Memory In Aged Rats Research Articles

Acute and chronic nicotine effects on working memory in aged rats.

Acute and chronic nicotine administration has been repeatedly been found in our laboratory to improve working memory performance of normal adult rats in the radial-arm maze. The current study was conducted to determine if acute or chronic nicotine administration would improve working memory performance in aged rats. Sixteen young adult (3-7 months) and 32 aged (24-28 months) male Sprague-Dawley rats were trained on an eight-arm radial maze. A significant age-related choice deficit was seen during the 21 sessions of training. After training, half of the rats in each age group were implanted with nicotine-containing osmotic minipumps and the other half implanted with vehicle-containing pumps. Consistent with previous work, the young adult rats given chronic nicotine (approximately 5 mg/kg per day as measured as nicotine base) showed a significant improvement in working memory performance. In contrast, the aged rats did not show a significant effect of this dose of chronic nicotine. After a 2 week withdrawal period the remaining rats underwent a series of acute drug challenges with nicotinic and muscarinic agonists and antagonists as well as the dopaminergic antagonist haloperidol. Mecamylamine and haloperidol impaired the memory performance of the young adult rats, whereas the aged rats showed no effect. In contrast, scopolamine impaired performance of both young adult and aged rats in a similar manner. Both pilocarpine and nicotine improved the memory performance of the aged rats, but did not improve the young adult rats, possibly due to a ceiling effect on performance. During the cholinergic agonist drug phase, the aged rats which had previously been given chronic nicotine infusions showed better performance than those which had not. The resistance of the aged rats to chronic nicotine-induced working memory improvements and acute mecamylamine-induced working memory deficits may have resulted from the decline in nicotinic receptors seen with aging. Chronic co-administration of the nicotinic antagonist mecamylamine in a previous study was found to abolish the chronic nicotine-induced working memory improvement. The aged rats were resistant to haloperidol-induced deficits which may have resulted from the decrease in dopaminergic receptors seen with aging. Interestingly, acute cholinergic agonists including nicotine did improve working memory performance in the aged rats and previous chronic nicotine infusion was beneficial during the period of acute cholinergic agonist challenge. This suggests that nicotinic treatment may be of use for treating age associated memory impairments but that special dosing regimens may be required.

Nicotine enhances the learning and memory of aged rats

The cognitive performance of young adult (2–3-month-old) and aged (22–24 month-old) rats was characterized in one of three different behavioral tasks, and the ability of daily nicotine treatment to alleviate age-related learning and memory deficits was evaluated. Aged rats received an IP injection of either nicotine (0.2 mg/kg) or saline vehicle 15 min prior to daily testing; young control rats received saline vehicle injections. Compared to young controls, aged control rats were severely impaired in the acquisition of one-way active avoidance pole jumping over 12 days of testing. Nicotine pretreatment of similar aged rats markedly improved overall learning and the rate of learning compared to aged controls. In Lashley III maze performance, aged control rats made substantially more alternation errors than young controls; however, aged rats pretreated with nicotine made significantly fewer errors over the entire 20-day test period compared to aged controls. During 30 days of 17-arm radial maze testing, aged control animals were severely impaired in general learning and reference (long-term) memory, but only mildly impaired in working (short-term) memory. Nicotine pretreatment of similar aged rats induced a substantial enhancement in overall learning and reference memory, but did not affect working memory. These results indicate that chronic nicotine administration can improve the impaired learning/memory abilities of aged rats in several tasks, and suggest that stimulation of central nicotinic receptors may be of considerable therapeutic value to treat age-related memory impairment.

