Amphetamine disrupts both working and reference memories of rats trained in a radial maze

To assess the effects of amphetamine on working and reference memory rats were trained on a 12-arm radial maze with six arms baited and six arms unbaited until stable performance was achieved. Administration of 2.0 mg/kg d-amphetamine sulfate increased both working and reference memory errors, but only if a 5-min delay was imposed after three successful choices. With no delay this dose had no reliable effect on either working or reference memory. Lower doses (0.5 or 1.0 mg/kg) were ineffective even when a delay was imposed during the test. We suggest that amphetamine heightens arousal, which disrupts accurate retention when the rat's attention to the relevant cues is interrupted, as during a brief delay. Alternative explanations are discussed.     

Evidence for neocortical involvement in reference memory

Rats were trained on an eight-arm radial maze task using a procedure that provides for an assessment of both working and reference memory. Following training, rats received parietal cortex, medial prefrontal cortex, visual cortex, or nucleus basalis magnocellularis lesions. Rats with visual cortex lesions showed no change in performance on either working or reference memory. Rats with parietal cortex lesions displayed a temporary deficit in reference, but no deficit on working memory. Animals with medial prefrontal cortex lesions showed a temporary deficit on both working and reference memory. Rats with extensive lateral frontal and parietal cortex depletion of acetylcholinesterase following nucleus basalis magnocellularis lesions had a marked disruption only of reference but not of working memory. It is concluded that neocortex and possibly the cholinergic projections to neocortex play an important role in mediating reference memory.     

The Effects of L-glucose on memory in mice are modulated by peripherally acting cholinergic drugs.

D-Glucose improves memory in animals and humans and in subjects with memory pathologies. To date, the accepted conclusion drawn from animal research is that D-glucose improves memory via alterations in central cholinergic systems. However, recent evidence suggests that a sugar which does not cross the blood-brain barrier also facilitates memory (Talley, Arankowsky-Sandoval, McCarty, & Gold, 1999). The present study examined the effects of peripherally administered L-glucose, a stereoisomer of D-glucose, in male mice. Intraperitoneal administration of L-glucose (300 mg/kg) before testing enhanced place learning in the Morris water maze. Mice injected with L-glucose had significantly shorter escape latencies than mice injected with saline (1 ml/kg). Effects were observed on both reference memory and working memory tasks. L-Glucose did not facilitate performance on either task when it was simultaneously administered with cholinergic antagonists that are excluded from the central nervous system. Thus, simultaneous administration of either methyl-scopolamine (0.3 mg/kg), a peripherally acting muscarinic receptor blocker, or hexamethonium (1 mg/kg), a peripherally acting nicotinic receptor blocker, reversed the effect of L-glucose on memory. These findings suggest that the memory effects of l-glucose may be mediated by facilitated acetylcholine synthesis and/or release in the peripheral nervous system.     

Dose- and delay-dependent working/episodic memory impairments following intraventricular administration of ethylcholine aziridinium ion (AF64A).

The present study examined the effects of intraventricular administration of the cholinergic neurotoxin ethylcholine aziridinium ion (AF64A) on performance of a radial arm maze task. Male Sprague-Dawley rats were trained to perform a delayed-nonmatch to sample radial arm maze task in which a 1-h delay was imposed between the fourth and fifth arm selections. Following acquisition, animals were injected bilaterally with AF64A (1.5 or 0.75 nmol/side) or artificial cerebrospinal fluid into the lateral cerebral ventricles and allowed 7 days to recover before behavioral testing resumed. Significant dose- and delay-dependent impairments in the radial maze performance were observed in AF64A-treated rats as evidenced by fewer correct choices following the delay and by more errors to complete the task. Long-term testing in this task revealed significant recovery of memory performance. These findings indicate dose-dependent impairments in memory following intraventricular administration of AF64A and spontaneous behavioral recovery following such insult.     

