Selective lesions of the dentate gyrus produce disruptions in place learning for adjacent spatial locations

The hippocampus (HPP) plays a known role in learning novel spatial information. More specifically, the dentate gyrus (DG) hippocampal subregion is thought to support pattern separation, a mechanism for encoding and separating spatially similar events into distinct representations. Several studies have shown that lesions of the dorsal DG (dDG) in rodents result in inefficient spatial pattern separation for working memory; however, it is unclear whether selective dDG lesions disrupt spatial pattern separation for reference memory. Therefore, the current study investigated the role of the dDG in pattern separation using a spatial reference memory paradigm to determine whether the dDG is necessary for acquiring spatial discriminations for adjacent locations. Male Long-Evans rats were randomly assigned to receive bilateral intracranial infusions of colchicine or saline (control) into the dDG. Following recovery from surgery, each rat was pseudo-randomly assigned to an adjacent arm or separate arm condition and subsequently tested on a place-learning task using an eight-arm radial maze. Rats were trained to discriminate between a rewarded arm and a nonrewarded arm that were either adjacent to one another or separated by a distance of two arm positions. Each rat received 10 trials per day and was tested until the animal reached a criterion of nine correct choices out of 10 consecutive trials across 2 consecutive days of testing. Both groups acquired spatial discriminations for the separate condition at similar rates. However, in the adjacent condition, dDG lesioned animals required significantly more trials to reach the learning criterion than controls. The results suggest that dDG lesions decrease efficiency in pattern separation resulting in impairments in the adjacent condition involving greater overlap among the distal cues. Conversely, in the separate condition, there was less overlap among distal cues during encoding and less need for pattern separation. These findings provide further support for a critical role for the dDG in spatial pattern separation by demonstrating the importance of a processing mechanism that is capable of reducing interference among overlapping spatial inputs across a variety of memory demands.     

Involvement of the medial prefrontal cortex in two alternation tasks using different environments

Spatial alternation performance in rats is usually evaluated with the T-Maze. The first aim of this study was to analyze the effect of a selective lesion of medial prefrontal cortex (mPFC) on performance in a T-maze. Second, we wanted to validate a new test using alternation in a water maze (AWM). The mPFC of 21 male Sprague-Dawley rats was lesioned bilaterally using in situ microinjection of ibotenic acid. Thirteen control rats received injections of the vehicle only. Results show that mPFC lesioned rats were significantly impaired in the T-Maze as well as in the AWM compared to controls. These results validate the AWM as a frontal cortex dependent task probing working memory and/or behavioral flexibility. We suggest that the AWM may be more powerful than the T-maze as an investigational tool, given that is can be easily compared to other water maze tasks that evaluate other (nonfrontal) cognitive modules.     

Bilateral entorhinal cortex lesions impair acquisition of delayed spatial alternation in rats

Entorhinal cortex lesions induce significant reorganization of several homotypic and heterotypic inputs to the hippocampus. This investigation determined whether surviving heterotypic inputs after bilateral entorhinal lesions would support the acquisition of a learned alternation task. Rats with entorhinal lesions or sham operations were trained to acquire a spatial alternation task. Although the sham-operated rats acquired the task within about 3 weeks postsurgery, rats with bilateral entorhinal lesions failed to learn the task after 12 consecutive weeks of training despite heterotypic sprouting of the cholinergic septodentate pathway and the expansion of the commissural/associational fiber plexus within the dentate gyrus. Thus, heterotypic sprouting failed to ameliorate significantly the effects of bilateral entorhinal lesions. Rather, entorhinal lesions produced a persistent impairment of spatial memory, characterized by a mixture of random error production and perseverative responding.     

