A double dissociation between the rat hippocampus and medial caudoputamen in processing two forms of knowledge

Rats with hippocampus, medial caudoputamen (CPU), lateral CPU, or control lesions were trained on declarative and procedural knowledge variants of a novel rodent sequential learning task. Medial CPU lesions impaired rats' ability to learn the procedure of running through a sequence of open maze arms but did not disrupt their capacity to explicitly generate (i.e.. "declare") maze arm sequences. Hippocampus lesions produced the opposite set of results. Rats with lateral CPU lesions were not impaired on either version of the task. Transfer tests indicated that control rats predominantly used egocentric cues to solve the procedural task and allocentric spatial cues to solve the declarative task. These findings suggest a double dissociation between the medial CPU and hippocampus in processing egocentric-procedural and allocentric-declarative sequential information, respectively.     

On the role of posterior parietal and prefrontal cortex in visuo-spatial perception and attention

Summary Monkeys with bilateral removal of caudal prefrontal cortex (area 8) or dorso-lateral parietal cortex (areas 5 and 7) or the inferior temporal cortex (area TE) were presented with two versions of a go-left/go-right visuo-spatial discrimination. In the first task they had to displace either the left or right of two identical plaques according to whether both plaques were black or white respectively. There were no performance differences among groups. In the second task, the two plaques were always red and the appropriate response was indicated by whether a spatially remote third plaque was black or white. Both the prefrontal and parietal groups were impaired relative to the inferotemporal group on this task. The results indicate that whether an impairment occurs on a task that is thought to test the perception of egocentric space may depend on whether the animal has to notice and attend to a remote cue, and that an attentional disorder may also explain impairments reported on tests of allocentric perception where the critical cue is spatially remote from the response site.     

Dissociation of item and order memory following parietal cortex lesions in the rat

Rats with parietal cortex lesions were tested for both item and order memory for a list of spatial events in a probe recognition procedure. Rats with parietal cortex lesions were impaired for all events within the item memory task but had good memory for the early events within the order memory task. These data suggest a dissociation of function between item and order memory for parietal cortex damaged animals. In conjunction with previous findings with rats with medial prefrontal cortex lesions, these data suggest that item and order memory can be coded and represented independently.     

Extensive cytotoxic lesions of the rat retrosplenial cortex reveal consistent deficits on tasks that tax allocentric spatial memory

Despite the connections of the retrosplenial cortex strongly suggesting a role in spatial memory, the lesion data to date have been equivocal. Whether subjects are impaired after retrosplenial lesions seems to depend on whether the lesions were aspirative or excitotoxic, with the latter failing to produce an impairment. A shortcoming of previous excitotoxic lesion studies is that they spared the most caudal part of the retrosplenial cortex. The present study thus used rats with extensive neurotoxic lesions of the retrosplenial cortex that encompassed the entire rostrocaudal extent of this region. These rats were consistently impaired on several tests that tax allocentric memory. In contrast, they were unimpaired on an egocentric discrimination task. Although the lesions did not appear to affect object recognition, clear deficits were found for an object-in-place discrimination. The present study not only demonstrates a role for the retrosplenial cortex in allocentric spatial memory, but also explains why previous excitotoxic lesions have failed to detect any deficits.     

Neonatal lesions of the entorhinal cortex induce long-term changes of limbic brain regions and maze learning deficits in adult rats

We here investigated the effects of neonatal lesions of the entorhinal cortex (EC) in rats on maze learning and on structural alterations of its main projection region, the hippocampus, as well as other regions with anatomical connections to the EC that are involved in maze learning. Since early brain damage is considered to be involved in certain neuropsychiatric diseases, this approach sought to model certain aspects of this etiopathogenesis. Bilateral neonatal lesions were induced on postnatal day 7 by microinjection of ibotenic acid (1.3 microg/0.2 microl phosphate-buffered saline (PBS)) into the EC. Naive and sham-lesioned rats served as controls. Rats were trained and tested on an eight-arm radial maze for allocentric and egocentric learning. Subsequently, gold-chloride staining and immunohistochemical staining for the microtubule-associated protein MAP-2 was used to assess myelination and dendritic density in the hippocampus, striatum and medial prefrontal cortex (mPFC) of these rats. Additionally, parvalbumin-expressing, presumably GABAergic interneurons, were evaluated in these regions. Performance in both the allocentric and the egocentric strategy was disturbed after neonatal EC lesion as shown by an increase of repeated arm entries, which indicates disturbed working memory. Histological evaluation revealed that the density of parvalbumin-immunopositive neurons and myelin sheaths was reduced in the hippocampus but not in the striatum and mPFC in neonatally lesioned rats. Density of MAP-2 staining did not differ between groups in all regions tested. Since structural alterations were only found in the EC and hippocampus our findings support their eminent role in working memory and show that no functional restoration occurs after neonatal lesions.     