Exponential decay of spatial memory of rats in a radial maze

The persistence of spatial memory of rats (n = 14) was investigated in an eight-arm radial maze. The animals were trained until the mean number of errors in the first eight choices was 0.2. The decay of performance with time was studied using delays of 5, 20, 60, 120, or 240 min between choices 4 and 5, during which the animal was removed from the apparatus. A delay of 60 min significantly impaired performance. The mean number of errors was not significantly different from the random choice level after a delay of 120 min. The increase in the number of errors with time was exponential. Comparison of the results with those of previous studies suggests that the nature of training may have effects on memory persistence in the radial maze.     

Scopolamine effects on memory retention in mice: a model of dementia?

Scopolamine-treated normal young human subjects exhibit memory dysfunctions analogous to those observed in demented patients. The dysfunctions are reversible by physostigmine but not by d-amphetamine which suggests that the memory impairment is specifically related to reduced cholinergic transmission caused by scopolamine. Scopolamine-induced amnesia has been proposed as a model for dementia where reduced cholinergic function is the suspected cause. We report seven experiments in young adult mice which examine scopolamine's effects on memory retention and whether its amnestic effects are specifically blocked by cholinergic agonists or cholinomimetics. Young adult mice were trained to avoid footshock in a T maze and their retention tested 1 week after training. Pretraining subcutaneous injection of scopolamine improved retention scores of "undertrained" mice at a dose of 0.01 mg/kg but impaired at a dose of 0.1 mg/kg. Post-training injection showed no effect at 0.01 mg/kg, enhanced retention scores at 0.1 mg/kg, and impaired at 1.0 mg/kg. The impairment by 1.0 mg/kg was blocked by injection 45 min post-training of each of two cholinergic drugs but was also counteracted by six drugs which act upon five other neural systems (catecholamine, serotonin, glycine, GABA, and hormonal). When scopolamine was injected 40 min pretraining, and each of eight drugs was injected immediately after training, the amnestic effect of scopolamine was only partially counteracted. This suggests that scopolamine impaired acquisition, in addition to some impairment of memory processing. This was confirmed by a direct study of acquisition rates of the avoidance response; 0.1 mg/kg of scopolamine impaired acquisition. The overall results indicate that pretraining administration of scopolamine impairs learning and to some degree memory processing. Counteracting scopolamine-induced amnesia, by either pretraining or post-training drug administration, is not specific to the cholinergic system.     

Effects of opiate antagonists on spatial memory in young and aged rats

The effects of post-training opiate antagonist administration on spatial memory were assessed in young and aged male Long Evans rats. In Experiment I rats were trained to visit each arm of an eight-arm radial maze once in a session to obtain a food reward placed at the end of each arm. During training aged rats required significantly more trials to achieve criterion performance when compared to young mature rats. However, administration of the opiate antagonist naloxone (2.0 mg/kg) immediately after each training trial did not significantly alter the rate of achieving accurate performance in either age group. In Experiment II young and aged rats that were previously trained to a comparable criterion on the radial maze were tested on the same maze apparatus in novel spatial environments. When animals were exposed to novel spatial information, the effects of post-trial opiate antagonists were examined using a within-subjects counter-balanced design. In Experiment IIa naloxone (2 mg/kg) enhanced the performance of both young and aged rats. In Experiment IIB naltrexone (1.0 mg/kg) was found to have a comparable effect of enhancing the performance of both age groups. In addition, in Experiment IIb a significant age-related deficit was found in rats tested in novel spatial environments. These results indicate that opiate antagonists are capable of improving memory for new spatial information in both young and aged rats on a task that is sensitive to behavioral deficits during normal aging.     

