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.     

Dissociation of Hippocampal and Striatal Contributions to Spatial Navigation in the Water Maze

Two experiments were conducted to compare the effects of fornix/fimbria and caudate-putamen lesions in Long–Evans hooded rats (Rattus norvegicus) trained on two water maze tasks that differed in the type of spatial localization required for optimum solution. In Experiment 1, the lesioned rats and surgical controls were trained on the standard place task in the water maze (Morris, 1981) and given two postacquisition tests (a platform removal probe and platform relocation test). In Experiment 2, rats with similar lesions and control rats were trained on a modified cue navigation task. Fornix/fimbria lesions impaired a late stage of place task acquisition but did not impair acquisition of the cue task. Caudate-putamen lesions resulted in a severe place acquisition impairment and a transient cue acquisition impairment, both of which were characterized by an initial tendency to swim near the wall of the pool. Post-hoc analyses of the direction and angles of departure from the start points suggested that rats with fornix/fimbria lesions used non-allocentric spatial strategies to solve the place task. These rats also demonstrated a significantly weakened spatial bias for the former training quadrant on the platform removal probe and reduced flexibility in navigating to a novel platform location on the platform relocation test. In contrast, rats with caudate-putamen lesions showed a significant spatial bias for the former training quadrant but failed to cross the exact location within the quadrant where the platform was formerly positioned. The results suggest that the hippocampus mediates the allocentric spatial component of the water maze place task while the dorsomedial striatum may play an important role in the acquisition of the procedural aspects of both place and cue versions of the task.     

Fimbria/fornix lesions facilitate the learning of a nonspatial response task

The spatial cognitive map theory of O’Keefe and Nadel (1978) predicts that lesions of the hippocampal system should impair learning on spatial tasks but not learning on nonspatial tasks. However, there is evidence that such lesions can facilitate learning on certain nonspatial tasks. Their theory does not predict such facilitation. Nevertheless, it is reasonable to expect that animals possessing a spatial cognitive map would have an inherent bias to engage a mapping strategy and thus be at a disadvantage on certain nonspatial tasks in comparison with animals without the mapping capacity and bias. In the present study, fimbria/fornix lesions impaired learning on a spatial task, but actually facilitated learning on a nonspatial task of equal difficulty. Thus, brain lesions that interfere with map functioning can facilitate learning on tasks for which a mapping strategy interferes with task solution. The results require a modification of the spatial cognitive map theory.     

Memory for Duration: Role of Hippocampus and Medial Prefrontal Cortex

In this task rats had to learn that a three-dimensional object stimulus (a rectangle) that was visible for 2 s would result in a positive (go) reinforcement for one object (a ball) and no reinforcement (no go) for a different object (a bottle). However, if the rectangle stimulus was visible for 8 s then there would be no reinforcement for the ball (no go), but a reinforcement for the bottle (go). After rats learned this conditional discrimination by responding differentially in terms of latency to approach the object, they received large (dorsal and ventral) lesions of the hippocampus, lesions of the medial prefrontal cortex (anterior cingulate and precentral cortex), lesions of the cortex dorsal to the dorsal hippocampus, or served as sham-operated controls. Following recovery from surgery they were retested. The results indicate that there were major impairments following hippocampal lesions, in contrast to cortical control and medial prefrontal cortex lesions, as indicated by smaller latency differences between positive and negative trials on postsurgery tests. In order to ensure that the deficits observed with hippocampal lesions were not due to a discrimination problem, new rats were trained in an object (gray cylinder) duration discrimination task. In this go/no go procedure, the rats were reinforced for a 2-s exposure (duration) of the gray cylinder, but not a 10-s duration, or vice versa. The results indicate that after hippocampal lesions, there was an initial deficit followed by complete recovery. There were no significant changes for the medial prefrontal, cortical control, or sham-operated animals. It appears that the hippocampus, but not the medial prefrontal cortex, is actively involved in representing in short-term memory temporal attribute information based on the use of markers for the beginning and end of the presence (duration) of a stimulus (object).     

