The effects of ibotenic acid lesions of the nucleus accumbens on spatial learning and extinction in the rat

Rats with ibotenic acid lesions of the nucleus accumbens (N. Acc) were studied in two spatial learning paradigms: a T-maze and a Morris water maze. Learning of a spatial discrimination task and its reversal in the T-maze were disrupted by the N. Acc lesions. As both original and reversal learning were impaired, there was no evidence of a specific lesion effect on reversal learning. The lesioned rats did not perseverate excessively in their choice of the previously reinforced arm. There was evidence of behavioural inflexibility during extinction when the lesioned rats failed to slow the pace at which they ran the maze in the absence of reward. Spontaneous alternation was not significantly affected by the lesion. Acquisition of the second spatial task, locating the hidden platform in the Morris water maze, was also impaired. The lesioned rats did eventually learn the task and successfully reached the platform with similar latencies and heading errors to controls. Thus, the N. Acc lesion impaired but did not abolish spatial learning in the T-maze and the water maze. The deficits observed in this study may reflect a role for the N. Acc in the reorganisation of behaviour in response to external change.     

Neuroanatomical bases of spatial memory

Although many brain areas have been implicated in spatial memory processes, recent investigations have focused on the hippocampal formation. The present experiment was designed to determine the relative importance of the hippocampal system as compared to the amygdala, the caudate nucleus, or the frontal cortex. Groups of rats were trained to perform on an eight-arm radial maze and then given lesions in one of these brain areas. The post-operative performance of rats with lesions in the fimbria-fornix was never significantly greater than that expected by chance. In contrast, the performance of rats with lesions in the amygdala, the caudate nucleus or the sulcal frontal cortex was not significantly different from that of controls. The performance of rats with lesions in the medial frontal cortex was substantially impaired relative to that of the controls during the first few post-operative test sessions, but improved so that by the end of testing the rats were performing as well as were controls. The recovery of function by the rats with lesions in the medial frontal cortex was a function of experience testing on the maze and not simply the passage of time following surgery. Thus, only rats with functional hippocampal systems were able to perform the maze task accurately while those rats with lesions in the hippocampal system were not.     

Effects of enriched postoperative housing conditions on spatial memory deficits in rats with selective lesions of either the hippocampus,subiculum or entorhinal cortex

Long-Evans male, adult rats received selective and bilateral lesions of either the hippocampus, subiculum or lateral entorhinal cortex, and were then housed for 30 days in either enriched or standard conditions. Rats were then tested in the eight-arm radial maze to assess spatial working memory and the strategies that were employed (i.e. pattern of arms visited). Lesions of the hippocampus induced both a working-memory impairment and a loss in the use of allocentric strategies to perform the task. Rats with lesions of the subiculum were also impaired but less than hippocampectomized rats and showed a similar pattern of arm visits as control rats. In contrast with other lesioned rats, rats with lateral entorhinal cortex lesions performed the task like control rats. Postoperative enriched housing conditions (EHC) globally enhanced performance of rats, but did not affect the strategies selected by the rats to solve the task. The beneficial effect of EHC was particularly obvious in rats with lesions of the subiculum. In enriched rats with such lesions, performance was not significantly different from that of control rats housed in standard conditions. The present results indicate that 1) the structures within the hippocampal formation are not similarly involved in spatial learning and memory processes and in the management of navigational demands of the radial maze, and 2) enriched conditions may enhance the spared spatial abilities of some lesioned rats thus promoting functional recovery.     

Lesions of perirhinal cortex produce spatial memory deficits in the radial maze

Rats with bilateral electrolytic lesions of perirhinal cortex (PRC) or sham control (SHAM) lesions were tested in spatial reference and working memory tasks in the radial arm maze. In experiment 1, one arm of the maze was baited and always located in a fixed position relative to the extra-maze environment. PRC lesioned animals made a significantly greater number of errors than did SHAM animals during initial training in this reference memory task and exhibited a delay-dependent impairment on trial 5 in a series when a delay period of 5, 60, 120, or 240 s was inserted between trials 4 and 5. In experiment 2, when a second group of the animals was tested on the standard radial arm maze working memory task, the performance of the PRC group was markedly impaired relative to controls. These data demonstrate that electrolytic PRC lesions result in a deficit in both spatial reference and spatial working memory tasks. These effects are interpreted as being consistent with the idea that PRC plays an important role in episodic memory processes. These processes may include the storage of information, which is required for the performance of spatial tasks. Hippocampus 1998;8:114–121. © 1998 Wiley-Liss, Inc.     