东莨菪碱对大鼠空间参考记忆和工作记忆的不同影响

观察东莨菪碱对空间参考记忆和空间工作记忆的编码、保持和提取过程的作用。应用Morris水迷宫实验测定大鼠的空间参考记忆和空间工作记忆,分别在训练的不同阶段腹腔注射东莨菪碱（1mg/kg）和相同容量的生理盐水,比较各东莨菪碱组和生理盐水组之间游泳潜伏期、路径长度、轨迹和游泳速度的差异。结果发现：与注射生理盐水相比,在训练前和探测实验前注射东莨菪碱的大鼠在探测实验中对目标象限不表现出空间偏爱,说明东莨菪碱干扰参考记忆的信息编码和提取过程;而在训练结束后注射东莨菪碱的大鼠探测实验的结果与生理盐水组相比没有显著差异,说明东莨菪碱对参考记忆的保持过程没有影响。在工作记忆实验中,无论第一次测试前、第一次测试后和第2次测试前注射东莨菪碱,均造成大鼠游泳潜伏期延长,说明东莨菪碱干扰工作记忆的编码、保持和提取过程。研究提示M受体在空间工作记忆和参考记忆中发挥不同作用     

Differential effects of estrogen on hippocampal- and striatal-dependent learning

Estrogen's role in learning and memory may be to predispose animals to use specific cognitive strategies (Korol & Kolo, 2002). Specifically, estrogen may facilitate hippocampal-dependent learning, while at the same time attenuate striatal-dependent learning. As a stringent test of this hypothesis, place or response learning on an eight-arm radial maze was compared between ovariectomized (OVX) female Long-Evans rats and rats with chronic estrogen replacement (OVX+E; 5mg 17-beta estradiol 60-day release tablet). Reference and working memory errors were monitored separately for both place and response learning tasks. OVX+E rats learned the place task significantly faster than the response task, and faster than OVX rats. OVX rats required fewer days to reach criterion on the response task than OVX+E rats. Estrogen selectively enhanced reference memory performance, but only during place learning. The specific pattern of estrogen effects on learning suggests that future studies include verification of cognitive strategies used by animals.     

Spatial Location Learning in Mice with Ibotenate Lesions of Entorhinal Cortex or Subiculum

This study examined the effects of ibotenate lesions of either the entorhinal cortex (EC) or the subiculum (SUB) on the ability of mice to memorize a single spatial location (initial discrimination), and on their capacity to switch to a new location (transfer) following the initial learning in an eight-arm radial maze. Results indicated that mice with ibotenate lesions of the EC or SUB were impaired in postoperative acquisition of the spatial discrimination task, making more reference, but not working memory, errors and displaying fewer first correct response trials than sham-operated control mice. Furthermore, additional damage to the ventral hippocampus exacerbated the impairment of performance induced by lesions of the SUB alone. In addition, all mice, except for the combined lesion group, exhibited similar performance levels when they were trained to choose another arm of the maze that had not previously been baited (transfer). These findings suggest that both the EC and the SUB play important roles in spatial information processing in mice.     

Development of reference and working spatial memory in preschool children

Three groups of preschool children (aged 18 to 28, 33 to 42, and 47 to 58 months) were given a radial search test similar to the radial arm maze used with nonhuman subjects. The children searched for chocolate sweets among 10 labeled locations in a room, 5 of which were baited with a sweet. Older children outperformed the intermediate group, who in turn outperformed the youngest group in requiring fewer choices to retrieve all of the sweets. Working memory and reference memory aspects of performance were then separated: Reference memory (restriction of choices to the baited subset) in older children was superior to that in the youngest group but not to that in the intermediate group. In terms of working memory (avoidance of repeat responses to already visited locations), the older group made fewer errors than the intermediate group, who, in turn, made fewer errors than the youngest group. We concluded that working and reference components of spatial memory in children may share common elements, perhaps the ability to recognize places as familiar, although reference memory may develop earlier than working memory.     

