Prefrontal cortex and hippocampus in posttraumatic functional recovery: spatial delayed alternation by rats subjected to transection of the fimbria-fornix and/or ablation of the prefrontal cortex

Lesions of the prefrontal cortex and the hippocampus often lead to impairment of the same behavioural tasks (e.g., allocentric as well as egocentric spatial orientation and spatial delayed alternation). In case of allocentric and egocentric spatial orientation we have previously found that the two structures mutually contribute to the posttraumatic functional recovery of such tasks. We therefore presently tested the hypothesis that this would even be true in case of spatial delayed alternation. The acquisition of a spatial delayed alternation task in a T-maze was studied in four groups of rats: animals in which the fimbria-fornix had been transected bilaterally, rats who had received bilateral ablations of the anteromedial prefrontal cortex, animals in which both of these structures had been lesioned, and a sham operated control group. All three lesion groups demonstrated an impaired task acquisition. The group given prefrontal cortical lesions in isolation underwent a complete functional recovery. Both of the fimbria-fornix transected groups were significantly impaired even when compared to the group given prefrontal cortical ablations in isolation. The two fimbria-fornix lesioned groups did, however, exhibit levels of functional recovery. The group in which both structures had been lesioned demonstrated a task acquisition, which was significantly inferior to that of the group given fimbria-fornix transections in isolation. After completion of the task acquisition period, all animals were subjected to two behavioural challenges including a session on which the duration of the inter-trial delay was doubled. This expansion of the inter-trial delay rather selectively impaired the task performance of the group given fimbria-fornix transections in isolation. Consequently, both during the acquisition period and in one of the challenges a differentiation of functional recovery was seen between the combined lesioned group and the group given fimbria-fornix lesions only. This indicates that even in case of a spatial delayed alternation task the prefrontal cortex normally contributes significantly to mediation of posttraumatic functional recovery after isolated lesions of the fimbria-fornix. The results are discussed in the context of models of posttraumatic functional recovery.     

Erythropoietin improves spatial delayed alternation in a T-maze in fimbria-fornix transected rats

Systemically administered human recombinant erythropoietin (EPO) may have the potential to reduce the cognitive and behavioural symptoms of a mechanical brain injury. In a series of studies we address this possibility. We have previously found that EPO given to fimbria-fornix transected rats at the moment of injury is able substantially to improve the posttraumatic acquisition of allocentric place learning tasks administered in a water maze as well as in an 8-arm radial maze. It is, however, essential to evaluate this clinically important ability of EPO within other cognitive domains, as well. Consequently, we presently studied the effects of similarly administered EPO in fimbria-fornix transected and control operated rats, respectively--evaluating the posttraumatic behavioural/cognitive abilities in a spatial delayed alternation task performed in a T-maze. Administration of EPO to the hippocampally injured rats was associated with a substantial reduction of the lesion-associated behavioural impairment--while such an impairment was clearly seen in the saline injected fimbria-fornix transected group. In contrast, EPO had no detectable effect on the task acquisition of non-lesioned animals. The results of the present study confirm our previous demonstrations that EPO is able to reduce or eliminate the behavioural/cognitive consequences of mechanical injury to the hippocampus--and emphasize that this ability is present across a broader spectrum of cognitive domains.     

Erythropoietin improves spatial delayed alternation in a T-maze in rats subjected to ablation of the prefrontal cortex

Systemically administered human recombinant erythropoietin (EPO) may have the potential to reduce the cognitive and behavioural symptoms of mechanical brain injury. In a series of studies we address this possibility. Previously, we studied the effects of EPO given to fimbria-fornix transected rats at the moment of injury. We have found that such treatment improves substantially the posttraumatic acquisition of allocentric place learning tasks administered in a water maze and in an 8-arm radial maze as well as a spatial delayed alternation task administered in a T-maze. It is, however, essential also to evaluate this clinically important ability of EPO after other types of mechanical brain injury. Consequently, we presently studied the effects of similarly administered EPO in rats subjected to bilateral subpial aspiration of the anteromedial prefrontal cortex as well as control operated rats, respectively. We evaluated the posttraumatic behavioural/cognitive abilities of these animals in a spatial delayed alternation task performed in a T-maze. Administration of EPO to the prefrontally ablated rats was associated with a reduction of the lesion-associated behavioural impairment--while such an impairment was clearly seen in the saline injected prefrontally ablated group. In sham operated rats administration of EPO did not influence the task acquisition significantly. The results of the present study confirm our previous demonstrations that EPO is able to reduce the behavioural/cognitive consequences of mechanical brain injury. This ability is emphasized by its relative independence on the type of lesion as well as the neural structure affected.     

