Spatial navigation in complex and radial mazes in APP23 animals and neurotrophin signaling as a biological marker of early impairment

Impairment of hippocampal function precedes frontal and parietal cortex impairment in human Alzheimer's disease (AD). Neurotrophins are critical for behavioral performance and neuronal survival in AD. We used complex and radial mazes to assess spatial orientation and learning in wild-type and B6-Tg(ThylAPP)23Sdz (APP23) animals, a transgenic mouse model of AD. We also assessed brain content of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). Performance was alike in wild-type and APP23 animals in the radial maze. In contrast, performance in the complex maze was better in wild-type than APP23 animals. Contrary to the wild-type, hippocampal BDNF levels decreased on training in APP23 animals. Hippocampal and frontal cortex NGF levels in APP23 animals correlated with the time to solve the complex maze, but correlated inversely with escape time in wild-type animals. NT-3 levels were alike in wild-type and APP23 animals and were unchanged even after training. Both types of mazes depend on hippocampal integrity to some extent. However, according to the cognitive mapping theory of spatial learning, the complex maze because of the increased complexity of the environment most likely depends more strongly on preserved hippocampal function than the radial maze in the working memory configuration applied here. Greater impairment in complex maze performance than in radial maze performance thus resembles the predominant affliction of the loss of hippocampal function in human AD. NGF and BDNF levels on maze learning are different in wild-type and transgenic animals, indicating that biological markers of AD may be altered on challenge even though equilibrium levels are alike.     

Life-long environmental enrichment differentially affects the mnemonic response to estrogen in young, middle-aged, and aged female mice

The present study was designed to examine whether life-long exposure to standard or enriched housing affects the ability of estrogen to improve spatial and object memory throughout the lifespan. Three-week-old female mice were maintained in standard or enriched housing up to and through ovariectomy and behavioral testing at 5, 17, or 22 months of age. Spatial memory was tested in the Morris water maze and object memory was tested using an object recognition task. Immediately after training each day, mice were injected intraperitoneally with vehicle or 0.2 mg/kg 17beta-estradiol. Among young females, object recognition was enhanced by estradiol alone, an effect that was reduced by enrichment. In contrast, spatial water maze performance was impaired by estradiol alone, but improved by the combination of both estradiol and enrichment. At middle-age, object recognition was enhanced by estradiol or enrichment alone, and the combination of both treatments. Spatial memory in the water maze was also improved by both treatments at middle-age, but the beneficial effects of estradiol were limited to standard-housed females. Finally, whereas enrichment in aged females significantly enhanced performance in both tasks, estradiol had no effect at this age in either task. In total, the data indicate that life-long enrichment can significantly alter the extent to which estradiol affects memory in mice throughout the lifespan. Importantly, the interaction between these treatments is highly dependent on age and type of memory tested.     

A model of working memory capacity in the radial-arm maze task

The radial arm maze is one of the most commonly used tests for assessing working memory in laboratory animals. However, to date, there exists no quantitative method of estimating working memory capacity from performance on this task. Here, we present a mathematical model of performance on the radial arm maze from which we can derive estimates of capacity. We derive explicit results for the two most commonly used measures of performance as functions of number of arms in the maze and memory capacity, assuming a uniform random search. We simulate random non-uniform search strategies. Comparing our model to previous experiments, we show that our model predicts a working memory capacity in the range of 3-9 at the level of performance observed in these experiments. This estimate is within the typical estimate of human working memory capacity. Performance of rats on large mazes (e.g. 48 arms) has been used as evidence that the working memory capacity of rats may be significantly larger than that of humans. We report that memory capacity in the range 3-9 is sufficient to explain the performance of rats in very large radial mazes. Furthermore, when we simulate non-uniform random search strategies observed in the experiments, the resulting estimates do not differ significantly from those assuming a uniform random search. We conclude that a list-based model of working memory with modest capacity is more powerful than previously expected.     