Glucose attenuation of atropine-induced deficits in paradoxical sleep and memory

When administered systemically, glucose attenuates deficits in memory produced by several classes of drugs, including cholinergic antagonists and opiate agonists. Glucose also enhances memory in aged rats, mice, and humans. In addition, glucose ameliorates age-related reductions in paradoxical sleep. Because deficits in paradoxical sleep are most marked in those individual aged rats that also have deficits in memory, treatments which improve one of these functions may similarly improve the other. The present experiments show that glucose attenuates deficits in paradoxical sleep and memory after atropine administration, with similar dose-response curves for both actions. In the first experiment, rats received saline, atropine (1 mg/kg), glucose (100 mg/kg) or combinations of atropine + glucose (10, 100, 250, and 500 mg/kg) 30 min before assessment on a spontaneous alternation task. In the second experiment, 3-h EEGs were assessed for spontaneous daytime sleep in rats administered saline, atropine (1 mg/kg), glucose (100 mg/kg) or combinations of atropine + glucose (10, 100 and 250 mg/kg). In both experiments, glucose significantly attenuated deficits at an optimal dose of 100 mg/kg. A third experiment assessed blood glucose levels after injections of atropine + glucose (100 mg/kg) and determined that blood glucose levels were similar to those produced by other treatments which enhance memory. These results are consistent with the view that paradoxical sleep and at least one test of memory are similarly influenced by atropine and glucose.

Glucocorticoids, hippocampal corticosteroid receptor gene expression and antidepressant treatment: relationship with spatial learning in young and aged rats

The emergence of cognitive deficits in a subgroup of aged rats is associated with increased hypothalamic-pituitary-adrenal axis activity, decreased hippocampal mineralocorticoid and/or glucocorticoid receptor gene expression and neuronal loss. Short-term treatment with antidepressant drugs in young rats increases hippocampal corticosteroid receptor gene expression. In this study, the effects of chronic antidepressant administration on hippocampal mineralocorticoid and glucocorticoid receptor gene expression and spatial memory in young and aged rats were investigated. Young (eight months) and old (22 +/- 1 months) Lister-hooded rats were ranked according to watermaze performance. Matched pairs of rats were treated with amitriptyline (10 mg/kg) or saline daily for nine weeks, then reassessed in the watermaze. Amitriptyline significantly improved spatial memory in the young rats (33% increase in transfer test time) and increased hippocampal mineralocorticoid, but not glucocorticoid receptor messenger RNA expression. By contrast, in aged rats, amitriptyline had no effect on spatial memory or hippocampal corticosteroid receptor gene expression, either in cognitively unimpaired or cognitively-impaired animals. In aged rats, basal plasma corticosterone levels, which were significantly higher than in young animals, correlated negatively with spatial memory, while hippocampal glucocorticoid receptor mRNA expression correlated negatively with plasma corticosterone levels and positively with spatial memory. Amitriptyline had no significant effect on basal morning plasma corticosterone levels in either young or aged rats, but significantly decreased evening corticosterone levels in aged rats. Our data support the notion that corticosterone exerts a concentration-dependent biphasic influence, via selective activation of hippocampal mineralocorticoid and glucocorticoid receptor, on spatial memory. Amitriptyline improves spatial memory in young rats and increases hippocampal mineralocorticoid receptor gene expression. The lack of amitriptyline effect on spatial memory in aged rats may reflect decreased plasticity of both the synaptic processes underlying spatial memory and the regulation of hippocampal mineralocorticoid/glucocorticoid receptor expression, with mineralocorticoid receptors fully occupied due to elevated basal plasma corticosterone levels (in part a consequence of inadequate glucocorticoid receptor function).

Improved learning and memory in aged rats with chronic administration of the nicotinic receptor agonist GTS-21

The ability of two synthetic nicotine receptor ligands, GTS-21 and DMAB, to chronically enhance the cognitive function of aged rats was evaluated in three diverse tasks and compared to the cognition-enhancing effects of nicotine administration. 15 min prior to daily behavioral testing, aged 22–24 month old rats received an i.p. injection of nicotine (0.2 mg/kg), GTS-21 (1 mg/kg), DMAB (2 mg/kg), or saline vehicle and were tested in either one-way active avoidance pole jumping, Lashley III maze, or a 17-arm radial maze. GTS-21 pretreatment was as effective as nicotine for enhancing the acquisition of aged rats in both one-way active avoidance and Lashley III maze training. In 17-arm radial maze testing, GTS-21 improved both general learning and reference (long-term) memory to the same extent as nicotine. Although DMAB pretreatment enhanced reference memory in 17-arm radial maze testing to the same extent as nicotine, it did not affect general learning in this complex task and did not exert any cognition-enhancing effects in Lashley III maze training. These results indicate that GTS-21 has cognition-enhancing abilities in aged rats that are comparable to those of nicotine in a variety of behavioral tasks. Since GTS-21 acts preferentially on brain nicotinic receptors and is less toxic than nicotine, these results further indicate that GTS-21 may have substantive therapeutic value in the treatment of age-associated memory impairment (AAMI) and/or Alzheimer's disease.