The roles of the medial prefrontal cortex and hippocampus in a spatial paired-association task

Although the roles of both the hippocampus and the medial prefrontal cortex (mPFC) have been suggested in a spatial paired-associate memory task, both areas were investigated separately in prior studies. The current study investigated the relative contributions of the hippocampus and mPFC to spatial paired-associate learning within a single behavioral paradigm. In a novel behavioral task, a pair of different objects appeared repeatedly across trials, but in different arms in a radial maze, and different rules were associated with those arms for reward. Specifically, in an "object-in-place" arm, the rat was required to choose a particular object associated with the arm. In a "location-in-place" arm, the animal was required to choose a certain within-arm location (ignoring the object occupying the location). Compared to normal animals, rats with ibotenic acid-based lesions in the hippocampus showed an irrecoverable impairment in performance in both object-in-place and location-in-place arms. When the mPFC was inactivated by muscimol (GABA(A) receptor agonist) in the normal animals with intact hippocampi, they showed the same severe impairment as seen in the hippocampal lesioned rats only in object-in-place arms. The results confirm that the hippocampus is necessary for a biconditional paired-associate task when space is a critical component. The mPFC, however, is more selectively involved in the object-place paired-associate task than in the location-place paired-associate task. The current task powerfully demonstrates an experimental situation in which both the hippocampus and mPFC are required and may serve as a useful paradigm for investigating the neural mechanisms of object-place association.     

The effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage

Clozapine is an atypical antipsychotic drug that has been shown to improve spatial memory in some animal models; however its efficacy in reversing spatial memory impairment in rats with hippocampal lesions is unknown. To address this issue, we tested the effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage in three separate experiments. In each experiment, adult male rats received sham surgery or direct stereotaxic infusions of the excitotoxin, NMDA, into the hippocampus. In the first study, seven days after surgery, the sham control animals received daily saline injections while the lesioned animals were split into two groups that received daily saline or clozapine (2.0 mg/kg, sc) injections. During the fifth week of injections, all animals were tested in a food-motivated delayed spatial alternation task. Saline-treated rats with excitotoxic hippocampal damage displayed significant deficits in delayed spatial alternation. Daily clozapine injections completely reversed this deficit. In a second experiment, it was found that clozapine treatment limited to the testing days only did not improve alternation performance in lesioned rats. Finally, in a third experiment, chronic clozapine treatment did not improve alternation performance in lesioned rats that were pre-trained in the alternation task prior to surgery. These results suggest that chronic, but not acute, clozapine treatment enables rats with hippocampal damage to develop new spatial learning, but can not rescue old spatial learning established prior to damage. These results may have implications for the treatment of cognitive deficits caused by hippocampal dysfunction in disorders such as schizophrenia, Alzheimer's disease, and others.     

Memory for temporal order of new and familiar spatial location sequences: role of the medial prefrontal cortex

Rats with medial prefrontal cortex or sham control lesions were tested on an eight-arm radial maze task to examine memory for the temporal order of a variable and a constant sequence of spatial locations as a function of temporal distance. During the study phase of each trial, rats were allowed to visit each of eight arms once in an order that was randomly selected or fixed for that trial. The test phase required the rats to choose which of two arms occurred earlier in the sequence of arms visited during the study phase. The arms selected as test arms varied according to temporal distance (0, 2, 4, or 6) or the number of arms that occurred between the two test arms in the study phase. For the variable sequences based on new information, control rats showed an increasing temporal distance function. Relative to control rats, medial prefrontal cortex-lesioned rats displayed a temporal order memory deficit across all distances. For the constant sequence based on familiar information, control rats performed well across all distances. Relative to controls, the medial prefrontal cortex-lesioned rats displayed a performance deficit. The results support the idea that the medial prefrontal cortex contributes to mnemonic operations associated with temporal order for new and familiar spatial location information.     

Effects of dorsal-striatum lesions and fimbria-fornix lesions on the problem-solving strategies of rats in a shallow water maze

In solving a spatial problem, animals can use a place, cue, or response strategy. The present research was designed to evaluate the role of dorsal striatum (DS) in spatial problem solving and to compare it with that of fimbria fornix (FF). Rats were trained with a place + cue task in a shallow pool, then were divided into three groups (DS, FF, control), and lesions were made in the corresponding areas. After retraining, four probe tests were given: Test 1 (start position moved), Test 2 (goal and start positions moved), Test 3 (invisible goal), and Test 4 (curtain test). The test results suggest that the DS and Control groups performed the original task by using the place strategy, whereas the FF group used the cue strategy, which strongly implies that the DS group was impaired in the use of the cue strategy. This research also provides evidence supporting the usefulness of a shallow pool in evaluating animal behavior.     