Working memory theory of hippocampal function needs qualification

To compare the predictive value of "cognitive map" and "working memory" theories of hippocampal function, the performance of rats with dorsal hippocampal lesions was compared to that of control rats in a series of experiments. In Experiment I, experimental rats learned a spatial alternation task with normal ease, but in Experiment II, they were significantly impaired on an elevated 8-arm radial maze. In Experiment III, the performance of the same experimental and control rats was compared on two versions of a 16-arm enclosed radial maze. In the first version, carpet inserts served as cues to mark eight unbaited arms and each of the remaining arms contained one food pellet. While both experimental and control rats successfully avoided the set of cued arms, experimental rats reentered uncued baited arms more frequently than did control rats. In the second version no intramaze cues were provided, but the spatial distribution of baited and unbaited arms remained the same as that used in the first version. In this uncued version, experimental rats both entered unbaited arms and reentered baited arms more frequently than did control rats, i.e., they were impaired in both "reference" and "working" memory. These findings are compatible with the hypothesis that hippocampal lesions result in an impaired capacity to form cognitive maps but they are not compatible with the working memory hypothesis. Furthermore, twelve separate evaluators classed experimental rats as using fewer mapping and more orientation strategies than control rats in the 8-arm 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     

How rats perform spatial working memory tasks: Limitations in the use of egocentric and idiothetic working memory

Rats of the Dark Agouti strain were trained on delayed alternation under conditions that should encourage egocentric working memory. In two experiments a T-maze was set within a cross-maze so that different arms could be used for the sample and test runs. The maze had high opaque side-walls, and testing was conducted in low light levels so that distal visual cues might be eliminated. By rotating the maze 90° between the sample and choice run and by using two identical mazes set side by side it was possible to nullify other spatial strategies. Experiments 1 and 2 showed that rats preferentially used place information, intramaze cues, and direction cues, even though only egocentric or idiothetic (nonmatch-to-turn) working memory could successfully solve every trial. Rats were able to maintain an accurate sense of location within the maze even though distal cues were not visible and the animal was moved between the sample and choice runs. Experiment 2 confirmed that another rat strain (Long-Evans) shows the same learning profiles. Both experiments indicate that rats are very poor at using either egocentric or idiothetic information to alternate, and that retention delays as short as 10 s can eliminate the use of these forms of memory.     

How rats perform spatial working memory tasks: limitations in the use of egocentric and idiothetic working memory

Rats of the Dark Agouti strain were trained on delayed alternation under conditions that should encourage egocentric working memory. In two experiments a T-maze was set within a cross-maze so that different arms could be used for the sample and test runs. The maze had high opaque side-walls, and testing was conducted in low light levels so that distal visual cues might be eliminated. By rotating the maze 90° between the sample and choice run and by using two identical mazes set side by side it was possible to nullify other spatial strategies. Experiments 1 and 2 showed that rats preferentially used place information, intramaze cues, and direction cues, even though only egocentric or idiothetic (nonmatch-to-turn) working memory could successfully solve every trial. Rats were able to maintain an accurate sense of location within the maze even though distal cues were not visible and the animal was moved between the sample and choice runs. Experiment 2 confirmed that another rat strain (Long-Evans) shows the same learning profiles. Both experiments indicate that rats are very poor at using either egocentric or idiothetic information to alternate, and that retention delays as short as 10 s can eliminate the use of these forms of memory.     

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.     

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     

Working memory deficits in retinoid X receptor gamma-deficient mice

Retinoid signaling has been recently shown to be required for mnemonic functions in rodents. To dissect the behavioral and molecular mechanisms involved in this requirement, we have analyzed the spatial and recognition working memory in mice carrying null mutations of retinoid receptors RARbeta and RXRgamma. Double mutants appeared deficient in spatial working memory as tested in spontaneous alternation in the Y-maze and delayed nonmatch to place (DNMTP) test in the T-maze. These mutant mice did acquire, however, spatial place reference or right/left discrimination tasks in the T-maze set-up, indicating that basic sensorimotor functions, spatial orientation, and motivational factors are unlikely to account for deficits in working memory-sensitive tasks. Double-mutant mice were also deficient in novel object recognition at intermediate, but not short delays. RXRgamma appeared to be the functionally predominant receptor in modulation of the working memory, as RXRgamma, but not RARbeta single null mutant mice exhibited deficits similar to those observed in the double mutants. The mechanism of this modulation is potentially related to functions of RXRgamma in frontal and perirhinal cortex, structures in which we detected RXRgamma expression and which are functionally implicated in working memory processes.     