Impaired spatial memory in aged rats is associated with alterations in inositol phospholipid metabolism.

WE have investigated changes in inositol phospholipid turnover and membrane arachidonic acid concentration in the dentate gyrus and frontal cortex of animals aged 3-6 months, 14 months or 22 months which were trained in the Morris water maze. Ageing was associated with poorer performances in the behavioural test, characterized by increased variability in retention and acquisition amongst individuals, a decrease in membrane arachidonic acid concentration and increased unstimulated inositol phospholipid metabolism in synaptosomes prepared from frontal cortex and dentate gyrus. Arachidonic acid stimulated inositol phospholipid metabolism in synaptosomes, but in the older groups, stimulation was associated with good performance in the Morris water maze. In slices prepared from frontal cortex, responsiveness of inositol phospholipid metabolism to glutamate was also age- and performance-dependent. The findings highlight a correlation between age, inositol phospholipid metabolism and performance in the Morris water maze.

D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats

D-cycloserine, a partial agonist of the NMDA receptor-associated glycine site, can enhance cognition. The present experiment examines the behavioral effects of D-cycloserine on cognitive deficits in male Fischer-344 rats, 24 months old. Rats 24 months old ( n = 42) received either vehicle or one of 3 doses of D-cycloserine prior to testing. Young rats, 4 months old ( n = 13), received vehicle prior to testing. Place discrimination and repeated acquisition were tested in the water maze and a variety of sensorimotor tasks were given. Aging impaired performance in all tasks. D-cycloserine improved performance in place discrimination and repeated acquisition. No doses affected sensorimotor function. These results support the hypothesis that D-cycloserine has cognition enhancing properties and that it may be useful in treating disorders involving cognitive impairment.

Activation of the medial septal area attenuates LTP of the lateral perforant path and enhances heterosynaptic LTD of the medial perforant path in aged rats

Age-related memory impairments may be due to dysfunction of the septohippocampal system. The medial septal area (MSA) provides the major cholinergic projection to the hippocampus and is critical for memory. Knowledge of the neurobiological mechanisms by which the cholinergic system can attenuate age-related memory loss can facilitate the development of effective cognitive enhancers. At present, one of the best neurobiological models of memory formation is long-term potentiation/long-term depression (LTP/LTD). In previous studies, intraseptal infusion of the muscarinic agonist oxotremorine, which excites MSA neurons, improved memory in aged rats. The present study examined LTP and LTD in aged Fisher 344 rats following intraseptal infusion of oxotremorine. LTP and LTD were assessed using the slope of the EPSP recorded from the hilar region of the dentate gyrus. Induction of LTP was blocked in the lateral perforant path, but not in the medial perforant path, following intraseptal infusions of oxotremorine. The generation and amplitude of heterosynaptic LTD was enhanced in the medial perforant path, but not in the lateral perforant path. The results provide evidence that pharmacological activation of the MSA can modulate LTP and LTD in the hippocampus of aged rats. The implications of these results with respect to memory and synaptic plasticity in the hippocampus are discussed.

Correlation between zinc level in hippocampal mossy fibers and spatial memory in aged rats.

Correlation between zinc level in hippocampal mossy fibers and spatial memory in aged rats.

Effects of combined acetylcholinesterase inhibition and serotonergic receptor blockade on age-associated memory impairments in rats

We recently reported that post-training administration of serotonergic receptor antagonists attenuated the inhibitory-avoidance memory deficits normally exhibited by aged rats. In the present study, we determined whether a subeffective dose of the serotonergic type-2 receptor antagonist, ketanserin, would augment the facilitative effects produced by the acetylcholinesterase inhibitor, physostigmine, on memory in aged rats using the same task. The drugs were injected intraperitoneally alone, or in combination, immediately following training. Retention testing occurred 24 hours following training. A dose-dependent enhancement of memory was demonstrated as a result of the two treatment conditions (physostigmine 0.01–10.0 μ/kg, ketanserin 1.0 mg/kg + physostigmine 0.001–0.01 μ/kg). The facilitation of memory produced by the combined treatment was observed at doses well below those required to produce a similar effect when each drug was administered alone. The results provide additional evidence for an interaction between the cholinergic and serotonergic neurotransmitter systems in learning and memory, and may have important implications in the treatment of age-related memory impairments.