Egocentric spatial orientation in a water maze by rats subjected to transection of the fimbria-fornix and/or ablation of the prefrontal cortex

The acquisition of a water maze based task requiring egocentric spatial orientation in the absence of distal cues was studied in four groups of rats: animals in which the fimbria-fornix had been transected, rats that received bilateral ablations of the anteromedial prefrontal cortex, animals in which both of these structures had been lesioned, and a sham-operated control group. Isolated lesions of both the anteromedial prefrontal cortex and the hippocampus were associated with a significantly impaired task acquisition. Both of these individually lesioned groups did, however, eventually demonstrate full functional recovery by reaching the task proficiency of the sham-operated control group. In contrast, the group in which both of these structures had been lesioned failed to demonstrate full functional recovery and was severely and long-lastingly impaired when compared to all other groups. Behavioural challenges in the form of a no-platform session and two reversals of platform position demonstrated that while the sham-operated control group and the group subjected to fimbria-fornix transections in isolation utilized rather pure egocentric orientation strategies, the two prefrontally lesioned groups (and especially the combined lesion group) employed a different set of solution strategies which at least partly relied on a "circling" method. Even in the behaviour of the prefrontally lesioned groups, however, indications of a certain level of cognitive representations of the platform positions were seen. It is concluded that both the prefrontal cortex and the hippocampus contribute to the mediation of egocentric spatial orientation. Furthermore, the hippocampus is a significant and potentially irreplaceable part of the neural substrate of functional recovery of the presently studied task after prefrontal lesions--while the prefrontal cortex may play a similar role with respect to hippocampal lesions.     

Comparing the effects of selective cingulate cortex lesions and cingulum bundle lesions on water maze performance by rats

The ability of rats to learn the location of a hidden platform in a swim maze was compared in animals with excitotoxic lesions of the anterior or posterior (retrosplenial) cingulate cortex or radiofrequency lesions of the cingulum bundle or fimbria-fornix. Performance of this allocentric spatial task was unaffected by the posterior cingulate cortex lesions, while anterior cingulate cortex damage produced only a mild acquisition deficit. Transection of the fornix and lesions of the cingulum bundle produced similar patterns of impairment on initial acquisition, but the cingulum bundle lesions had less effect on reversal of the task. The results from the water maze, and from a subsequent T-maze alternation task, indicate that cingulum bundle lesions can produce a spatial deficit that is similar, but milder, to that observed after fornix transection. The results of the excitotoxic lesions suggest that previous studies examining conventional cingulate lesions may have been influenced by damage to adjacent fibre tracts, such as the cingulum bundle.     

Dissociable roles of the medial prefrontal cortex, the anterior cingulate cortex, and the hippocampus in behavioural flexibility revealed by serial reversal of three-choice discrimination in rats

Contributions of different limbic cortical areas to mediation of behavioural flexibility were examined using repeated acquisition of three-choice discrimination in operant chambers. Rats were trained on a series of positional discrimination tasks with three levers, where position of the correct lever remained the same within a task but shifted across tasks. Ibotenic acid lesions of the medial prefrontal cortex impaired acquisition of each discrimination task by increasing errors specifically in the early phase of each task. These errors were characterised by perseveration to the previously correct lever. By contrast, lesions of the anterior cingulate cortex resulted in the impairment of discrimination in general without inducing perseveration; the impairment was instead characterised by disruption of general error-correction processes. Hippocampal lesions severely impaired learning by increasing perseverative tendencies that were present throughout the learning stages in each task. These results extend our understanding of the contributions of the different nodes of the limbic cortico-striatal circuit to different aspects of behavioural flexibility.     