Anterior but not intralaminar thalamic nuclei support allocentric spatial memory

Medial thalamic damage is a common cause of severe memory disruption in humans. Both the anterior thalamic nuclei (ATN) and the intralaminar thalamic nuclei (ILN) have been suggested as primary sites of diencephalic injury underlying learning and memory deficits, but their respective roles have yet to be resolved. The present study explicitly compared two spatial memory tasks in male PVGc hooded rats with selective neurotoxic lesions to either (1) the ATN or (2) the rostral ILN (and adjacent lateral mediodorsal thalamic nuclei; ILN/LT lesions). As predicted, the ATN group, but not the ILN/LT group, exhibited clear deficits in the Morris water maze task for the initial acquisition of a fixed hidden platform and its reversal to a new position. The second task examined acquisition of egocentric spatial reference memory for a left or right body turn, using any three arms in an 8-arm water maze on any given trial; contrary to predictions, both lesion groups performed as well as the Sham group. The lack of deficits in ILN/LT rats on this second task contrasted with previous findings reporting a detrimental effect of ILN/LT lesions on egocentric working memory. The clear dissociation between the influence of ATN and ILN/LT lesions with respect to allocentric spatial reference memory in the Morris maze emphasizes that caution is required when interpreting the effects of non-ATN thalamic lesions on spatial memory when the lesions encroach substantial areas of the adjacent ATN region.     

The effects of guanfacine, alpha-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.     

Working memory task decreases the survival of newly born neurons in hippocampus

Throughout life new neurons are generated in dentate gyrus of hippocampus. Previous studies have found that spatial tasks can rescue newly born neurons from death. However, it is still unknown whether new neurons are similarly affected by all types of hippocampal-dependent tasks. Here we investigated the possible effects of working memory task (WMT) on immature neurons. Mice were trained in reference memory task and WMT respectively. The reference memory task used the classical hidden platform (HP) water maze task, while WMT used a delayed matching-to-place (DMTP) water maze task. Bromodeoxyuridine (BrdU) was administrated during the early or late phase of training, or 1week prior to training, in order to label dividing proliferating cells. After water maze training, the number of BrdU-labeled cells in dentate gyrus of hippocampus was compared. In addition, hippocampal brain-derived neurotrophic factor (BDNF) and Notch 1 receptor were characterized using Western blot. Serum corticosterone levels were also measured using enzyme immunoassay. Results showed that HP task and DMTP task did not change the number of BrdU-labeled cells produced during the early or late phase of training. As expected, the HP task increased the number of BrdU-labeled cells produced 1 week prior to training. However, DMTP task decreased the number of BrdU-labeled cells produced 1 week prior to training. Both tasks lead to a significant increase in serum corticosterone levels and did not change the expression of BDNF and Notch 1 receptor in hippocampus. Taken together, these results demonstrate that WMT has different effects on survival of immature neurons, and therefore suggests immature neurons may have more than one role depending on the demands of the tasks.     

Rats' sensitivity to their direction of movement and spontaneous alternation behaviour

The response of rats to their prior direction of movement was examined in three spontaneous alternation experiments. In the first, a straight alley run interpolated between two T-maze trials increased goal arm alternation when it was in the same direction as that of the animal's first T-maze goal arm entry and decreased the alternation tendency when it was in the opposite direction. Experiment II found that multiple runs in one direction in a straight alley increased the likelihood that rats would subsequently enter the goal arm of a T-maze which permitted movement in an opposite direction. In the third experiment, rats entered those goal arms of an eight-arm radial maze which permitted movement in any direction which was different from that during a preceding straight alley trial. The results of these experiments indicate that rats are quite sensitive to their direction of movement and use it as a cue in guiding their behaviour in a variety of experimental situations.     