Different types of environmental enrichment have discrepant effects on spatial memory and synaptophysin levels in female mice

Environmental enrichment paradigms that incorporate cognitive stimulation, exercise, and motor learning benefit memory and synaptic plasticity across the rodent lifespan. However, the contribution each individual element of the enriched environment makes to enhancing memory and synaptic plasticity has yet to be delineated. Therefore, the current study tested the effects of three of these elements on memory and synaptic protein levels. Young female C57BL/6 mice were given 3h of daily exposure to either rodent toys (cognitive stimulation) or running wheels (exercise), or daily acrobatic training for 6 weeks prior to and throughout behavioral testing. Controls were group housed, but did not receive enrichment. Spatial working and reference memory were tested in a water-escape motivated radial arm maze. Levels of the presynaptic protein synaptophysin were then measured in frontoparietal cortex, hippocampus, striatum, and cerebellum. Exercise, but not cognitive stimulation or acrobat training, improved spatial working memory relative to controls, despite the fact that both exercise and cognitive stimulation increased synaptophysin levels in the neocortex and hippocampus. These data suggest that exercise alone is sufficient to improve working memory, and that enrichment-induced increases in synaptophysin levels may not be sufficient to improve working memory in young females. Spatial reference memory was unaffected by enrichment. Acrobat training had no effect on memory or synaptophysin levels, suggesting a minimal contribution of motor learning to the mnemonic and neuronal benefits of enrichment. These results provide the first evidence that different elements of the enriched environment have markedly distinct effects on spatial memory and synaptic alterations.     

Exploration of virtual mazes by rhesus monkeys (<Emphasis Type="Italic">Macaca mulatta</Emphasis>)

A chasm divides the huge corpus of maze studies found in the literature, with animals tested in mazes on the one side and humans tested with mazes on the other. Advances in technology and software have made possible the production and use of virtual mazes, which allow humans to navigate computerized environments and thus for humans and nonhuman animals to be tested in comparable spatial domains. In the present experiment, this comparability is extended even further by examining whether rhesus monkeys (Macaca mulatta) can learn to explore virtual mazes. Four male macaques were trained to manipulate a joystick so as to move through a virtual environment and to locate a computer-generated target. The animals succeeded in learning this task, and located the target even when it was located in novel alleys. The search pattern within the maze for these animals resembled the pattern of maze navigation observed for monkeys that were tested on more traditional two-dimensional computerized mazes.     

丰富环境对脑缺血大鼠突触界面结构修饰和PSD-95基因表达的影响

探讨丰富环境干预对局部脑缺血大鼠突触界面结构修饰和突触后致密物-95 (postsynaptic density-95,PSD-95 ) mRNA表达的影响。栓塞健康雄性Sprague-Dawley大鼠的右侧大脑中动脉,建立脑中动脉栓塞(middle cerebral artery occlusion,MCAO)模型后,分为丰富环境缺血组(IE)、标准环境缺血组(IS),同时分别设丰富环境假手术组(SE)、标准环境假手术组(SS)。以Morris水迷宫检测大鼠的空间学习记忆能力,应用透射电镜、图像分析和细胞形态计量学技术,观察海马CA1区和额叶皮层突触界面结构变化,采用RT-PCR检测突触后脚手架蛋白PSD-95 mRNA的表达。结果表明：丰富环境干预能有效改善脑缺血导致的空间学习记忆能力下降,并对正常大鼠的空间学习记忆能力也有改善作用。同时,丰富环境干预能抑制局部脑缺血导致的突触数密度减少,该作用对额叶皮层特别明显;丰富环境干预不同程度地逆转脑缺血造成的突触界面参数变化,特别使突触间隙宽度显著减小、PSD厚度明显增加;并有效抑制因脑缺血诱导的PSD-95 mRNA表达下调。以上结果提示,丰富环境改善脑缺血大鼠的空间学习记忆能力可能与其促进缺血区边缘组织突触界面结构修饰,提高PSD-95 mRNA表达有关     

Validating the Electric Maze Task as a Measure of Planning

The Electric Maze Task (EMT) is a novel planning task designed to allow flexible testing of planning abilities across a broad age range and to incorporate manipulations to test underlying planning abilities, such as working-memory and inhibitory control skills. The EMT was tested in a group of 63 typically developing 7- to 12-year-olds. Participants completed 4 mazes designed to alter working-memory demands (by increasing the number of steps required from 6 to 8) and inhibitory control demands (by using a modified Dimensional Change Card Sort task) and 3 standardized measures using the Cambridge Neuropsychological Test Automated Battery. The EMT was found to correlate with measures of visual memory, working memory, and planning. The 6-step mazes were simpler for participants to solve and mapped on to performance on the visual memory task. The 8-step mazes were more difficult and mapped on to performance on the spatial working-memory and planning tasks. Children who were 10 to 12 years old were also better than 7- to 9-year-olds at solving all mazes, as evidenced by fewer errors and fewer errors later in solving the mazes. Younger children also struggled more than older children after a rule switch. Performance on the maze task differentiated 7- to 12-year-old children with better planning skills, and manipulations of the maze task were successful in altering the working-memory and inhibitory control demands.     