Ibotenate Lesions of Hippocampus and/or Subiculum: Dissociating Components of Allocentric Spatial Learning

This study examined the effects of ibotenic acid-induced lesions of the hippocampus, subiculum and hippocampus +/- subiculum upon the capacity of rats to learn and perform a series of allocentric spatial learning tasks in an open-field water maze. The lesions were made by infusing small volumes of the neurotoxin at a total of 26 (hippocampus) or 20 (subiculum) sites intended to achieve complete target cell loss but minimal extratarget damage. The regional extent and axon-sparing nature of these lesions was evaluated using both cresyl violet and Fink - Heimer stained sections. The behavioural findings indicated that both the hippocampus and subiculum lesions caused impairment to the initial postoperative acquisition of place navigation but did not prevent eventual learning to levels of performance almost as effective as those of controls. However, overtraining of the hippocampus + subiculum lesioned rats did not result in significant place learning. Qualitative observations of the paths taken to find a hidden escape platform indicated that different strategies were deployed by hippocampal and subiculum lesioned groups. Subsequent training on a delayed matching to place task revealed a deficit in all lesioned groups across a range of sample choice intervals, but the subiculum lesioned group was less impaired than the group with the hippocampal lesion. Finally, unoperated control rats given both the initial training and overtraining were later given either a hippocampal lesion or sham surgery. The hippocampal lesioned rats were impaired during a subsequent retention/relearning phase. Together, these findings suggest that total hippocampal cell loss may cause a dual deficit: a slower rate of place learning and a separate navigational impairment. The prospect of unravelling dissociable components of allocentric spatial learning is discussed.     

Distinct patterns of behavioural impairments resulting from fornix transection or neurotoxic lesions of the perirhinal and postrhinal cortices in the rat

The present study provides evidence that lesions of the fornix (FNX) and of the perirhinal/postrhinal cortex (PPRH), which both disconnect the hippocampus from other brain regions, can lead to distinct patterns of behavioural impairments on tests of spatial memory and spontaneous object recognition. For example, whereas FNX lesions impaired allocentric spatial delayed alternation in a T-maze but generally spared a test of spontaneous object recognition, PPRH lesions produced the opposite pattern of results. Indeed, on the T-maze task PPRH animals significantly outperformed controls when the retention delay was increased to 60 s. In addition, some evidence was found that contributions from both the fornix and perirhinal/postrhinal cortex may be required when object and spatial information must be integrated. In an object-in-place test, for example, PPRH animals failed according to two measures, and FNX animals failed according to one measure, to discriminate objects that had remained in fixed locations from those that had exchanged locations with other objects. Neither lesion, however, affected performance of a visuospatial conditional task, a Pavlovian autoshaping task, or a one-pair pattern discrimination task. It is suggested that the perirhinal/postrhinal cortex, rather than being specialised for a particular type of associative learning, is important for processing complex visual stimuli.     

Disconnecting hippocampal projections to the anterior thalamus produces deficits on tests of spatial memory in rats

A disconnection procedure was used to test whether projections from the hippocampus to the anterior thalamic nuclei (AT), via the fimbria-fornix (FX), form functional components of a spatial memory system. The behavioural effects of combined unilateral lesions in the AT and FX were compared when they were either in contralateral hemispheres (AT-FX Contra) or the same hemisphere (AT-FX Ipsi). Other groups received bilateral FX lesions and Sham surgeries. Expt 1 demonstrated that none of these lesions affected performance of an object recognition task, while performance of an object location task, which tests the subjects' preference for an object that has changed location, was impaired in the AT-FX Contra and FX groups. In a T-maze alternation task, however, the FX group was severely impaired while both the AT-FX Ipsi and AT-FX Contra lesion groups showed only a mild impairment. In order to test whether spared crossed projections might support spatial performance in the AT-FX Contra group we then examined the effects of a combined AT-FX Contra lesion coupled with transection of the hippocampal commissure. This combination of lesions produced a severe disruption in spatial memory performance in the water maze, radial arm maze and T-maze, which was significantly greater than that produced by ipsilateral and contralateral AT-FX lesions alone. These results support the notion that disconnection of the AT from their hippocampal inputs produces impairments on a range of spatial memory tasks, but indicate that there are an array of different routes that can subserve this function.     

Prefrontal cortical mediation of rats' place learning in a modified water maze

The acquisition of a place learning task in a water maze modified from the “standard” set-up by restriction of distal cues and addition of “proximal” cues (ping-pong balls in fixed positions on the surface of the water) was tested in three groups of rats: (I) animals subjected to bilateral ablation of the anteromedial prefrontal cortex, (II) rats in which the parietal “association” cortex had been removed bilaterally, and (III) a sham operated control group. The task acquisition of the prefrontaly ablated group was significantly impaired, whereas the animals in which the parietal cortex had been removed acquired the task as quickly as the control group. Upon reaching criterion level performance all animals were tested on “challenge” sessions on which the cues were manipulated. Such “challenges” demonstrated that the animals of all three groups discriminated between the distal cues and utilized such a discrimination for navigational purposes.     