Neurobiological and endocrine correlates of individual differences in spatial learning ability

The polysialylated neural cell adhesion molecule (PSA-NCAM) has been implicated in activity-dependent synaptic remodeling and memory formation. Here, we questioned whether training-induced modulation of PSA-NCAM expression might be related to individual differences in spatial learning abilities. At 12 h posttraining, immunohistochemical analyses revealed a learning-induced up-regulation of PSA-NCAM in the hippocampal dentate gyrus that was related to the spatial learning abilities displayed by rats during training. Specifically, a positive correlation was found between latency to find the platform and subsequent activated PSA levels, indicating that greater induction of polysialylation was observed in rats with the slower acquisition curve. At posttraining times when no learning-associated activation of PSA was observed, no such correlation was found. Further experiments revealed that performance in the massed water maze training is related to a pattern of spatial learning and memory abilities, and to learning-related glucocorticoid responsiveness. Taken together, our findings suggest that the learning-related neural circuits of fast learners are better suited to solving the water maze task than those of slow learners, the latter relying more on structural reorganization to form memory, rather than the relatively economic mechanism of altering synaptic efficacy that is likely used by the former.     

Protective effect of practice on cognition during aging: implications for predictive characteristics of performance and efficacy of practice

In the present study, the effect of previous experience on spatial memory, which required the retention of information either over long intervals or within a single session, was longitudinally tested in the water maze in male F-344 rats that were from 6 to 24 months of age. Performance in these tasks was found to be age-dependent (Markowska, 1999). Other behavioral tasks in the straight alley and with a visible platform in the water maze controlled the noncognitive components of performance. For all tasks, performance was significantly correlated between 12-month-old and 18-month-old rats, indicating that cognitive performance at the early, but not advanced, stage of aging could be predicted from performance at a younger age if the novelty of the first exposure to the task was eliminated. The protective effect of experience was more robust in the reference memory task as compared to the working memory task and was modified by age when training was initiated. Behavior during the probe trials was more sensitive to the effect of aging and more resistant to the beneficial effect of practice as compared to the performance in the platform trials. The speed of swimming of experienced rats progressively decreased with age only when tested in the cognitive tasks but not in the straight alley. This indicates that speed of swimming during cognitive tasks does not exclusively reflect the ability to swim, but might be also affected by the cognitive demands of the task. Protective effect of experience on cognition was not modified by restriction in diet.     

Hormonal and monoamine signaling during reinforcement of hippocampal long-term potentiation and memory retrieval

Recently it was shown that holeboard training can reinforce, i.e., transform early-LTP into late-LTP in the dentate gyrus during the initial formation of a long-term spatial reference memory in rats. The consolidation of LTP as well as of the reference memory was dependent on protein synthesis. We have now investigated the transmitter systems involved in this reinforcement and found that LTP-consolidation and memory retrieval were dependent on β-adrenergic, dopaminergic, and mineralocorticoid receptor (MR) activation, whereas glucocorticoid receptors (GRs) were not involved. Blockade of the β-adrenergic signaling pathway significantly increased the number of reference memory errors compared with MR and dopamine receptor inhibition. In addition, β-adrenergic blockade impaired the working memory. Therefore, we suggest that β-adrenergic receptor activation is the main signaling system required for the retrieval of spatial memory. In addition, other modulatory interactions such as dopaminergic as well as MR systems are involved. This result points to specific roles of different modulatory systems during the retrieval of specific components of spatial memory. The data provide evidence for similar integrative interactions between different signaling systems during cellular memory processes.     

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.     

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.