Evidence for the substantia nigra pars compacta as an essential component of a memory system independent of the hippocampal memory system

The aim of the present study was to test if the nigrostriatal pathway is an essential component for a water maze cued task learning and if it works independently of the hippocampal memory system. This hypothesis was tested using an animal model of Parkinson's disease in which male Wistar rats were lesioned in the substantia nigra pars compacta (SNc) by the intranigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), thus causing a partial depletion of striatal dopamine. SNc-lesioned and sham-operated animals were implanted bilaterally with guide cannulae above the dorsal hippocampus in order to be tested after the administration of 0.4 microl 2% lidocaine or saline into this structure. The animals were tested in a spatial or in a cued version of the water maze, memory tasks previously reported to model hippocampal-dependent spatial/relational and striatal-dependent S-R learning, respectively. Hippocampal inactivation, but not SNc lesion, impaired learning and memory in the spatial version of the water maze. An opposite situation was observed with the cued version. No significant interaction was observed between the SNc lesion and hippocampal inactivation conditions affecting scores in the spatial or in the cued version of the water maze. These results suggest that the nigrostriatal pathway is an essential part of the memory system that processes S-R learning and that it works independently of the hippocampal memory system that processes spatial/relational memories.     

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.     

Selective fimbria and thalamic lesions differentially impair forms of working memory in rats.

Several series of experiments were designed to compare the effects of selective lesions of the fimbria or of thalamic nuclei on three different tasks involving working memory in rats: object recognition, place recognition, and the radial arm maze test. The main effects of fimbria lesions were as follows: they produced deficits in the radial maze; object recognition was spared or even facilitated, whereas place recognition was impaired. Electrolytic lesions of either centromedian-parafascicularis (CM-Pf) or dorsomedialis (DM) nuclei produced highly significant deficits in the radial maze test but spared object and place recognition. Ibotenate lesions of the CM-Pf had no effect on any test, which means that the critical structure in the effects of the electrolytic lesions of the CM-Pf was the fasciculus retroflexus (FR). These data may contribute two main points to animal models of hippocampal and thalamic amnesia: (1) different forms of working memory in rats might have different neural bases and (2) the FR may be involved in learning and memory processes.     

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.     

Memory for frequency in rats: role of the hippocampus and medial prefrontal cortex

On a radial arm maze rats were tested for frequency memory of specific spatial locations, a task that presumably involves the coding of temporal information. On any trial during the study phase rats were allowed to visit three different spatial locations only once and one spatial location twice. During the test phase the rats were given a choice between a spatial location that had been visited once and spatial location that had been visited twice. The rats were reinforced for selecting the twice-visited spatial location. The number of spatial locations between a repetition (lag) was varied from one to three. After extensive training rats displayed memory for frequency only for a lag of three spatial locations, i.e., they displayed a repetition lag effect. Animals then received control, medial prefrontal cortex, or hippocampal lesions. Upon subsequent retests control rats continued to display frequency memory, but animals with medial prefrontal cortex or hippocampal lesions displayed a marked impairment. These data support the idea that both the hippocampus and medial prefrontal cortex code temporal order information.     

Spatial behavior in male and female crayfish (Orconectes rusticus): learning strategies and memory duration

Previous studies have demonstrated that animals use multiple strategies to solve spatial tasks. We used a T-maze to examine spatial behavior in crayfish, using visual and tactile stimuli as place cues and a food-scented escape tank as reinforcement to leave the maze. In trials on a single day and across multiple days, crayfish learned to exit the maze with significantly reduced latency and with fewer turns. In addition, we examined place memory in 40-min periods with the maze closed and found that crayfish spent longer in the vicinity of a previously open exit compared to a closed exit. Probe tests were conducted using a forced-choice procedure to determine whether crayfish remembered the route out of the maze using primarily place cues or response learning. We found that approximately equal numbers of animals used each strategy, and individuals were able to switch from one strategy to the other on different test days. Males and females did not differ significantly in their performance in the place memory test, maze exit task, or probe tests. Both sexes displayed place memory for the exit location and reduced latency to exit during trials 24 h, 48 h, 72 h, and 1 week after initial training trials, suggesting that spatial memories in crayfish are relatively enduring.     

Simplifying environmental cues in a Morris-type water maze improves place learning in old NMRI mice.

