank the aspartame-containing beverage. No gender differences in the effects of nicotine or sucrose on cognitive performance were detected. The results provide support that both nicotine and sucrose have positive effects on cognitive behavior, and that under some conditions the two variables have additive effects on performance.

Adolescent↗

Environmental enrichment: effects on spatial memory and hippocampal CREB immunoreactivity.

Environmental enrichment has been shown to improve performance in tests of spatial memory, induce neurogenesis in the hippocampus, enhance survival of newly formed granule cells, and inhibit spontaneous apoptosis. Although neuroplasticity of the mammalian brain declines with age, recent evidence suggests that the adult brain exhibits significant plasticity in response to environmental stimulation. The present study was designed to evaluate the effect of environmental enrichment on spatial memory and on immunoreactivity to cAMP response element binding protein (CREB) from the hippocampus. C57/BL/6 mice were trained in a Morris water maze after exposure to an enriched environment, either from 35 to 94 days or from 100 to 159 days of age. Hippocampal tissue from representative animals was later analyzed by Western blot for CREB immunoreactivity. Results indicate that environmental enrichment (particularly during the earlier period) improved performance on the Morris water maze and tended to increase immunoreactivity to CREB in the hippocampus. Social interaction by itself did not result in significant differences in navigational performance. Results with regard to social interaction and CREB immunoreactivity were mixed. Results are discussed in terms of evaluating the construct of enrichment, the correlation of CREB transcription and behavior change, and the importance of the developmental period for enrichment.

Animals↗