Cholinergic receptor blockade in prefrontal cortex and lesions of the nucleus basalis: implications for allocentric and egocentric spatial memory in rats

In this study we have examined the involvement of the prefrontal cortex (PFC) along with the Nucleus basalis magnocellularis (NBM) in two types of spatial navigation tasks. We evaluated the effects of excitotoxic (ibotenate-induced) lesions of the NBM in an allocentric and an egocentric task in the Morris water maze, using sham operations for a comparison. In both cases we also assessed the effects of local cholinergic receptor blockade in the PFC by infusing the muscarinic receptor antagonist scopolamine (4 or 20 microg). Anatomically, the results obtained showed that this lesion produced a profound loss of acetylcholinesterase (AChE) positive cells in the NBM, and a loss of AChE positive fibres in most of the neocortex, but hardly in the medial PFC. Behaviourally, such lesions led to a severe impairment in the allocentric task. Intraprefrontal infusions of scopolamine led to a short-lasting impairment in task performance when the high dose was used. In the second experiment, using the same surgical manipulations, we examined the performance in the egocentric task. Like in the allocentric task animals with NBM lesions were also impaired, but with continued training they acquired a level of performance similar to the sham-operated ones. This time, infusions of scopolamine in the medial PFC led to a severe disruption of performance in both groups of animals. We conclude that acetylcholine in the medial PFC is important for egocentric but not allocentric spatial memory, whereas the NBM is involved in the learning of both tasks, be it to a different degree.     

Associative recognition and the hippocampus: Differential effects of hippocampal lesions on object‐place,object‐context and object‐place‐context memory

The hippocampus is thought to be required for the associative recognition of objects together with the spatial or temporal contexts in which they occur. However, recent data showing that rats with fornix lesions perform as well as controls in an object‐place task, while being impaired on an object‐place‐context task (Eacott and Norman ( 2004 ) J Neurosci 24:1948–1953), suggest that not all forms of context‐dependent associative recognition depend on the integrity of the hippocampus. To examine the role of the hippocampus in context‐dependent recognition directly, the present study tested the effects of large, selective, bilateral hippocampus lesions in rats on performance of a series of spontaneous recognition memory tasks: object recognition, object‐place recognition, object‐context recognition and object‐place‐context recognition. Consistent with the effects of fornix lesions, animals with hippocampus lesions were impaired only on the object‐place‐context task. These data confirm that not all forms of context‐dependent associative recognition are mediated by the hippocampus. Subsequent experiments suggested that the object‐place task does not require an allocentric representation of space, which could account for the lack of impairment following hippocampus lesions. Importantly, as the object‐place‐context task has similar spatial requirements, the selective deficit in object‐place‐context recognition suggests that this task requires hippocampus‐dependent neural processes distinct from those required for allocentric spatial memory, or for object memory, object‐place memory or object‐context memory. Two possibilities are that object, place, and context information converge only in the hippocampus, or that recognition of integrated object‐place‐context information requires a hippocampus‐dependent mode of retrieval, such as recollection. © 2009 Wiley‐Liss, Inc.     

Rhinal and dorsolateral prefrontal cortex lesions produce selective impairments in object and spatial learning and memory in canines

To examine the effects of rhinal and dorsolateral prefrontal cortex lesions on object and spatial recognition memory in canines, we used a protocol in which both an object (delayed nonmatching to sample, or DNMS) and a spatial (delayed nonmatching to position or DNMP) recognition task were administered daily. The tasks used similar procedures such that only the type of stimulus information to be remembered differed. Rhinal cortex (RC) lesions produced a selective deficit on the DNMS task, both in retention of the task rules at short delays and in object recognition memory. By contrast, performance on the DNMP task remained intact at both short and long delay intervals in RC animals. Subjects who received dorsolateral prefrontal cortex (dlPFC) lesions were impaired on a spatial task at a short, 5-second delay, suggesting disrupted retention of the general task rules; however, this impairment was transient, and long-term spatial memory performance was unaffected in dlPFC subjects. The present results provide support for the involvement of the RC in object, but not visuospatial, processing and recognition memory, whereas the dlPFC appears to mediate retention of a nonmatching rule. These findings support theories of functional specialization within the medial temporal lobe and frontal cortex and suggest that rhinal and dorsolateral prefrontal cortices in canines are functionally similar to analogous regions in other mammals.     