Deterioration of spatial and nonspatial reference and working memory in aged rats: Protective effect of life-long calorie restriction

—Two different aspects of learning (spatial and nonspatial) and two different types of memory (reference and working) were simultaneously measured in populations of 3- (young), 11- (adult), and 25-month-old (aged) rats fed ad libitum either a standard (ST) or a hypocaloric (HY) diet. All groups, regardless of age or diet, showed ability in learning all four versions of the task. However, old ST rats were significantly slower and less efficient at learning than the young and adult ST rats. In contrast, senescent HY rats' cognitive abilities did not differ from those of their young and adult counterparts. The decline in reference and working memory in the aged ST rats was more pronounced in the spatial than the nonspatial version of the task. This study confirms and extends to more specific aspects of memory our earlier finding that age-related cognitive deterioration in rats was antagonized by life-long calorie restriction.

Spatial memory in aged rats: population heterogeneity and effect of levocarnitine acetyl.

The existence in a population of aging rats of classes that display a different performance in the Morris water-maze test was investigated by cluster analysis procedure. These classes identified at 18 months of age showed a different response to levocarnitine acetyl and had a different behavioral profile when tested at 25 months of age. These findings demonstrate the need for an alternative interpretation of variability in animal populations as measured by the standard statistical analyses. The data analysis strategy we propose here will allow for the use of variability as a useful source of information.

Old age and cognition: Enhancement of recent memory in aged rats by the calcium channel blocker nimodipine

Aged hooded rats were given extensive training on an 8-arm radial arm maze task. The testing procedure was so designed as to maximally challenge each animal's trial specific memory capacities. After performance had stabilized, the animals were administered different dosages of the dihydropyridine calcium channel blocker nimodipine. In all animals, the drug improved performance in the 8-arm maze but, more importantly, it did so in a dose-related manner. These results, along with other findings, support the notion that calcium homeostasis may be an important factor determining the behavioral consequences of aging and particularly memory dysfunctions.

The effects of guanfacine, α-2 agonist, on the performance of young and aged rats in spatial navigation task

The aim of the present experiment was to study the effects of a low dose (0.001 mg/kg) of guanfacine, alpha-2 agonist, on the acquisition and retention of a water maze task measuring spatial reference memory in young and aged rats. Aged rats were impaired in the acquisition of this task. Both young and aged rats treated with guanfacine had shorter escape latencies than their saline treated counterparts. However, guanfacine treatment increased the speed of swimming in aged rats. According to the results of the probe trial, guanfacine may slightly improve the acquisition/retention of water maze task in young rats, whereas it may slightly impair the acquisition/retention of aged rats. The results suggest that a low dose of guanfacine administered peripherally may have different effects on young and aged rats in water maze performance, and a low dose of guanfacine does not improve spatial reference memory in aged rats.

Poor Blood Glucose Regulation Predicts Sleep and Memory Deficits in Normal Aged Rats

Poor glucose regulation predicts memory deficits in individual elderly humans. The present experiment determined whether glucose regulation was also related to memory and to sleep in aged rodents. Glucose regulation, inhibitory avoidance, and daytime sleep were assessed in young (3-month-old) and old (24-month-old) rats. Correlations were obtained between glucose regulation and the other variables in individual rats. In old rats, the magnitude of increases in blood glucose levels after glucose injections (500 mg/kg) was inversely correlated with retention of inhibitory avoidance and duration of paradoxical sleep bouts. In young rats, these measures were not significantly correlated. Because the deficits in sleep and memory in aged rats were largely confined to those rats with poor glucose control, peripheral glucose regulation may be a useful biological marker that accompanies cognitive and neurobiological dysfunction during aging.

Working memory in aged rats.

Working memory in aged rats.