Lesions of the dorsal hippocampus or parietal cortex differentially affect spatial information processing

The present experiments used 2 versions of a modified Hebb-Williams maze to test the role of the dorsal hippocampus (dHip) and parietal cortex (PC) in processing allocentric and egocentric space during acquisition and retention. Bilateral lesions were made to either the dHip or PC before maze testing (acquisition) or after maze testing (retention). The results indicate that lesions of the dHip impair allocentric maze acquisition, whereas lesions of the PC impair egocentric maze acquisition. During retention, lesions of the PC produced a significant impairment on both maze versions, whereas lesions of the dHip produced short-lived, transient impairments on both maze versions. These results suggest that during acquisition, the hippocampus and PC process spatial information in parallel; however, long-term retention of spatial information requires the PC with the dHIP as necessary for retrieval and/or access but not necessarily storage.     

Memory for visuospatial location following selective hippocampal sclerosis: the use of different coordinate systems

This study addressed the role of the medial temporal lobe regions and, more specifically, the contribution of the human hippocampus in memory for body-centered (egocentric) and environment-centered (allocentric) spatial location. Twenty-one patients with unilateral atrophy of the hippocampus secondary to long-standing epilepsy (left, n = 7; right, n = 14) and 15 normal control participants underwent 3 tasks measuring recall of egocentric or allocentric spatial location. Patients with left hippocampal sclerosis were consistently impaired in the allocentric conditions of all 3 tasks but not in the egocentric conditions. Patients with right hippocampal sclerosis were impaired to a lesser extent and in only 2 of the 3 tasks. It was concluded that hippocampal structures are crucial for allocentric, but not egocentric, spatial memory.     

Prefrontal serotonin depletion impairs egocentric, but not allocentric working memory in rats

Working memory is a cognitive ability chiefly organized by the prefrontal cortex. Working memory tests may be resolved based on allocentric or egocentric spatial strategies. Serotonergic neurotransmission is closely involved in working memory, but its role in spatial strategies for working memory performance is unknown. To address this issue, prefrontal serotonin depletion was induced to adult male rats, and three days after the behavioral expression of both allocentric and egocentric strategies were evaluated in the "Y" maze and in a crossed-arm maze, respectively. Serotonin depletion caused no effects on allocentric-related behavioral performance, but lesioned rats performed deficiently when the egocentric working memory was evaluated. These results suggest that serotonin may be more closely related with the organization of working memory that uses own movement-guided responses than with that involving the use of external visuospatial signals. Further neurochemical studies are needed to elucidate possible interactions between serotonergic activity and other neurotransmitter systems in the organization of working memory-related allocentric and egocentric strategies.     

Getting lost in Alzheimer’s disease: A break in the mental frame syncing

Despite the clinical significance of topographical disorientation in Alzheimer’s disease, it is not clear which cognitive spatial processes are primarily impaired. Here, we argue that a deficit in “mental frame syncing” between egocentric and allocentric spatial representations causes early manifestations of topographical disorientation in AD. Specifically, patients show impairment in translating from an allocentric hippocampal representation to an egocentric parietal one for the purpose of effective spatial orientation and navigation. We suggest that a break in “mental frame syncing”, underpinned by damage to the hippocampus and retrosplenial cortex, may be a crucial cognitive marker both for early and differential diagnosis of AD. Identification of these spatial deficits could facilitate the development of early cognitive rehabilitation interventions and the possibility of identifying individuals most at risk for progression to AD during the preclinical stages.     

Role of the caudate nucleus in recovery from neonatal mediofrontal cortex lesions in the rat

Ablation of medial prefrontal cortex impairs spatial discrimination learning in adult but not in neonatally lesioned rats. Orbital prefrontal cortex and adjacent convexity neocortex need not be left intact to observe this sparing of function. This study examined the possibility that the caudate nucleus, remaining intact after early medial prefrontal cortex lesions, might be involved in the observed behavioral sparing. Neonatal rats given combined lesions of the medial prefrontal cortex and head of the caudate nucleus were compared to age/litter-matched sham-operated controls on spatial alternation and place response acquisition and “reversal” tests. The results show that the performance of these neonatally lesioned subjects was deficient on both tests. The discussion centers on possible recovery mechanisms in rats given prefrontothalamic system damage early in life.     