Old virgin female NMRI mice aged 17 months were compared with mice aged 3 months for their spatial learning abilities in two versions of the Morris water maze. The first one was a simplified version with a salient configuration of cues comparable to a black/white discrimination and the second one was the classical version of the Morris test with many distal cues surrounding the maze. In the simplified version, old mice presented a slower rate of acquisition and a transient poorer retention compared to young mice. However, old mice achieved a final level of performance statistically comparable to their young counterparts as assessed by latencies to escape onto the concealed platform and by the spatial bias measured in probe trials at intervals during testing. When subsequently subjected to classical Morris maze learning, the same old animals showed marked learning deficits and were persistently impaired in their latencies to escape onto the platform. They presented no spatial bias for the location of the platform in the different probe trials. When the goal was cued at the end of the experiment, the performances of old mice rapidly improved, showing that motivation, motor disabilities, or fatigue and ability to use proximal cues cannot explain the place learning deficit. Our results were discussed in terms of cognitive versus sensory/perceptual disabilities in aged rats and mice.     

Disruption of delayed memory for a sequence of spatial locations following CA1- or CA3-lesions of the dorsal hippocampus

Axon-sparing neurotoxic lesions of CA1 or CA3 were produced in the dorsal hippocampus to test dissociative lesion effects on spatial working memory for sequential items. Rats were required to remember four different sections sequentially presented on a newly devised maze (i.e., Tulum maze) during a study phase. Each section was cued by a unique object that was specifically associated with each location within the section during the study phase. Following a 15-s delay and during the test phase, rats were required to revisit the location within a section randomly chosen among the previously visited sections in the absence of the cued object. Both CA1 and CA3 lesions similarly disrupted accurate relocation of a previously visited place. However, differential effects of the CA1 and CA3 lesions were observed in serial position curves. CA3-lesions disrupted performance for the first three serial positions, but did not disrupt performance for the last serial position (recency). In contrast, CA1-lesions disrupted performance for all serial positions. The results suggest that temporal separation of spatial memory may depend on the conjoint function of CA1 and CA3 of the hippocampus with a disruption of a spatial pattern completion process following CA3 lesions and a disruption of a temporal pattern separation process following a CA1 lesion.     

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.     

Blocking and overshadowing between intra-maze and extra-maze cues: A test of the independence of locale and guidance learning

Rats were trained on an elevated maze where the rewarded alternative was defined either in terms of intra-maze cues (rubber or sandpaper flooring on rewarded and unrewarded arms, regardless of their position) or in terms of extra-maze cues (the correct arm always pointed toward a particular corner of the room, and was sometimes covered with rubber and sometimes with sandpaper), or where both sets of cues were simultaneously relevant. In Experiment 1 rats pretrained with either intra-maze or extra-maze cues alone relevant learned less about the other set of cues than non-pretrained control groups, when, in a second phase of the experiment, both sets of cues were simultaneously relevant. Experiment 2 confirmed that intra-maze cues could block extra-maze cues, and ruled out one alternative explanation of the results of Experiment 1. Experiment 3 showed that extra-maze cues overshadowed intra-maze cues, but that there was no reciprocal overshadowing of extra-maze by intra-maze cues. This was despite the fact that animals learned the intra-maze discrimination significantly faster than the extra-maze discrimination. Experiment 3 also suggested that rats did not solve the extra-maze discrimination by learning to approach or avoid specific extra-maze cues, but rather by locating the correct arm by reference to the entire set of extra-maze cues. The results suggest that locale or place learning and cue or guidance learning, in O'Keefe and Nadel's (1978) terminology, interact with one another in much the same way as does learning about any pair of stimuli in a Pavlovian conditioning experiment.     

The role of exploration in win-shift and win-stay performance on a radial maze

Win-shift spatial memory tasks in a radial maze reinforce animals for avoiding previously visited rewarded arms; win-stay tasks reinforce them for returning to those arms. Win-shift tasks have generally been found much easier to perform, and this may be explained either in terms of foraging models which postulate avoidance of locations where food has been found, or in terms of the predominance of spontaneous alternation (exploration). Experiment 1 examined spontaneous alternation behavior in the radial maze as a function of whether the first visit to an arm had been rewarded or not, and showed that alternation was more probable after nonreward than after reward in both hungry and thirsty rats (a result which conflicts with the foraging account of the win-shift superiority). Experiment 2 replicated the finding that win-stay discrimination performance was inferior to win-shift. A manipulation (lengthening the delay between initial and test choices) which weakens spontaneous alternation, reduced, but did not reverse, the win-shift superiority. In Experiment 3, in order to eliminate the influence of spontaneous alternation, versions of the win-stay and win-shift tasks were devised in which, unlike the original task, all arms were familiar at the choice trial. Under those conditions win-stay was performed better than win-shift. It is concluded that spontaneous alternation plays a major role in many spatial memory tasks, and that the results can best be accounted for by combining principles of exploration and simple associative learning, without recourse to foraging models.     