High-fat diets impair spatial learning in the radial-arm maze in mice

It has been suggested that hyperglycemia and insulin resistance triggered by energy-dense diets can account for hippocampal damage and deficits of cognitive behaviour. We wonder if the impairment of learning and memory processes detected in diet-induced obese (DIO) mice is linked to diet composition itself. With this purpose we have evaluated learning performance in mice undergoing a short-term high-fat (HF) treatment, which leads to a pre-obese state characterized by increased adiposity without significant changes of glucose and insulin plasma levels. C57BL/6J mice were fed either a HF (45 kcal% from fat) or control diet (10 kcal% from fat) during 8 weeks. Learning performance was evaluated by using the four-arm baited version of the eight-arm radial maze test (RAM). Mice were trained to learn the RAM protocol and then memory was tested at different time-points. Time spent to consume food placed in baited arms and errors committed to find them were measured in all sessions. DIO mice significantly spent more time in learning the task and made a greater number of errors than controls. Moreover, retention tests revealed that both working and total memory errors were also more numerous in DIO mice. The current results show that short-term DIO impairs spatial learning and suggest that impairment of hippocampal learning elicited by HF diets might be perceptible before metabolic alterations linked to obesity develop.     

Anisomycin impairs long-term working memory in a delayed alternation task

A long-term temporal component of working memory of rats trained on the radial maze has been shown to be susceptible to disruption by the protein synthesis inhibitor, anisomycin. It is not clear whether protein synthesis played a role in working memory because accurate performance on the radial maze required the storage of a large amount of information, or because the information was to be held in store for relatively long periods of time. This experiment tested these hypotheses by assessing the effect of anisomycin on choice accuracy in a comparatively simple spatial delayed alternation task. Results indicate that under the present training conditions, protein involvement in working memory is related more to the length of the retention interval than to the amount of information retained.     

Effects of the nicotinic receptor blocker mecamylamine on radial-arm maze performance in rats

Lesions of cholinergic neurons have been found by many investigators to impair choice accuracy in the radial arm maze. Because muscarinic receptor blockers, such as scopolamine, have also repeatedly been found to impair choice accuracy in the radial-arm maze, it has generally been thought that the critical effect of cholinergic lesions is the deafferentation of muscarinic receptors. The possible involvement of nicotinic receptors in the cholinergic bases of cognitive performance in the radial-arm maze has not been as well investigated. The present study examined the effects of the blockade of nicotinic receptors on performance of female Sprague-Dawley rats in the radial-arm maze. Acute administration of the the nicotinic receptor blocker, mecamylamine (10 mg/kg) was found to significantly impair radial-arm maze choice accuracy. This dose also caused a significant increase in response latency in the maze. The effect on choice behavior but not locomotor speed seemed to be due to the central effects of mecamylamine, because administration of the peripheral nicotine receptor blocker, hexamethonium (20 mg/kg), did not impair choice accuracy, even though it did increase response latency to a similar degree as the 10-mg/kg dose of mecamylamine. Lower doses of mecamylamine (2.5 and 5 mg/kg) did not impair choice accuracy. These results indicate that central nicotinic as well as muscarinic cholinergic receptors are involved with cognitive functioning.     

The effect of scopolamine and physostigmine on working and reference memory in pigeons

A comparison of the effects of scopolamine and physostigmine on working memory and reference memory in White Carneaux pigeons was undertaken. In Experiment 1, the pigeons received injections of scopolamine hydrobromide (0.03 mg/kg), or saline. Scopolamine hydrobromide had greater disruptive effects on working memory trials than on reference memory trials, and the centrally active form of scopolamine disrupted working memory trial accuracy more than the peripherally active form. The differential sensitivity of accuracy on working memory trials to disruption by central cholinergic blockade was obtained even though the discrimination required on reference memory trials was more difficult. In Experiment 2, the pigeons received injections of scopolamine hydrobromide (0.015 mg/kg), physostigmine (0.075 mg/kg) both scopolamine and physostigmine, or saline. Physostigmine given with scopolamine was able to reverse the scopolamine-induced reduction of accuracy on working memory trials. In neither study did scopolamine promote accelerated forgetting as the delay interval was increased. These results indicate that manipulation of central cholinergic neurotransmitter systems influences working memory processes in the pigeon, but these effects occur without alterations in the ability of the birds to actively maintain information during the retention interval.     