Cognitive mapping in rats: The role of the hippocampal and frontal systems in retention and reversal

These experiments determined the extent to which the hippocampal system and the medial frontal cortex are selectively involved in cognitive mapping in spatial environments.Rats were trained to discriminate between two 3-dimensional objects based on either the location of the objects in the test environment, or on the stimulus characteristics of the objects themselves. Following the acquisition of one of these discrimination tasks, each rat was given a series of transfer tests to determine the extent to which a cognitive mapping strategy had been used to solve the task. Each rat was then given a lesion in the fimbria-fornix or the medial frontal cortex, or a control operation. In the location discrimination, rats with fimbria-fornix lesions, as compared to control rats: (a) performed poorly at the beginning of retention testing; (b) relearned the task to criterion performance; (c) performed normally during the transfer tests indicating that they used a cognitive mapping strategy, and (d) performed poorly in the discrimination reversals. In the object discrimination, these rats performed as well as controls during retention and transfer tests, but had a slight impairment during discrimination reversals. The performance of rats with lesions in the medial frontal cortex was worse than that of the controls during the retention of both discriminations, and during the reversal of the location, but not the object discrimination. These results are related to predictions of current theories implicating the hippocampus and medial frontal cortex in spatially organized behaviors, particularly those behaviors requiring cognitive mapping.     

Functional difference between rat perirhinal cortex and hippocampus in object and place discrimination tasks

The present study was designed to determine the degree of functional dissociation between the rat perirhinal cortex and hippocampus for reference memory performance on object and place discrimination tasks. In one experiment, 30 rats were trained on a two-pair concurrent object discrimination task in an elevated radial arm maze. Rats with a perirhinal cortex lesion needed significantly more days to attain the criterion in the relearning of a pre-operatively acquired object discrimination task than the control rats and rats with a hippocampal lesion. However, there were no significant differences between the three groups in the days to attain the criterion in learning post-operatively the original object discrimination task with new discriminanda and its relearning. The rats with a hippocampal lesion did not show any impairment in object discrimination. In a second experiment, 27 rats were trained on a place discrimination task in the same maze. Rats with a hippocampal lesion required more days to attain the criterion than the control rats to relearn the pre-operatively acquired place discrimination task, and they had fewer correct responses in the first three sessions with new discriminanda than the control rats. Rats with a perirhinal cortex lesion, on the other hand, showed mild relearning impairment. These results suggest that there is a functionally single dissociation between the perirhinal cortex and hippocampus for reference memory performance on object and place discrimination tasks. They also suggest the possible involvement of the perirhinal cortex in spatial reference memory performance.     

Visual recognition impairment follows ventromedial but not dorsolateral prefrontal lesions in monkeys

Visual recognition in monkeys appears to involve the participation of two limbothalamic pathways, one including the amygdala and the magnocellular portion of the medial dorsal nucleus (MDmc) and the other, the hippocampus and the anterior nuclei of the thalamus (Ant N). Both MDmc and Ant N project, in turn, to the prefrontal cortex, mainly to its ventral and medial portions. To test whether the prefrontal projection targets of the two limbothalamic pathways also participate in memory functions, performance on a variety of learning and memory tasks was assessed in monkeys with lesions of the ventromedial prefrontal cortex (Group VM). Normal monkeys and monkeys with lesions of dorsolateral prefrontal cortex (Group DL) served as controls. Group VM was severely impaired on a test of object recognition, whereas Group DL did not differ appreciably from normal animals. Conversely, the animals in Group VM were able to learn a spatial delayed response task, whereas 2 of the 3 animals in Group DL could not. Neither group was impaired in the acquisition of visual discrimination habits, even though the successive trials on a given discrimination were separated by 24-h intervals. The patterns of deficit suggest that ventromedial prefrontal cortex constitutes another station in the limbothalamic system underlying cognitive memory processes, whereas the dorsolateral prefrontal cortex lies outside this system. The results support the view that the classical delayed-response deficit observed after dorsolateral prefrontal lesions represents a perceptuo-mnemonic impairment in spatial functions selectively rather than a memory loss of a more general nature.     