Dietary restriction inhibits spatial learning ability and hippocampal cell proliferation in rats1

Abstract: We investigated the effect of dietary restriction on spatial learning ability and hippocampal cell proliferation in adult rats using two spatial learning tasks and immunohistochemical staining with 5‐bromo‐2′‐deoxyuridine (BrdU). Sixteen rats were divided into restricted or ad lib feeding groups at 70 days of age, and were trained in the delayed‐matching‐to‐place (DMTP) task (a working memory task) from 93 days of age, and then the Morris water maze task (a reference memory task). Dietary restriction had no effect on the DMTP task with 30 s delay and on the water maze task. However, in the DMTP task with 30 min delay, restricted rats performed significantly more poorly than ad lib rats. Quantitative analysis of hippocampal cell proliferation revealed that the density of newborn cells in restricted rats was significantly lower than that in ad lib rats. These results suggest that a loss of proliferating capacity in the hippocampus may be a candidate for an anatomical and biological basis for the cognitive decline caused by dietary restriction.     

Testosterone fails to reverse spatial memory decline in aged rats and impairs retention in young and middle-aged animals

Recently, the vasopressin (AVP) innervation in the rat brain was shown to be restored in senescent rats following long-term testosterone administration. In order to investigate whether this restoration is accompanied by an improvement in learning and memory, both sham- and testosterone-treated young (4.5 months), middle-aged (20 months), and aged (31 months) male Brown-Norway rats were tested in a Morris water maze. All animals learned to localize a cued platform equally well, indicating that the ability to learn this task was not affected by sensory, motoric, or motivational changes with aging or testosterone treatment. There were no significant differences in retention following cue training. Subsequent training with a hidden platform in the opposite quadrant of the pool (place training) revealed impaired spatial learning in middle-aged and aged animals. Retention following place training was significantly impaired in the sham-treated aged rats as compared with sham-treated young rats. Testosterone treatment did not improve spatial learning nor retention of spatial information, but, on the contrary, impaired retention in young and middle-aged animals. The present results confirm earlier reports on an impairment of spatial learning and memory in senescent rats but fail to support a role of decreased plasma testosterone levels and central AVP innervation in this respect.     

Spatial learning in a T-maze by the crayfish Orconectes rusticus

The T-maze has commonly been used to investigate the mechanisms underlying spatial learning in vertebrates and has yielded much information about how animals use response and place cues to orient toward a goal. We designed a T-maze to study the spatial learning abilities of crayfish (Orconectes rusticus), using tactile stimuli as a place cue and escape from warm water for reinforcement. An initial experiment found that most animals did not display a side-turning bias when first placed in the maze, and hence animals were randomly assigned to escape from the left or the right arm, one of which contained a smooth floor and the other a rough floor. We found that, over repeated trials, the latency to escape and the number of turns made prior to escaping significantly decreased indicating that crayfish learned to escape from the maze more rapidly and efficiently. Learning occurred over the course of six trials on a single day, and over 5 days of testing, providing evidence for spatial memory lasting 24 hr. In probe trials, in which experienced animals started the maze in an arm opposite to that used during training trials, crayfish did not display a preference for either response-based learning or place-based learning. Instead they engaged in renewed exploration of the entire maze. These findings suggest that, in addition to remembering the location of the exit, crayfish also remembered the overall configuration of the maze.     

Pre-training to find a hidden platform in the Morris water maze can compensate for a deficit to find a cued platform in a rat model of Parkinson's disease

The bilateral intranigral infusion of 1 micromol 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in adult male Wistar rats caused a specific and partial loss of substantia nigra pars compacta (SNc) dopamine neurons, a partial depletion of striatal dopamine, and a deficit to learn the intra-maze cued version of the Morris water maze. Pre-training the SNc rats in the spatial version of the water maze or simply maintaining the animals on the water maze platform reversed this deficit. This improvement was even observed when the order of the extra-maze cues presented to the rats during pre-training of the spatial version was changed during training of the intra-maze cued version. However, this deficit was not reversed either by maintaining the animals on the platform if the spatial cues were surrounded and covered with a curtain or by swimming sessions in the maze without the escape platform and the curtain. These findings suggest that none of the following elements alone, learned during the spatial task pre-training, could help SNc rats learn the intra-maze cued task: improvement of swimming skills or knowledge of the existence of the escape platform; distance between the platform and the border of the pool; location of a particular extra-maze cue; relations among extra-maze cues. However, the simultaneous presence of the escape platform and extra-maze cues (irrespective of their relational configuration) during the pre-training sessions proved to be necessary for this improving effect to occur.     