Perirhinal cortex and place-object conditional learning in the rat

The present study examined whether excitotoxic lesions of the perirhinal cortex can affect acquisition of a place-object conditional task in which object and spatial information must be integrated. Testing was carried out in a double Y-maze apparatus, in which rats learned a conditional rule of the type, "In Place X, choose Object A, not Object B (A+ vs. B-); in Place Y, choose Object B, not Object A (A- vs. B+)." Perirhinal cortex lesions significantly impaired acquisition of this task while sparing performance of an allocentric spatial memory task performed in a radial arm maze. Perirhinal cortex lesions also had no apparent effect on a 1-pair object discrimination task performed in the double Y maze or on retention and acquisition of 4-pair concurrent discrimination problems performed in a computer-automated touch screen testing apparatus. The results suggest that, although the perirhinal cortex and hippocampus can be functionally dissociated, their normal mode of operation includes the integration of object and spatial information.     

Neurotoxic lesions of the rat perirhinal cortex fail to disrupt the acquisition or performance of tests of allocentric spatial memory

Rats with neurotoxic lesions of the perirhinal cortex (n = 9) were compared with sham controls (n = 14) on a working memory task in the radial arm maze. Rats were trained under varying levels of proactive interference and with different retention intervals. Finally, performance was assessed when the maze was switched to a novel room. None of these manipulations differentially impaired rats with perirhinal lesions. Rats were next trained on delayed matching-to-place in the water maze. Even with retention delays of 30 min, there was no evidence of a deficit. Although interactions between the perirhinal cortex and hippocampus may be important for integrating object-place information, the perirhinal cortex is often not necessary for tasks that selectively tax allocentric spatial memory.     

Multiple reference frames used by the human brain for spatial perception and memory

We review human functional neuroimaging studies that have explicitly investigated the reference frames used in different cortical regions for representing spatial locations of objects. Beyond the general distinction between “egocentric” and “allocentric” reference frames, we provide evidence for the selective involvement of the posterior parietal cortex and associated frontal regions in the specific process of egocentric localization of visual and somatosensory stimuli with respect to relevant body parts (“body referencing”). Similarly, parahippocampal and retrosplenial regions, together with specific parietal subregions such as the precuneus, are selectively involved in a specific form of allocentric representation in which object locations are encoded relative to enduring spatial features of a familiar environment (“environmental referencing”). We also present a novel functional magnetic resonance imaging study showing that these regions are selectively activated, whenever a purely perceptual spatial task involves an object which maintains a stable location in space during the whole experiment, irrespective of its perceptual features and its orienting value as a landmark. This effect can be dissociated from the consequences of an explicit memory recall of landmark locations, a process that further engages the retrosplenial cortex.     

Deficit in the water-maze after lesions in the anteromedial extrastriate cortex in rats.

The Morris water-maze task was used to evaluate the role of the anteromedial extrastriate visual cortex in the processing of visuospatial information in rats. Six gray male rats received bilateral ibotenic acid injections targeted stereotactically to the rostral part of the anteromedial extrastriate visual cortex. These operated subjects and six other unoperated control rats were tested in the maze. Histological analysis confirmed the localization, symmetry, and depth of lesions in the rostral part of anteromedial area (AMa) in the operated subjects. In these animals, a significantly greater latency to reach the submerged platform was found (U = 0, p = 0.004). The Morris water-maze may be considered as a reference memory task. It presents a stronger demand on the use of allocentric spatial visual cues than on the use of egocentric cues for navigation. Therefore, the present data lend support to the participation of area AMa in the integration of allocentric visuospatial cues or as a link in the memory system involved in the acquisition of this task.     

Medial prefrontal cortex lesions cause deficits in a variable-goal location task but not in object exploration.

The role of the medial prefrontal cortex (PFC) in goal-directed behavior was examined in rats with aspiration lesions. In Experiment 1, PFC lesions resulted in an impaired ability to relearn the location of a behaviorally defined goal arm of a plus-maze after it was moved from an initially fixed position. Lesioned rats also exhibited a significantly greater degree of perseveration compared with control animals. Experiment 2 was an object exploration task in which rats had to respond to a change in the layout of the environment. PFC-lesioned rats performed identically to controls, therefore demonstrating that the deficits observed in Experiment 1 did not result from a deficit in the ability to explore the environment. The results are discussed in terms of several competing, but not mutually exclusive explanations of the role of the PFC in navigation and spatial representation.     