Tactile stimulation during development alters behaviour and neuroanatomical organization of normal rats

The purpose of this study was to examine the anatomical and behavioural sequelae in the normal brain associated with tactile stimulation treatment during development. Using a split litter design, male and female rats were randomly assigned to either the tactile stimulation group (tactile stimulation for 15 min, three times/day, from postnatal day 3 to 21), or the no-tactile stimulation group. In adulthood, the rats were tested on the Whishaw tray reaching task, activity box, novel object recognition, and elevated plus maze. Following behavioural testing, rats were sacrificed for Golgi-Cox analysis. Dendritic length, dendritic branching, and spine density were analyzed in two areas of the prefrontal cortex (mPFC and OFC) and spine density in the amygdala. Tactile stimulation significantly altered rat behaviour on the novel object recognition task and Whishaw tray reaching task, but failed to have an effect on behaviour in the elevated plus maze or activity box. Importantly, tactile stimulation dramatically altered dendritic morphology in the prefrontal cortex and amygdala of both male and female rats. Tactile stimulation significantly increased dendritic branching, dendritic length, and spine density in all brain regions examined. These findings demonstrate that similar to early adversity, positive experiences early in development can dramatically alter neuroplasticity.     

The role of the prefrontal cortex in object-place learning: a test of the attribute specificity model

In order to test an attribute specificity model of prefrontal cortex function, rats with lesions in the prelimbic-infralimbic (PL-IL) or anterior cingulate and precentral (AC-PC) subregions of the medial prefrontal cortex and controls were trained on an object-place paired associate task. Rats with AC-PC lesions acquired the task as readily as controls. In contrast, the PL-IL lesioned rats did not learn the task. Whenever higher order processing is required to solve a task, the data support an attribute-specificity model of prefrontal cortex function in that the PL-IL cortices support both object and place attribute information in a variety of tasks including object-place paired associate learning.     

A comparison of egocentric and allocentric age-dependent spatial learning in the beagle dog

Spatial discriminations can be performed using either egocentric information based on body position or allocentric information based on the position of landmarks in the environment. Beagle dogs ranging from 2 to 16 years of age were tested for their ability to learn a novel egocentric spatial discrimination task that used two identical blocks paired in three possible spatial positions (i.e. left, center and right). Dogs were rewarded for responding to an object furthest to either their left or right side. Therefore, when the center location was used, it was correct on half of the trials and incorrect on the other half. Upon successful acquisition of the task, the reward contingencies were reversed, and the dogs were rewarded for responding to the opposite side. A subset of dogs was also tested on an allocentric spatial discrimination task, landmark discrimination. Egocentric spatial reversal learning and allocentric discrimination learning both showed a significant age-dependent decline, while initial egocentric learning appeared to be age-insensitive. Intra-subject correlation analyses revealed a significant relationship between egocentric reversal learning and allocentric learning. However, the correlation only accounted for a small proportion of the variance, suggesting that although there might be some common mechanism underlying acquisition of the two tasks, additional unique neural substrates were involved depending on whether allocentric or egocentric spatial information processing was required.     

Disrupted allocentric but preserved egocentric spatial learning in transgenic mice with impaired glucocorticoid receptor function

Spatial and non-spatial learning of mice with an incorporated antisense RNA complementary to a fragment of cDNA coding for the glucocorticoid receptor (GR) were evaluated in allocentric and egocentric radial maze and water maze tasks, and in spontaneous object recognition and sensorimotor learning paradigms. Mice with impaired GR function did not acquire two maze paradigms based on allocentric spatial navigation, radial maze non-matching to position and water maze spatial discrimination learning. Comparison of performance in spaced and massed trials indicated that this may be due to a general inability to store information into allocentric reference memory or in retrieval processes. However, both groups of animals learned the rules of an egocentric radial maze task at similar rates and there was no difference in their ability to recognise objects once animals had equal opportunity to explore the sample objects. Sensorimotor performance was impaired in transgenic animals, but it is suggested that this is due to non-specific factors rather than to disrupted sensorimotor learning per se. These results are consistent with a disruption of hippocampal function. Histological examination of the hippocampus revealed no obvious structural abnormalities in transgenic animals. Therefore, the data suggest that functional underactivity of GRs at the level of the hippocampus induces a deficit in allocentric navigation while sparing egocentric navigation and object recognition.