Investigating virtual reality navigation in amnestic mild cognitive impairment using fMRI

Spatial navigation requires a well-established network of brain regions, including the hippocampus, caudate nucleus, and retrosplenial cortex. Amnestic Mild Cognitive Impairment (aMCI) is a condition with predominantly memory impairment, conferring a high predictive risk factor for dementia. aMCI is associated with hippocampal atrophy and subtle deficits in spatial navigation. We present the first use of a functional Magnetic Resonance Imaging (fMRI) navigation task in aMCI, using a virtual reality analog of the Radial Arm Maze. Compared with controls, aMCI patients showed reduced activity in the hippocampus bilaterally, retrosplenial cortex, and left dorsolateral prefrontal cortex. Reduced activation in key areas for successful navigation, as well as additional regions, was found alongside relatively normal task performance. Results also revealed increased activity in the right dorsolateral prefrontal cortex in aMCI patients, which may reflect compensation for reduced activations elsewhere. These data support suggestions that fMRI spatial navigation tasks may be useful for staging of progression in MCI.     

The relationship of structural ischemic brain damage to neurobehavioural deficit: the effect of postischemic MK-801

Global cerebral ischemia is well known to cause neuronal necrosis in selectively vulnerable sectors of the hippocampus. Since the hippocampus of the rat is involved in spatial navigation, learning, and memory, selective deficits in these abilities may arise from ischemic brain damage. Previous studies have shown (a) a detectable neurobehavioural deficit due to ischemic brain damage limited to half of the CA1 sector of the hippocampus and (b) a reduction of ischemic neuronal necrosis with the noncompetitive N-methyl-D-Aspartate (NMDA) antagonist MK-801. This study was designed to determine the relationship between the improvement in structural brain damage in postischemically treated rats and any improvement in neurobehavioural performance, using a learning-set water task. Seventeen male Wistar rats received 10.5 min of forebrain ischemia induced by carotid clamping and hypotension. Brain temperature was estimated with probes in the temporalis muscle. Ten of these animals received no therapy (controls), and seven animals received 5 mg/kg MK-801 iv, 20 min postischemia. Six additional rats underwent a sham operation. Postischemic hypothermia was prevented with heating lamps. Four controls and one MK-801 treated animal died. The survivors were then tested on a place learning-set task in a swimming pool paradigm, and quantitative histopathologic analysis of their entire brains was done. The learning-set task revealed defects in spatial navigation, reflected as increased errors and latency in the performance of the untreated control rats. The performance of the MK-801 treated group progressively approached that of sham-operated rats over the course of testing and was significantly better than controls. Importantly, no long-term detrimental effect of MK-801 on the learning-set task performance was seen. Quantitative neuropathology revealed significantly less damage in the MK-801 treated group in all major brain regions. In the hippocampus, MK-801 treated animals showed hippocampal damage limited to the vulnerable portion of the pyramidal cell band comprising 48.8% of the CA1 pyramidal cells, as opposed to 72.4% in untreated controls. Extra-hippocampal damage was evident only in untreated control animals. MK-801 totally prevented neuronal necrosis in both the cerebral cortex and striatum and also prevented infarction in the neocortex and thalamus. Three conclusions emerge from the study. First, postischemic MK-801 mitigates structural brain damage in several brain regions in the absence of concomitant hypothermia. Second, neurobehavioural performance appears to be improved by MK-801 when performance trends are examined, but is somewhat less sensitive than quantitated histopathology due to compounding interanimal variation in performance abilities.(ABSTRACT TRUNCATED AT 400 WORDS)     