Place and taste aversion learning: role of basal forebrain, parietal cortex, and amygdala.

Animals with nucleus basalis magnocellularis (NBM), parietal cortex, dorsolateral frontal cortex, amygdala or control lesions were tested in a neophobia and taste aversion learning task. Only animals with basolateral amygdala lesions were impaired in taste aversion learning and in displaying neophobia to a novel flavor. This finding suggested a dissociation between the function of the NBM component of the basal forebrain cholinergic system and the amygdala. The same animals with NBM or control lesions were then tested for acquisition of a spatial navigation task using a dry-land version (cheese board) of the Morris water maze. Animals with NBM lesions were impaired in this task relative to control animals. Animals with parietal cortex lesions displayed a comparable deficit in the place navigation task. These findings suggest parallel functions for the NBM component of the basal forebrain system and the parietal cortex. The role of the NBM in mediating memory appears to be limited in that it does not play a role in all learning situations.     

Relational memory for object identity and spatial location in rats with lesions of perirhinal cortex, amygdala and hippocampus

Previous studies dissociate medial temporal lobe regions using non-relational object versus relational spatial tasks. We compared a relational object identity task to the commonly used, relational spatial Morris water task. Lesions of perirhinal cortex, amygdala and hippocampus led to impaired performance on only the relational object preference task. Rats with perirhinal cortex and amygdala lesions performed normally on the Morris water task, but showed reduced perseveration in the correct quadrant on the probe trial. Rats with hippocampal damage were impaired on all measures of the Morris water task. Our findings demonstrate that perirhinal and amygdala damage creates impairments for relational tasks that rely on information processed by these structures (object identity and stimulus valence, respectively). In addition, these structures contribute non-essentially to performance of relational spatial tasks. The hippocampus is critical for all tasks that require the use of relational representations, regardless of whether the disambiguating information is provided by object identity or spatial arrangements. The current pattern of results suggests that the previous object-spatial dissociations among medial temporal lobe regions may be due to the relational nature of the spatial tasks versus the non-relational nature of the object tasks. Further, they illustrate that discrete dissociations among different types of processing may be an oversimplification.     

Effect of excitotoxic lesions of rat medial prefrontal cortex on spatial memory

The involvement of medial prefrontal cortex (mPFC) in spatial learning was examined in two memory tasks using spatial components, the Morris water maze and the three-panel runway. Using the Morris water maze task, with an invisible platform, the effects of NMDA mPFC lesions were assessed in a procedure reflecting spatial learning and memory, including a spatial reversal. In the three-panel runway, a delayed matching-to-position procedure was used in which rats were required to find food at the end of the runway after passing through one of three panel gates set into four barriers spaced equally apart along the maze. In addition, mPFC lesions were assessed behaviorally in two behavioral tests known to be sensitive to mPFC dysfunction: the food hoarding paradigm and spontaneous locomotion in the open field. Consistent with the documented effects of mPFC damage, NMDA mPFC lesions impaired food hoarding behavior and increased spontaneous exploratory locomotion. In the Morris water maze and the three-panel runway, mPFC-lesioned rats showed relatively few effects, supporting the conclusion that the damage inflicted to the mPFC had no consequence for the processing of spatial information. However, mPFC lesioned animals showed slower acquisition during both the training trial in the three-panel runway and the reversal training in the Morris water maze. These results suggest that spatial memory did not depend on mPFC integrity in the Morris water maze and the three-panel runway experiments, and address the issue of deficits induced by mPFC lesions in memory tasks dependent on non-mnemonic processes such as attentional processes and/or a reduced behavioral flexibility to environmental changes.     

A comparison of the effects of hippocampal or prefrontal cortical lesions on three versions of delayed non-matching-to-sample based on positional or spatial cues

We trained rats to perform one of three versions of delayed non-matching-to-sample (DNMS): DNMS between two retractable levers in an enclosed operant chamber; varying-choice DNMS between two arms selected at random on every trial in an uncovered eight-arm radial arm maze; or recurring-choice DNMS between the same two arms on every trial in a covered radial maze (N=33/task). Rats with medial prefrontal cortical lesions showed delay-independent impairments on the retractable lever and recurring-choice tasks, but performed varying-choice DNMS normally. Rats with hippocampal lesions exhibited delay-independent impairments of the retractable lever task and delay-dependent impairments of both radial maze tasks. When rats trained initially to perform recurring choice DNMS were switched to varying choice DNMS, the impairments of both the prefrontal and hippocampal groups were reduced, although hippocampal animals remained significantly impaired. When rats trained initially to perform varying choice DNMS were switched to recurring choice DNMS, the impairment of the hippocampal group was exacerbated while the prefrontal group remained unimpaired. Thus training the prefrontal group to perform the varying choice task first seemed to protect from impairment when these rats were subsequently trained to perform recurring choice DNMS. This protection provides evidence against the possibility that factors related to proactive interference or to temporal discrimination can account for the effects of prefrontal lesions on delayed conditional discriminations involving two response alternatives in fixed locations.     