Wistar rats with high versus low rearing activity differ in radial maze performance

Substantial work has shown that rats although identical in stock, sex, age, and housing conditions can differ considerably in terms of behavior and physiology. Such individual differences, which can be detected by specific behavioral screening tests, are rather stable, that is, they probably reflect a behavioral disposition or trait. Here, we asked whether and how such differences might affect performance in a task of spatial learning and memory, the radial maze. As in our previous work, we used the degree of rearing activity in a novel open field to assign male adult outbred Wistar rats into those with high versus low rearing activity (HRA/LRA rats). They were then tested in a plus-maze for possible differences in anxiety-related behavior. Finally, and most importantly, they were food deprived and underwent maze training using an 8-arm radial maze with four non-baited and four baited arms. One of these arms consistently contained a larger bait size than the other three. In the open field, HRA rats not only showed more rearing behavior, but also more locomotor activity than LRA rats. In the plus-maze, HRA rats again showed more locomotion, but did not differ in open arm time or percentage of open arm entries, that is, conventional measures of anxiety-related behavior. In the radial maze, HRA rats consistently needed less time to consume all pellets than LRA rats, which was due to faster locomotion on the arms and less time spent at the food pits (especially in baited arms) of HRA rats. During the initial days of training, they were also more efficient in obtaining all food pellets available. Furthermore, HRA rats visited more arms and made relatively less reference memory errors than LRA rats. This allowed them to forage food quickly, but was paralleled by more working memory errors than in LRA rats. In general, working memory errors were more frequent in the arm with the large bait size, but there were no indications that HRA and LRA rats responded differently dependent on reward size. Finally, LRA rats lost slightly more weight than HRA rats during the period of food deprivation. These results are discussed with respect to the role of cognitive and motivational mechanisms, which as subject-inherent factors can contribute substantially to inter-individual variability in the radial maze.     

Intraseptal administration of muscimol produces dose-dependent memory impairments in the rat

The present study examined the effects of intraseptal administration of the GABAergic agonist muscimol on performance of a radial-arm maze (RAM) task. Male Long-Evans rats were trained to perform a RAM task in which a 1-h delay was imposed between the sample and the test session. In this task rats have access to four out of eight maze arms during a predelay session. Following a 1-h delay, rats are returned to the maze and allowed to freely choose among all eight arms. Arms not blocked during the predelay session are baited, and entry into an arm chosen during the predelay session or a repeated entry into a postdelay chosen arm constitutes an error. Following acquisition, animals were implanted with a single cannula aimed at the medial septum. A within-subjects design was utilized to examine the effects of intraseptal administration of muscimol (0.0, 0.75, 1.5 or 3.0 nmol) on performance in this task. All drugs or artificial cerebrospinal fluid were administered immediately following the predelay session. Muscimol, a GABA-A agonist, produced a dose-dependent impairment in maze performance as evidenced by fewer correct choices in the first four postdelay choices and an increase in the number of errors. Intraseptal administration of muscimol did not significantly alter latency per choice on the RAM task nor did it affect locomotor activity levels. Muscimol-induced impairments were also observed when a 4-h delay was imposed between the fourth and the fifth maze selection, suggesting that the behavioral deficit represents an inability to store or retain spatial working memories rather than a general performance deficit. These data indicated that pharmacological manipulation of GABA-A receptors within the medial septum modifies working memory processes. The potential interaction of GABAergic and cholinergic mechanisms in the modulation of working memory processes is discussed.     