Maze navigation by honeybees: learning path regularity

We investigated the ability of honeybees to learn mazes of four types: constant-turn mazes, in which the appropriate turn is always in the same direction in each decision chamber; zig-zag mazes, in which the appropriate turn is alternately left and right in successive decision chambers; irregular mazes, in which there is no readily apparent pattern to the turns; and variable irregular mazes, in which the bees were trained to learn several irregular mazes simultaneously. The bees were able to learn to navigate all four types of maze. Performance was best in the constant-turn mazes, somewhat poorer in the zig-zag mazes, poorer still in the irregular mazes, and poorest in the variable irregular mazes. These results demonstrate that bees do not navigate such mazes simply by memorizing the entire sequence of appropriate turns. Rather, performance in the various configurations depends on the existence of regularity in the structure of the maze and on the ease with which this regularity is recognized and learned.     

Effects of daily environmental enrichment on memory deficits and brain injury following neonatal hypoxia-ischemia in the rat

Environmental enrichment (EE) results in improved learning and spatial memory, as well as attenuates morphological changes resulting from cerebral ischemia in adult animals. This study examined the effects of daily EE on memory deficits in the water maze and cerebral damage, assessed in the hippocampus and cerebral cortex, caused by neonatal hypoxia-ischemia. Male Wistar rats in the 7th postnatal day were submitted to the Levine-Rice model of neonatal hypoxia-ischemia (HI), comprising permanent occlusion of the right common carotid artery and a period of hypoxia (90 min, 8%O(2)-92%N(2)). Starting two weeks after the HI event, animals were stimulated by the enriched environment (1h/day for 9 weeks); subsequent to the stimulation, performance of animals in the water maze was assessed. HI resulted in spatial reference and working memory impairments that were completely reversed by EE. Following the behavioral study, animals were killed and the hippocampal volume and cortical area were estimated. There was a significant reduction of both hippocampal volume and cortical area, ipsilateral to arterial occlusion, in HI animals; environmental stimulation had no effect on these morphological measurements. Presented data indicate that stimulation by the daily environmental enrichment recovers spatial memory deficits caused by neonatal hypoxia-ischemia without affecting tissue atrophy in either hippocampus or cortex.     

A comparison of the effects of fimbria-fornix, hippocampal, or entorhinal cortex lesions on spatial reference and working memory in rats: short versus long postsurgical recovery period.

Using a radial maze task and different postoperative recovery periods, this experiment assessed and compared the reference and working memory performances of adult Long-Evans male rats subjected to entorhinal cortex, fimbria-fornix, and hippocampus lesions. Sham-operated rats were used as controls. In order to see whether the duration of the postsurgical recovery period would influence acquisition of the complex radial maze task, training began 1 month following surgery (Delay 1) for half the rats in each group, while for the other half training was started 6.5 months following surgery (Delay 2). The results indicated that at both recovery periods the entorhinal cortex lesions failed to affect either working or reference memory in the spatial task. Conversely, both fimbria-fornix and hippocampus lesions impaired both reference and working memory. While the reference memory deficit was generally similar in both fimbria-fornix and hippocampal lesion groups, analysis of the results for working memory indicated that at the longer delay rats with fimbria-fornix lesions were still impaired but in animals that had the hippocampus removed, working memory did not differ from that of controls. These results suggest that there was some recovery in those rats with hippocampal lesions (e.g., on the working memory task) but both hippocampal and fimbria-fornix animals were still impaired compared to controls when training was delayed 6.5 months following the operations.     

A comparison of four corvid species in a working and reference memory task using a radial maze

Birds were tested in an open-room radial maze with learned spatial locations that varied from trial to trial (working memory) and locations that remained spatially stable (reference memory). Three of the species, the Clark's nutcracker (Nucifraga columbiana), pinyon jay (Gymnorhinus cyanocephalus), and Western scrub jay (Aphelocoma coerulescens) store food to varying degrees. The other species, the Eurasian jackdaw (Corvus monedula) does not. Pinyon jays and scrub jays performed better than the nutcrackers and jackdaws in both working and reference memory components of the maze. The pinyon jay and jackdaw performed as would be expected on the basis of their natural history and previous research, but the scrub jay and nutcracker did not. Results are consistent with phylogenetic relationships among the 4 species, but could also be explained by differences in response strategies or interference in processing both types of memory components of the maze.     