The Effects of Lesions to the Mammillary Region and the Hippocampus on Conditional Associative Learning by Rats

Rats with extensive lesions to the mammillary body region, the hippocampus, or rats which had received a control operation were trained postoperatively on two visuo-spatial conditional associative learning tasks in which they had to learn to associate spatial cues with particular visual/auditory stimuli. The animals were subsequently trained on a spatial working memory task, the eight-arm radial maze. Rats with lesions to the mammillary body region were able to acquire the conditional associative learning tasks at a rate comparable to that of operated control animals, whereas those with hippocampal lesions were not. By contrast, rats with a lesion of the mammillary body region or the hippocampus were significantly impaired in comparison with the operated control animals in the radial maze. The findings suggest that lesions to the mammillary body region impair spatial working memory without affecting the capacity to associate particular exteroceptive cues with spatial locations.     

Double dissociation between hippocampal and prefrontal lesions on an operant delayed matching task and a water maze reference memory task

The hippocampus and prefrontal cortex have both been implicated in various aspects of the acquisition, retention and performance of delayed matching to position (DMTP) tasks in the rat, although their precise respective contributions remain unclear. In the present study, rats were trained preoperatively on DMTP before receiving excitotoxic bilateral lesions of either the entire hippocampus or the medial prefrontal cortex. Rats with lesions of the prefrontal cortex exhibited a significant delay-dependent impairment on retention of the DMTP task, whereas hippocampal lesions were without effect. Rats were also exposed to a switch in the contingencies to a 'non-matching' rule, as an analogue of switching between decision rules in the human Wisconsin Card Sorting Test, in which human patients with prefrontal damage are impaired. Both lesion groups acquired the new contingency at control levels, providing no evidence towards a role for either of these areas in this type of rule-switching. The same rats were also assessed in a spatial reference memory task in the water maze, which revealed an impairment in escape latencies and path length that was specific to the hippocampal lesions. The results corroborate previous evidence that the hippocampus is not necessary for at least some aspects of working memory performance in the DMTP task, whereas the delay-dependent deficit in the prefrontal lesion group support this task as a potentially powerful tool for assessing the cognitive changes associated with frontal damage and repair.     

Effects of metrifonate on radial arm maze acquisition in middle-aged rats

The efficacy of metrifonate, a well-tolerated cholinesterase (ChE) inhibitor, in attenuating the normal aging- and corticosterone-induced impairments of radial maze performance of rats was compared. Middle-aged Fischer 344 rats were screened for their spatial orientation performance in the Morris water escape task. Good and bad performers were selected: good performers (N=22) were treated with subcutaneous sustained-release corticosterone pellets, resulting in hippocampal cell damage and impaired spatial orientation in the radial maze; age-induced bad performers (N=20) were tested without additional pharmacological intervention. Metrifonate (MFT), administered daily during radial maze testing, 30 min before training, at a dose of 15 mg/kg p.o., facilitated the acquisition of the task in age-impaired rats, but not in corticosterone-impaired rats.     

Excitotoxic lesions of the rostral thalamic reticular nucleus do not affect the performance of spatial learning and memory tasks in the rat

Rats with cytotoxic lesions of the rostral pole of the thalamic reticular nucleus were compared with surgical control animals on a series of spatial learning and memory tests. While evidence was found for an initial, transient impairment on forced-choice alternation in a T-maze, this rapidly disappeared, and overall performance was unaffected. Subsequent experiments found no evidence that lesions of the rostral reticular nucleus affected the acquisition or performance of tests in the radial arm maze and the Morris water maze. Thus, it appears that the rostral pole of the thalamic reticular nucleus often does not play a necessary role in the performance of tests of spatial learning and memory, in spite of its interconnections with other regions that are required for normal spatial memory.     