The effects of hippocampal lesions on learning, memory, and reward expectancies

The hippocampus appears to be critical for the formation of certain types of memories. Hippocampal-lesioned animals fail to exhibit some spatial, contextual, and relational associations. After aspiration lesions of the hippocampus and/or cortex, male rats were allowed to recover for three weeks before being trained on a matching-to-position task. The matching-to-position task was altered to influence the type of cognitive strategies a subject would use to solve the task. The main behavioral manipulation was the reinforcement contingency assignment: Use of a differential outcomes procedure (DOP) or a nondifferential outcomes procedure (NOP). The DOP involves correlating each to-be-remembered event with a distinct reward condition via Pavlovian trace conditioning, whereas the NOP results in random reward contingency. We found that hippocampal lesions did retard learning the matching rule, regardless of the reinforcement contingency assignment. However, when delay intervals were added to the task memory performance of subjects with hippocampal lesions was dramatically impaired--if subjects were not trained with the DOP. When subjects were trained with the DOP, the hippocampal lesion had a marginal effect on delayed memory performance. These findings demonstrate two important points regarding lesions of the hippocampus: (1) hippocampal lesions have a minimal effect on the on the ability of rats to use reward information to solve a delayed discrimination task; (2) rats with hippocampal lesions have the ability to learn about reward information using Pavlovian trace conditioning procedures.     

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.     

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.     

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.     

Place learning in scopolamine-treated rats: the roles of distal cues and catecholaminergic mediation

Experiments 1 and 2 tested the hypothesis that cholinergic receptor antagonists impair place learning in a water maze by interfering with the processing of distal, visual cues. Extramaze cues were offered to rats in the form of geometrical patterns arranged on the inner circumference of a curtain surrounding the water maze. In Experiment 1 the animals were offered both the distal cues and proximal cues in the form of pingpong balls in fixed positions on the surface of the water while only distal cues were present in Experiment 2. Animals were injected with either scopolamine (0.5 mg/kg body wt) or saline 20 min prior to the daily place learning sessions. Upon reaching criterion level performance the animals were tested on "rotation" sessions on which the distal cues were displaced. The outcome of such "rotations" demonstrated that-regardless of the presence or absence of proximal cues-scopolamine-treated rats relied at least as much as normal animals on the distal cues. The acquisition phase of both Experiments 1 and 2 demonstrated an almost complete lack of scopolamine-associated impairment in acquisition and performance of the place learning task. In Experiment 3 (when scopolamine was no longer administered) the subjects of Experiment 2 were exposed to a series of pharmacological "challenges" of their place learning performance and eventually to surgical ablation of the anteromedial prefrontal cortex. The outcome of the pharmacological challenges and the postoperative test of task performance demonstrated that the place learning performance of animals which had acquired the task under scopolamine was mediated by a neural substrate dissimilar to the substrate of task performance in normal animals. Rats acquiring the task while deprived of the cholinergic system demonstrated above-normal contributions to task mediation from catecholaminergic-probably dopaminergic-mechanisms and tentative results pointed to a "shift" toward prefrontal task mediation.     

Rat hippocampus and memory for places of changing significance

Rats were tested once daily on a four-choice delayed match from sample task with a water reward. Each day the correct place changed, and a single exposure to it was provided on information trials. Lesions of the hippocampal formation that involved the fornix, or dorsal hippocampus bilaterally, produced a severe impairment in the performance of previously trained rats. By contrast, lesions of the ventral hippocampus did not preclude reacquisition of the place-memory task. Some otherwise impaired rats with fornical lesions were able to find the water when aided by nonplace cues that consistently signaled reward. Reducing the number of choices from four to two did not aid the impaired rats. Certain lesions of the hippocampal formation in the rat produce a deficit appropriately described as amnesia. The memory deficit is consistent with a role for the hippocampus in processing of place information and shows some parallels to the amnesia seen in persons with temporal lobe lesions.     

The effects of aging and dorsal hippocampal lesions: performance on spatial and nonspatial comparable versions of the water maze

Aged intact and young hippocampal-lesioned rats show similar deficits on the spatial water maze. However, this does not necessitate that the source of these deficits in the aged animals is due to hippocampal damage. These water maze deficits may arise from other aging factors such as changes in thermoregulation, muscle fatigue, swim ability, and response to stress. Consequently, it is imperative to examine the performance of aged rats on a comparable nonhippocampal version of this task. Past attempts to develop a hippocampus-independent version of the water maze were confounded because these tasks were easier (i.e., the rats spent much less time swimming in the water) than the spatial versions of the task. The current study examined performance on a hippocampus-independent task comparable in difficulty to the spatial water one. Middle-aged (16-m) and old (25-m) male F344 rats were given sham or dorsal hippocampus lesions and tested on both a spatial and a nonspatial water maze. The middle-aged rats with hippocampal lesions were impaired on the spatial task but not on the nonspatial task. Conversely, aged animals showed a similar impairment on both types of water maze tasks. Additionally, hippocampal lesions exacerbated the age-related impairment on both tasks. These findings indicate that caution must be used when interpreting the results of water maze tasks for aged animals.     