Rats use a sense of direction to alternate on T-mazes located in adjacent rooms

Lister hooded rats were trained on a forced-sample T-maze alternation task in an environment lacking spatial landmarks. An early study of spontaneous alternation on the T-maze had shown that rats use a "spatial sense" to select alternate maze arms across mazes. As this phenomenon may provide a useful tool for studying the neural substrates of a directional sense, we wished to confirm this finding on a different version of the T-maze task, with well-trained animals. We found that rats successfully selected the appropriate maze arm when the choice phase of the task was presented on a second maze, oriented in the same direction, and located in an adjacent room. However, choice performance fell to chance level when the second maze was oriented 90° relative to the first. This result suggests that the rats do not simply alternate turns across the two environments, but rather that they rely on a sense of direction that is carried across environments. Electronic Publication     

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.     

Spatial learning in pigs: effects of environmental enrichment and individual characteristics on behaviour and performance

This study investigated the effects of both environmental enrichment and individual behavioural characteristics on spatial cognitive capabilities of pigs, using a novel latent spatial learning paradigm based on Tolman’s detour experiments (1948). Pigs were housed either in ‘barren’ pens or in pens enriched with straw bedding from birth. Pigs were restrained in a Backtest at 10 and 17 days postpartum. Based on their escape behaviour in this test, which has been shown to reflect their behavioural style, six ‘high-resisting’(HR) and six ‘low-resisting’ (LR) pigs were selected from each housing environment (n = 24 in total). At 12 weeks of age, pairs of pen mates (LR and HR) were exposed to a maze three times (exploration trials). Pigs were then placed individually in the maze, and social reinstatement proved to be a strong incentive to find the exit leading to the home pen. We subsequently blocked the direct route to the exit, forcing animals to find a detour (memory test 1, MT1). This test was repeated once to investigate the relative improvement, i.e. detour learning (memory test 2, MT2). Housing condition and Backtest response strongly affected exploration patterns. In spite of this, no effects on performance during the subsequent memory tests were found. Performance was substantially improved in MT2, indicating that once a goal is apparent, pigs are able to solve a complex spatial memory task easily. In conclusion, social reinstatement provided a good incentive to complete a spatial task, and the substantial improvement in performance between MT1 and MT2 stresses the need for task complexity when testing spatial memory in pigs. Housing conditions or individual behavioural style did not affect spatial memory during MT1 or MT2. However, housing environment and behavioural style strongly affected explorative behaviour of pigs in an unfamiliar maze during both exploration trials and memory tests. This implicates that apparent effects of environmental enrichment on spatial learning and memory in pigs might reflect differences in explorative patterns rather than in cognitive processes.     

Algorithmic responding on the radial maze in rats does not always imply absence of spatial encoding

Two experiments were conducted to determine whether consistent algorithmic response patterning on 8- and 10-arm versions of the radial maze is independent of spatial encoding. On the 8-arm version well-trained hooded rats were tested in darkness, after maze rotation that rendered room cues ambiguous with respect to arm positions, or with room cues unsystematically relocated. Ambiguous maze rotation was also used with well-trained subjects on the 10-arm version. If algorithmic patterning is a learned, non-spatial strategy, animals using it consistently ought not to have been affected by changes in the spatial layout of the test environment, and the type of pattern used by each subject would have remained constant. On the 8-arm radial maze, responses were most often made to arms 2 or 3 from that just visited. In many animals patterns were interchangeable, switching occurring between preferred angles of turn from day to day. Performance fell when animals were tested in darkness and upon ambiguous maze rotation early (but not later) in training. Testing in darkness increased the angle through which animals turned when responding, perhaps due to the disturbance of intramaze cue use. On the 10-arm maze the “consecutive arm” pattern was used persistently by several animals and appeared to protect their performance from disruption by ambiguous maze rotation. Animals not using rigid patterning were adversely affected. However, on both mazes animals using patterning correctly identified maze arms that had been omitted from otherwise patterned choice sequences. Animals adopted continuous patterning only when spatial encoding had been established. Response patterning appears to serve a mnemonic function and in rats complements rather than replaces the use of a spatial representation of the environment. It was concluded that a complex, flexible relationship exists between spatial functioning and its expression via motor responses.     