Contribution of the anterior thalamic nuclei to conditional learning in rats

The anterior thalamic region is intimately linked anatomically and functionally with the hippocampus, which is critical for various forms of spatial learning. Rats with lesions to the anterior thalamic nuclei and a control group were trained on a visual-spatial conditional associative learning task in which they had to learn to go to one of two locations depending on the particular visual cue presented on each trial; the rats approached the cues from different directions. The animals were subsequently tested on a spatial working memory task, the eight-arm radial maze. Performance on both these tasks had previously been shown to be impaired by hippocampal lesions. Rats with anterior thalamic damage were able to acquire the conditional associative task at a rate comparable to that of the control animals, but were impaired on the radial maze task. The finding of a dissociation between the effects of lesions of the anterior thalamic nuclei on two different classes of behavior known to be associated with hippocampal function suggest that while different neural stations within the extended hippocampal circuit may all play a role in spatial learning, the role of each of these regions in such learning may be more selective than previously considered.     

Effects of electrolytic lesions of the medial prefrontal cortex or its subfields on 4-arm baited, 8-arm radial maze, two-way active avoidance and conditioned fear tasks in the rat

The present study tested the effects of electrolytic lesions in two mPFC subregions, the dorsal anterior cingulate area (dACA) and prelimbic cortex, as well as the effects of a larger medial prefrontal cortex (mPFC) lesion which included both subregions, on 4-arm baited, 4-arm unbaited, 8-arm radial maze task and its reversal (Experiments 1 and 4), two-way active avoidance (Experiments 2 and 5) and conditioned emotional response (Experiments 3 and 6). Rats with large or small lesions of the mPFC learned the location of the 4 baited arms in the training and reversal stages of the radial maze task similarly to sham rats, indicating that these lesions did not affect animals' capacity to process and remember spatial information. dACA and mPFC lesions produced a transient deficit in the acquisition of the radial maze task, suggestive of an involvement of these regions in mnemonic processes. However, in view of the normal performance of these groups by the end of training and during reversal, this deficit is better interpreted as stemming from a difficulty to learn the memory-based strategy used to solve the task. Only mPFC lesion led to better avoidance performance at the beginning of training and tended to increase response during the presentation of a stimulus previously paired with shock, compared to sham rats. Both effects can be taken as an indication of reduced emotionality following mPFC lesion. The results are discussed in relation to known behavioral functions of the mPFC and the suggested functional specialization within this region.     

Characteristics of memory impairment following lesioning of the basal forebrain and medial septal nucleus in rats

Memory impairment in rats with lesions of the basal forebrain (BF) and medial septal nucleus (MS) including cell bodies of the cortical and septohippocampal cholinergic systems, respectively, were compared in order to evaluate the functional contribution of the two cholinergic systems to memory. Biochemical assay revealed that lesioning of the BF and MS resulted in marked and selective decreases in both choline acetyltransferase and acetylcholinesterase activities in the cerebral cortex and hippocampus, respectively. Rats with BF lesions exhibited a severe deficit in a passive avoidance task; acquisition of passive avoidance by repeated training was sluggish, and the acquired response was rapidly eliminated in a subsequent extinction test. However, only slight impairment of passive avoidance was observed in rats with MS lesions. Memory impairment in rats with BF or MS lesions was also investigated using two spatial localization tasks, the Morris water task and the 8-arm radial maze task. Both BF and MS lesions elicited a significant impairment in the Morris water task that required reference memory, as demonstrated by an apparent increase in the latency to escape onto a hidden platform in a large water tank. The impairment was much more obvious in the BF-lesioned rats. In contrast, in the radial maze task primarily requiring working memory, rats with lesions of the MS showed severe disruption, exhibiting a marked increase in total errors, a decrease in the number of initial correct responses, and an apparent change in the strategy pattern. However, corresponding changes in the rats with BF lesions were slight. These results suggest that BF lesions may lead to substantial long-term memory impairment while MS lesions may primarily produce short-term or working memory impairment, indicating a qualitatively different contribution of the two cholinergic systems to memory. It is also suggested that these two experimental animal models may be useful for evaluation of therapeutic drugs for senile dementia of the Alzheimer type.     