Fornix, medial prefrontal cortex, nucleus accumbens, and mediodorsal thalamic nucleus: roles in a fear-based context discrimination task

The goal of the present study was to evaluate the contributions of various brain structures anatomically and functionally linked to the hippocampus and amygdala in a fear-based context discrimination task. The brain areas of interest included the fornix, medial prefrontal cortex, mediodorsal (MD) thalamic nucleus, and nucleus accumbens. Damage to the MD thalamic nucleus and medial prefrontal cortex produced the largest impairment in context-specific fear responses. Damage to the fornix impaired some fear responses (freezing, ultrasonic vocalizations, defecation, and approach/avoidance) while leaving conditioned fear expression of heart rate and urination unaltered. Damage to the nucleus accumbens was also coupled with deficits in the discriminative expression of some (heart rate, urination, and ultrasonic vocalizations) but sparing of context-appropriate freezing, defecation, and approach/avoidance behaviors.     

Excitotoxic lesions of the parafascicular nucleus produce deficits in a socially transmitted food preference

The parafascicular (PF) nucleus, a posterior component of the intralaminar nuclei of the thalamus, is considered to be an essential structure in the feedback circuits of basal ganglia-thalamo-cortical systems that critically participate in cognitive processes. To study the PF contribution to processing of behaviorally significant information during specific episodes of learning, we investigated the effects of damaging the PF nucleus in the acquisition of a natural form of social olfactory learning, the socially transmitted food preference (STFP) task. This task is a non-spatial paradigm that exhibits some of the characteristics of relational memory because it requires that animals use information obtained in one episode to guide later behavior in different circumstances. Adult male Wistar rats were submitted to pretraining bilateral N-methyl-D-aspartate (0.15 M, pH 7.4) lesions of the PF (0.4 microl/side, 0.2 microl/min). The behavioral effects of PF lesions were compared to vehicle- and sham-operated control groups and two retention delays were considered in separate groups: immediately (Lesion-I, Vehicle-I, and Sham-I groups) and 24h after training (Lesion-24, Vehicle-24, and Sham-24 groups). PF lesions produced delay-independent impairments in the STFP suggesting that this nucleus might modulate the acquisition of this odor-odor association task. Results are discussed in the context of medial prefrontal cortex deafferentation induced by PF damage.     

Aged rats are impaired on an attentional set-shifting task sensitive to medial frontal cortex damage in young rats

Normal aging is associated with disruption of neural systems that subserve different aspects of cognitive function, particularly in the hippocampus and frontal cortex. Abnormalities in hippocampal function have been well investigated in rodent models of aging, but studies of frontal cortex function in aged rodents are few. We tested young (4–5 mo old) and aged (27–28 mo old) male Long-Evans rats on an attentional set-shifting task modified slightly from previous publication. After training on two problems in which the reward was consistently associated with the same stimulus dimension, and a reversal of one problem, a new problem was presented in which the reward was consistently associated with the previously irrelevant stimulus dimension (extradimensional shift [EDS]). Aged rats as a group were significantly impaired on the EDS, although some individual aged rats performed as well as young rats on this phase. In addition, some aged rats were impaired on the reversal, although a group effect did not reach significance in this phase. Impairment in neither reversal nor EDS was associated with impairments in spatial learning in the Morris water maze. Young rats with neurotoxic lesions of medial frontal cortex are also selectively impaired on the EDS. These results indicate that normal aging in rats is associated with impaired medial frontal cortex function. Furthermore, age-related declines in frontal cortex function are independent of those in hippocampal function. These results provide a possible basis for correlating age-related changes in neurobiological markers in frontal cortex with cognitive decline.