Effects of dietary restriction on radial-arm maze performance and flavor memory in aged rats

Two groups of aged rats, a dietary restricted group fed approximately 10 g per day from 6 weeks of age and a group fed ad lib throughout their life span, were compared with a young adult group on an 8-arm radial maze and a flavor memory task. The young adult displayed efficient performance on the radial-arm maze within the 15 day test period. In contrast, both aged groups exhibited significantly poorer performance in the maze in comparison with the young adult group neither aged group differed from chance at the end of the 15 days. The flavor memory task required the animals to consume a novel flavor. Their loss of neophobia, as indexed by their subsequent consumption, was then taken as an indication of the extent to which they remembered the novel flavor and its effects. The young adult group lost their neophobia more rapidly than either of the aged groups, which did not appear to differ from each other. Taken together, this pattern of results indicates that dietary restriction does not protect animals from the memory loss observed in aged animals.

Working memory in aged rats.

The performances of young and aged rats were compared on a spatial (spatial delayed nonmatching-to-sample) and a nonspatial (object delayed nonmatching-to-sample) test of working memory. Although evidence was found that aging showed acquisition of both of these tasks, performance over different retention intervals of up to 60 s was normal once the task was mastered. An impairment was found, however, in the performance of the spatial test when the number of locations to be remembered on each trial was increased from one to two. The conclusions of this study are that under some conditions, the retention capabilities of aged rats may not change and that some acquisition impairments do not reflect alterations in learning or memory per se, but, in common with other studies, deficits in the remembrance of spatial locations may be found.

Cholinergic septal grafts into the hippocampal formation improve spatial learning and memory in aged rats by an atropine-sensitive mechanism

Behaviorally impaired old rats were selected from a population of 75 21- to 23-month-old rats on the basis of the place-investigated abilities in the Morris' water-maze task. After the pretransplant test, half of the old impaired rats received bilateral intrahippocampal cell suspension grafts prepared from the fetal septal-diagonal band region, which is rich in developing cholinergic neurons; the other half were left as sham-operated controls. Twelve weeks after grafting, the rats were retested in the water-maze using alternating cue-navigation and place-navigation trials (i.e., with visible or nonvisible escape platform). While the old impaired controls had deteriorated further between the 2 tests and showed poor retention of the pretransplant performance level, the grafted rats were significantly improved in comparison with both their pretransplant performance and the performance of the old impaired controls in the posttransplant test. The graft-induced effect was due both to an improved retention of the performance level acquired in the test performed prior to transplantation surgery, and to an improved acquisition of spatial memory of the escape platform site during the posttransplant test week (measured as an improved focusing of search over the platform site after platform removal). The acetylcholine esterase inhibitor physostigmine had no or only marginal effects on the performance of any of the young or aged rat groups. By contrast, the recovered navigational abilities and spatial memory in the grafted animals were completely abolished after administration of the muscarinic receptor antagonist atropine. A similar atropine-sensitivity was seen in behaviorally nonimpaired aged rats but not in the well-trained young control rats. The results show that cholinergic septal grafts, implanted into the hippocampal formation, improved spatial learning in the impaired aged rats primarily, or perhaps exclusively, by a recovery of the rats' ability to use spatial cues for place-navigation in the water-maze, while other aspects of the performance deficits in the water-maze task in the aged rats were left unaffected by the septal grafts. On the basis of parallel morphological studies, it is proposed that the effects of the septal grafts on the spatial learning impairments in the aged rats are critically dependent on the direct action of cholinergic neurons in the grafts via synapses formed onto neuronal elements in the host by their ingrowing axons.

Preservation of accurate spatial memory in aged rats

Male rats were tested in an 8 arm radial maze from 6–26 months of age with 5 hr delay imposed between choices 4 and 5. At 26 months their spatial memory was more accurate than when they were first tested at 6 months and also more accurate than that exhibited by another 5 month old group tested concurrently. However, these old rats acquired a noval spatial habit more slowly than the younger animals. In a subsequent study, we compared the acquisition of accurate spatial memory by rats that were 3 or 21.5 months old at the start of training. Older rats adapted to the maze more slowly and required more sessions to achieve criterion with no delay imposed during the test. There was no reliable difference in acquisition when a 1 hr delay was imposed between choices 4 and 5, but the old rats learned more slowly with a 5 hr delay. On memory tests after criterion performance had been achieved, the older rats performed as well as the younger animals at all delay intervals. Aged rats are deficient in acquiring the skills required for accurate spatial memory, but once acquired these skills do not deteriorate. The possibility that other “memory” deficits associated with aging might be alleviated by overtraining is discussed.