Learning strategy selection in the water maze and hippocampal CREB phosphorylation differ in two inbred strains of mice

Learning strategy selection was assessed in two different inbred strains of mice, C57BL/6 and DBA/2, which are used for developing genetically modified mouse models. Male mice received a training protocol in a water maze using alternating blocks of visible and hidden platform trials, during which mice escaped to a single location. After training, mice were required to choose between the spatial location where the platform had been during training (a place strategy) and a visible platform presented in a new location (a cued/response strategy). Both strains of mice had similar escape performance on the visible and hidden platform trials during training. However, in the strategy preference test, C57BL/6 mice selected a place strategy significantly more often than DBA/2 mice. Because much evidence implicates the hippocampus and striatum as important neural substrates for spatial/place and cued/response learning, respectively, the engagement of the hippocampus was then assessed after either place or cue training by determining levels of cAMP response element-binding protein (CREB) and phosphorylated CREB (pCREB) in these two mouse strains. Results revealed that hippocampal CREB levels in both strains of mice were significantly increased after place in comparison to cued training. However, the relation of hippocampal pCREB levels to training was strain dependent; pCREB was significantly higher in C57BL/6 mice than in DBA/2 mice after place training, while hippocampal pCREB levels did not differ between strains after cued training. These findings indicate that pCREB, specifically associated with place/spatial training, is closely tied to differences in spatial/place strategy preference between C57BL/6 and DBA/2 mice.     

Allocentric spatial learning by hippocampectomised rats: A further test of the “spatial mapping” and “working memory” theories of hippocampal function

This paper reports a series of three experiments that tested the “spatial-mapping” and “working-memory” theories of hippocampal function. The experimental designs incorporate separate reference- and working-memory procedures of a water-escape task, using both spatial and non-spatial learning. In Experiment 1 (Reference memory), rats with hippocampal (HC) or cortical (CC) lesions and unoperated (UNOP) rats learned to swim to a rigid visible escape platform while avoiding contact with a floating one. In the nonspatial task, the platforms each occupied any of 8 possible positions in the pool over successive trials but differed in appearance. In the spatial task, the platforms were of identical appearance but the safe one always occupied a single fixed location. The HC rats showed a highly specific spatial learning impairment but did learn to perform consistently above chance towards the end of training. In Experiment 2 (working memory), new groups of rats were trained on similar spatial and nonspatial tasks, but the platform designated correct-in terms of its visual appearance or its spatial location-was randomly changed each day. No animal learned the nonspatial task despite extensive training. Performance on the spatial version unexpectedly revealed an impairment in the CC as well as the HC group relative to the UNOP rats. However, the HCs again performed at above chance levels and demonstrated rapid (I-trial) spatial learning towards the end training. Experiment 3 used a place navigation matching-to-sample task examine spatial working memory further. Each day, an underwater platform was hidden at any of 4 possible locations, and the rats were given 2 trials to search for it. Both UNOP and CC rats located the platform faster on Trial 2 than on Trial 1, even when the inter-trial interval was long as 30min. HC rats were no faster on Trial 2 than on Trial 1. We conclude that hippocampal lesions (1) severely but partially impair spatial but not visual reference memory and (2) give rise to different patterns impairment in different working-mermory tasks. The results are a chal lenge to both the spatial-mapping and working-memory theories.     

Place and response learning of rats in a Morris water maze: differential effects of fimbria fornix and medial prefrontal cortex lesions

The question examined in this study is concerned with a possible functional dissociation between the hippocampal formation and the prefrontal cortex in spatial navigation. Wistar rats with hippocampal damage (inflicted by a bilateral lesion of the fimbria fornix), rats with damage to the medial prefrontal cortex, and control-operated rats were examined for their performance in either one of two different spatial tasks in a Morris water maze, a place learning task (requiring a locale system), or a response learning task (requiring a taxon system). Performance of the classical place learning (allocentric) task was found to be impaired in rats with lesions of the fimbria fornix, but not in rats with damage of the medial prefrontal cortex, while the opposite effect was found in the response learning (egocentric) task. These findings are indicative of a double functional dissociation of these two brain regions with respect to the two different forms of spatial navigation. When the place learning task was modified by relocating the platform, the impairment in animals with fimbria fornix lesions was even more pronounced than before, while the performance of animals with medial prefrontal cortex lesions was similar to that of their controls. When the task was again modified by changing the hidden platform for a clearly visible one (visual cue task), the animals with fimbria fornix lesions had, at least initially, shorter latencies than their controls. By contrast, in the animals with medial prefrontal cortex damage this change led to a slight increase in escape latency.     

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.