Preserved learning about allocentric cues but impaired flexible memory expression in rats with hippocampal lesions

Several studies have shown that slight modifications in the standard reference spatial memory procedure normally used for allocentric learning in the Morris water maze and the radial maze, can overcome the classic deficit in allocentric navigation typically observed in rats with hippocampal damage. In these special paradigms, however, there is only intramaze manipulation of a salient stimulus. The present study was designed to investigate whether extramaze manipulations produce a similar outcome. With this aim a four-arm plus-shaped maze and a reference spatial memory paradigm were used, in which the goal arm was marked in two ways: by a prominent extramaze cue (intermittent light), which maintained a constant relation with the goal, and by the extramaze constellation of stimuli around the maze. Experiment 1 showed that, unlike the standard version of the task, using this special training procedure hippocampally-damaged rats could learn a place response as quickly as control animals; importantly, one day after reaching criterion, lesioned and control subjects performed the task perfectly during a transfer test in which the salient extramaze stimulus used during the acquisition was removed. However, although acquisition deficit was overcomed in these lesioned animals, a profound deficit in retention was detected 15 days later. Experiment 2 suggests that although under our special paradigm hippocampal rats can learn a place response, spatial memory only can be expressed when the requisites of behavioral flexibility are minimal. These findings suggest that, under certain circumstances, extrahippocampal structures are sufficient for building a coherent allocentric representation of space; however, flexible memory expression is dependent, fundamentally, on hippocampal functioning.     

Radial arm maze performance of mice: acquisition and atropine effects

CD-1 mice were successfully trained in a six-arm radial maze in which half of the arms were baited, a procedure which had been used to differentiate between reference and working memory. Stable performance was achieved following eight daily training sessions, as measured by decreasing running time and number of errors. This finding strengthens the foraging hypothesis as a basis for the performance of rodents in the radial maze. Acute subcutaneous administration of the cholinergic antagonist atropine sulfate (1-6 mg/kg) to trained mice produced dose-related increases in running time and working memory errors, with a slight decrease in reference memory errors. This is in agreement with other studies on the role of the cholinergic system in memory processes. The peripheral cholinergic blocker, atropine methyl nitrate (4 mg/kg), somewhat increased running time without decreasing performance accuracy. In contrast to the prolonged pharmacological and physiological effects of atropine, behavioral decrements disappeared within 3 hr. It is concluded that mice trained in the radial arm maze may be used for screening of the effects of drugs on cognitive function.     

Spatial learning in the 5-HT1B receptor knockout mouse: selective facilitation/impairment depending on the cognitive demand

Age-related memory decline is associated with a combined dysfunction of the cholinergic and serotonergic systems in the hippocampus and frontal cortex, in particular. The 5-HT1B receptor occupies strategic cellular and subcellular locations in these structures, where it plays a role in the modulation of ACh release. In an attempt to characterize the contribution of this receptor to memory functions, 5-HT1B receptor knockout (KO) mice were submitted to various behavioral paradigms carried out in the same experimental context (water maze), which were aimed at exposing mice to various levels of memory demand. 5-HT1BKO mice exhibited a facilitation in the acquisition of a hippocampal-dependent spatial reference memory task in the Morris water maze. This facilitation was selective of task difficulty, showing thus that the genetic inactivation of the 5-HT1B receptor is associated with facilitation when the complexity of the task is increased, and reveals a protective effect on age-related hippocampal-dependent memory decline. Young-adult and aged KO and wild-type (WT) mice were equally able to learn a delayed spatial matching-to-sample working memory task in a radial-arm water maze with short (0 or 5 min) delays. However, 5-HT1BKO mice, only, exhibited a selective memory impairment at intermediate and long (15, 30, and 60 min) delays. Treatment by scopolamine 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. Taken together, these studies revealed a beneficial effect of the mutation on the acquisition of a spatial reference memory task, but a deleterious effect on a working memory task for long delays. This 5-HT1BKO mouse story highlights the problem of the potential existence of "global memory enhancers."     

Working and reference memory of pigs (Sus scrofa domesticus) in a holeboard spatial discrimination task: the influence of environmental enrichment

Interest in cognitive research in pigs is increasing, but little is known about the impact of environmental conditions on pigs’ cognitive capabilities. The present study investigated the effect of environmental enrichment on cognitive performance of pigs in a holeboard spatial task, in which they had to discriminate four baited buckets out of 16. Pigs (n = 32) were either housed in stimulus-poor, barren pens, or in larger pens enriched with rooting substrates. Pigs were subjected to 30 holeboard trials. Both working memory (WM), that is, the ratio (baited visits/total number of (re)visits to baited buckets), and reference memory (RM), that is, the ratio ((re)visits to baited buckets/total number of visits to all buckets), improved over trials. WM scores were higher in pigs from enriched pens than in pigs from barren pens. Housing did not affect RM scores. Personality type of the pigs, as assessed early in life using a backtest, did not affect WM or RM. In conclusion, housing conditions of pigs did not affect reference memory, but environmental enrichment improved working memory of pigs in a spatial discrimination task. Based on the findings of this study, we suggest that cognitive functioning of pigs may be impaired under commonly used housing conditions.