Neonatal hippocampal lesions in rhesus macaques alter the monitoring, but not maintenance, of information in working memory

Neonatal hippocampal damage in rodents impairs medial prefrontal working memory functions. To examine whether similar impairment will follow the same damage in primates, adult monkeys with neonatal hippocampal lesions and sham-operated controls were trained on two working memory tasks. The session-unique delayed nonmatch-to-sample (SU-DNMS) task measures maintenance of information in working memory mediated by the ventral lateral prefrontal cortex. The object self-ordered (Obj-SO) task measures monitoring of information in working memory mediated by the dorsolateral prefrontal cortex. Adult monkeys with neonatal hippocampal lesions performed as well as sham-operated controls on the SU-DNMS task at either the 5- or 30-s delays but were severely impaired on the Obj-SO task. These results extend the earlier findings in rodents by demonstrating that early lesions of the hippocampus in monkeys impair working memory processes known to require the integrity of the dorsolateral prefrontal cortex while sparing lower order working memory processes such as recency. Although the present results suggest that the lack of functional hippocampal inputs may have altered the maturation of the dorsolateral prefrontal cortex, future studies will be needed to determine whether the nature of the observed working memory deficit is due to an absence of the hippocampus, a maldevelopment of the dorsolateral prefrontal cortex, or both.     

Spatial navigation in normal aging and the prodromal stage of Alzheimer's disease: Insights from imaging and behavioral studies

Normal aging and mild Alzheimer's disease (AD) are associated with declines in navigational skills, including allocentric and egocentric representations, cognitive mapping, landmark processing, and spatial memory. These changes, however, are associated with different patterns of structural and functional alterations in the neural network of navigation. In AD, these changes occur in the hippocampus, parahippocampal gyrus, parietal lobe, retrosplenial cortex, prefrontal cortex, and caudate nucleus, whereas in aging, modifications occur mainly in the prefrontal cortex and the hippocampus. The navigation abilities of patients with mild cognitive impairment (MCI) have been found to show different performance patterns, depending on their cognitive profiles. Since patients with MCI do not uniformly develop dementia of the Alzheimer type, it is important to identify reliable early cognitive markers of conversion to AD dementia. In this review, we propose that navigation deficits may help distinguish patients at higher risk of developing AD dementia from individuals with normal cognitive aging and those with other neurodegenerative diseases.     

Allocentric versus egocentric spatial memory after unilateral temporal lobectomy in humans

Thirty patients who had undergone either a right or left unilateral temporal lobectomy (14 RTL; 16 LTL) and 16 control participants were tested on a computerized human analogue of the Morris Water Maze. The procedure was designed to compare allocentric and egocentric spatial memory. In the allocentric condition, participants searched for a target location on the screen, guided by object cues. Between trials, participants had to walk around the screen, which disrupted egocentric memory representation. In the egocentric condition, participants remained in the same position, but the object cues were shifted between searches to prevent them from using allocentric memory. Only the RTL group was impaired on the allocentric condition, and neither the LTL nor RTL group was impaired on additional tests of spatial working memory or spatial manipulation. The results support the notion that the right anterior temporal lobe stores long-term allocentric spatial memories.     

Modality-specific frontal and parietal areas for auditory and visual spatial localization in humans.

Although the importance of the posterior parietal and prefrontal regions in spatial localization of visual stimuli is well established, their role in auditory space perception is less clear. Using positron emission tomography (PET) during auditory and visual spatial localization in the same subjects, modality-specific areas were identified in the superior parietal lobule, middle temporal and lateral prefrontal cortices. These findings suggest that, similar to the visual system, the hierarchical organization of the auditory system extends beyond the temporal lobe to include areas in the posterior parietal and prefrontal regions specialized in auditory spatial processing. Our results may explain the dissociation of visual and auditory spatial localization deficits following lesions involving these regions.     

Medial septal and nucleus basalis magnocellularis lesions produce order memory deficits in rats which mimic symptomatology of Alzheimer's disease

Rats with electrolytic lesions of the medial septum or ibotenic acid lesions of the nucleus basalis magnocellularis (NBM) were tested in an order memory task for an 8-item list of varying spatial locations within an 8-arm radial maze. Results indicated that rats with small medial septal lesions resulting in small AchE depletion of dorsal hippocampal formation were impaired only for the first, but not the last choice orders of the list. Animals with large medial septal lesions resulting in large AchE depletion of the dorsal hippocampal formation displayed an order memory deficit for all the choice orders of the list. In contrast, rats with small NBM lesions resulting in small AchE depletion of parietal and part of frontal cortex were impaired only for the last, but not the first choice orders of the list. Animals with large NBM lesions resulting in large AchE depletion of parietal and part of frontal cortex displayed an order memory deficit for all the choice orders of the list. The relationship between these findings and mnemonic symptomatology of Alzheimer's disease was discussed, as was the possible meaning of these results in providing an animal model for studying certain aspects of the disease.