Vasopressin disrupts radial-maze performance in rats

The memory enhancing properties of vasopressin, observed in active and passive avoidance procedures, could derive from its influence on central systems, but may also be mediated by its endocrinological properties. Very little is known about the effects of vasopressin on behavior in procedures other than the active and passive avoidance paradigms. The present experiments were designed to assess the effects of vasopressin on behavior observed in the eight-arm radial maze. In Experiment I, male Wistar rats (N = 7), which had been extensively trained to collect food from all eight arms in a radial maze, were subcutaneously injected with different doses of vasopressin 5 min before the start of the session (0.00, 1.25, 3.75, and 6.25 micrograms/kg). In Experiment II, another group of male Wistar rats (N = 7) received the same doses of vasopressin after having been extensively trained to collect food from four of the eight arms. In both experiments, subjects spent more time in the maze as the dose of vasopressin was increased. Vasopressin also disrupted performance by preventing the subjects from visiting all of the baited arms in the maze. Performance thus decreased, not because of the fact that vasopressin interfered with memory processes, but because of the fact that it produced behavioral inhibition. Thus, if vasopressin affects memory processes, such effects are likely to be mediated through vasopressin's actions on endocrine and behavioral systems, rather than through a direct action on the neural substrate underlying memory functioning.     

Delay-dependent working memory impairment in young-adult and aged 5-HT1BKO mice as assessed in a radial-arm water maze

Serotonin (5-HT) plays a modulatory role in mnemonic functions, especially by interacting with the cholinergic system. The 5-HT1B receptor is a key target of this interaction. The 5-HT1B receptor knockout mice were found previously to exhibit a facilitation in hippocampal-dependent spatial reference memory learning. In the present study, we submitted mice to a delayed spatial working memory task, allowing the introduction of various delays between an exposure trial and a test trial. The 5-HT1BKO and wild-type mice learned the task in a radial-arm water maze (returning to the most recent presented arm containing the escape platform), and exhibited a high level of performance at delays of 0 and 5 min. However, at the delay of 60 min, only 5-HT1BKO mice exhibited an impairment. At a delay of 90 min, all mice were impaired. Treatment by scopolamine (0.8 mg/kg) induced the same pattern of performance in wild type as did the mutation for short (5 min, no impairment) and long (60 min, impairment) delays. The 22-month-old wild-type and knockout mice exhibited an impairment at short delays (5 and 15 min). The effect of the mutation affected both young-adult and aged mice at delays of 15, 30, and 60 min. Neurobiological data show that stimulation of the 5-HT1B receptor inhibits the release of acetylcholine in the hippocampus, but stimulates this in the frontal cortex. This dual function might, at least in part, explain the opposite effect of the mutation on reference memory (facilitation) and delay-dependent working memory (impairment). These results support the idea that cholinergic-serotonergic interactions play an important role in memory processes.     

Search strategies used by APP transgenic mice during navigation in the Morris water maze

TgCRND8 mice represent a transgenic mouse model of Alzheimer's disease, with onset of cognitive impairment and increasing amyloid-beta plaques in their brains at 12 weeks of age. In this study, the spatial memory in 25- to 30-week-old TgCRND8 mice was analyzed in two reference and one working memory Morris water maze (MWM) tests. In reference memory tests, the mice were trained to escape to a hidden platform, which in one version of the test was marked by a visual cue. In the working memory test, the hidden platform was moved daily to different locations. The TgCRND8 mice were impaired in reference memory when trained in a hidden platform test. However, the mice developed spatial memory comparable to non-Tg littermates in a cued reference memory test. The mice showed also an impairment in spatial working memory. Analysis of search paths revealed that in contrast to non-Tg littermates, TgCRND8 mice did not use spatial strategies during their navigation. Instead, they learned to locate an escape platform using a nonspatial, chaining strategy. The study showed that (1) the impairment in the reference memory of TgCRND8 mice was reduced when a hidden platform was cued, and that (2) both working and reference memory systems of TgCRND8 mice, but not (3) the plasticity of choice between search strategies, are compromised by the transgene-induced pathology.