Brain system size and adult-adult play in primates: a comparative analysis of the roles of the non-visual neocortex and the amygdala

We investigated the relationship between the degree of spatial memory impairment in an 8-arm radial maze and the changes in the contents of acetylcholine (ACh) and noradrenaline (NA) in the dorsal and ventral hippocampus and the frontal cortex, along with histological changes in kaolin-induced hydrocephalic rats. Kaolin-induced hydrocephalic rats were divided into three groups (non-impaired, impaired and severely impaired) according to the degree of impairment in a radial maze. Thirty percent of the hydrocephalic rats could not solve a radial maze (severely impaired group), while the remaining hydrocephalic rats could (non-impaired rats in the standard task). Forty percent of the non-impaired rats in the standard task failed to solve the delayed-response task (impaired group), whereas the remaining rats were able to solve it (non-impaired group). A positive correlation was observed between the impairment of spatial memory and ventricular dilatation. The ACh content in the dorsal and ventral hippocampus, and the NA content in the ventral hippocampus were decreased in the severely impaired group. Moreover, the NA content in the ventral hippocampus was decreased in the impaired group. These results suggest that the impairment of spatial memory in kaolin-induced hydrocephalic rats is associated with dysfunction of the hippocampal cholinergic and noradrenergic systems.     

Differential effects of fornix and caudate nucleus lesions on two radial maze tasks: evidence for multiple memory systems

The present experiments were designed to examine the hypothesis that the mammalian brain contains anatomically distinct memory systems. Rats with bilateral lesions of caudate nucleus or fimbria-fornix and a control group were tested postoperatively on 1 of 2 versions of the radial maze task. In a standard win-shift version, each of the 8 arms of the maze was baited once, and the number of errors (revisits) in the first 8 choices of each trial was recorded. Fimbria-fornix rats were impaired in choice accuracy, while caudate animals were unimpaired relative to controls. Different groups of rats with similar lesions were tested on a newly developed win-stay version of the radial maze, in which the location of 4 randomly selected baited arms was signaled by a light at the entrance to each arm, and which required rats to revisit arms in which reinforcement had been previously acquired within a trial. Rats with fimbria-fornix lesions were superior to controls in choice accuracy on the win-stay radial maze task, while caudate animals were impaired relative to controls. The results demonstrate a double dissociation of the mnemonic functions of the hippocampus and caudate nucleus. Some implications of the presence of 2 memory systems in the mammalian brain are discussed.     

The conjoint importance of the hippocampus and anterior thalamic nuclei for allocentric spatial learning: evidence from a disconnection study in the rat

A disconnection procedure was used to test whether the hippocampus and anterior thalamic nuclei form functional components of the same spatial memory system. Unilateral excitotoxic lesions were placed in the anterior thalamic (AT) nuclei and hippocampus (HPC) in either the same (AT-HPC Ipsi group) or contralateral (AT-HPC Contra group) hemispheres of rats. The behavioral effects of these combined lesions were compared in several spatial memory tasks sensitive to bilateral hippocampal lesions. In all of the tasks tested, T-maze alternation, radial arm maze, and Morris water maze, those animals with lesions placed in the contralateral hemispheres were more impaired than those animals with lesions in the same hemisphere. These results provide direct support for the notion that the performance of tasks that require spatial memory rely on the operation of the anterior thalamus and hippocampus within an integrated neural network.     

Anterior thalamic lesions reduce spine density in both hippocampal CA1 and retrosplenial cortex,but enrichment rescues CA1 spines only

Injury to the anterior thalamic nuclei (ATN) may affect both hippocampus and retrosplenial cortex thus explaining some parallels between diencephalic and medial temporal lobe amnesias. We found that standard‐housed rats with ATN lesions, compared with standard‐housed controls, showed reduced spine density in hippocampal CA1 neurons (basal dendrites, ?11.2%; apical dendrites, ?9.6%) and in retrospenial granular b cortex (Rgb) neurons (apical dendrites, ?20.1%) together with spatial memory deficits on cross maze and radial‐arm maze tasks. Additional rats with ATN lesions were also shown to display a severe deficit on spatial working memory in the cross‐maze, but subsequent enriched housing ameliorated their performance on both this task and the radial‐arm maze. These enriched rats with ATN lesions also showed recovery of both basal and apical CA1 spine density to levels comparable to that of the standard‐housed controls, but no recovery of Rgb spine density. Inspection of spine types in the CA1 neurons showed that ATN lesions reduced the density of thin spines and mushroom spines, but not stubby spines; while enrichment promoted recovery of thin spines. Comparison with enriched rats that received pseudo‐training, which provided comparable task‐related experience, but no explicit spatial memory training, suggested that basal CA1 spine density in particular was associated with spatial learning and memory performance. Distal pathology in terms of reduced integrity of hippocampal and retrosplenial microstructure provides clear support for the influence of the ATN lesions on the extended hippocampal system. The reversal by postoperative enrichment of this deficit in the hippocampus but not the retrosplenial cortex may indicate region‐specific mechanisms of recovery after ATN injury. © 2014 Wiley Periodicals, Inc.