Removal of cholinergic input to perirhinal cortex disrupts object recognition but not spatial working memory in the rat

The perirhinal cortex of the temporal lobe has a crucial role in object recognition memory. Cholinergic transmission within perirhinal cortex also seems to be important for this function, as the muscarinic receptor antagonist scopolamine disrupts object recognition performance when administered systemically or directly into perirhinal cortex. In the present study, we directly assessed the contribution of cholinergic basal forebrain input to perirhinal cortex in object recognition. Selective bilateral removal of the cholinergic basal forebrain inputs to perirhinal cortex was accomplished by injecting the immunotoxin 192 IgG-saporin directly into perirhinal cortex in rats. These animals were significantly impaired relative to vehicle-injected controls in a spontaneous object recognition task despite intact spatial alternation performance. These results are consistent with recent reports of object recognition impairment following acute cholinergic receptor blockade and extend these findings by demonstrating that chronic removal of cholinergic basal forebrain input to an otherwise intact perirhinal cortex causes a severe object recognition deficit similar to that associated with more extensive cell body lesions of perirhinal cortex.     

Neurotoxic lesions of the rat perirhinal and postrhinal cortices and their impact on biconditional visual discrimination tasks

It has been argued that damage to the perirhinal cortex should impair visual discriminations when the stimuli have overlapping features. In Experiment 1, rats with perirhinal cortex lesions were trained on a series of visual discriminations in a water tank, culminating in a biconditional discrimination. No evidence was found of a perirhinal lesion deficit, although the same rats showed an object recognition deficit. In Experiment 2 the lesions were extended to involve both the perirhinal and postrhinal cortices in a new group of rats. An impairment was now found on acquisition of the biconditional task, but this was not specific as impairments were also found on two elemental visual discriminations. Taken together, the study failed to find evidence that the rat perirhinal cortex is necessary for configural visual discriminations and so revealed that some ambiguous visual discriminations can be learnt when this area is removed. Furthermore, there was no evidence that the parahippocampal region is selectively dedicated to configural learning, even though the loss of this area can impair the acquisition of some configural tasks.     

Interaction of frontal and perirhinal cortices in visual object recognition memory in monkeys

Monkeys were trained preoperatively in visual object recognition memory. The task was delayed matching‐to‐sample with lists of trial‐unique randomly generated visual stimuli in an automated apparatus, and the stimuli were 2D visual objects made from randomly generated coloured shapes. We then examined the effect of either: (i) disconnecting the frontal cortex in one hemisphere from the perirhinal cortex in the contralateral hemisphere by crossed unilateral ablations; (ii) disconnecting the magnocellular portion of the mediodorsal (MDmc) thalamic nucleus in one hemisphere from the perirhinal cortex in the contralateral hemisphere; or (iii) bilaterally ablating first the amygdala, then adding fornix transection, then finally perirhinal cortex ablation. We found that both frontal/perirhinal and MDmc/perirhinal disconnection had a large effect on visual object recognition memory, whereas both amygdalectomy and the addition of fornix transection had only a mild effect. We conclude that the frontal lobe needs to interact with the perirhinal cortex within the same hemisphere for visual object recognition memory, but that routes through the amygdala and hippocampus are not of primary importance.     

Perirhinal cortex lesions impair tests of object recognition memory but spare novelty detection

The present study examined why perirhinal cortex lesions in rats impair the spontaneous ability to select novel objects in preference to familiar objects, when both classes of object are presented simultaneously. The study began by repeating this standard finding, using a test of delayed object recognition memory. As expected, the perirhinal cortex lesions reduced the difference in exploration times for novel vs. familiar stimuli. In contrast, the same rats with perirhinal cortex lesions appeared to perform normally when the preferential exploration of novel vs. familiar objects was tested sequentially, i.e. when each trial consisted of only novel or only familiar objects. In addition, there was no indication that the perirhinal cortex lesions reduced total levels of object exploration for novel objects, as would be predicted if the lesions caused novel stimuli to appear familiar. Together, the results show that, in the absence of perirhinal cortex tissue, rats still receive signals of object novelty, although they may fail to link that information to the appropriate object. Consequently, these rats are impaired in discriminating the source of object novelty signals, leading to deficits on simultaneous choice tests of recognition.     

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.     

Perirhinal cortex lesions uncover subsidiary systems in the rat for the detection of novel and familiar objects

The present study compared the impact of perirhinal cortex lesions on tests of object recognition. Object recognition was tested directly by looking at the preferential exploration of novel objects over simultaneously presented familiar objects. Object recognition was also tested indirectly by presenting just novel objects or just familiar objects, and recording exploration levels. Rats with perirhinal cortex lesions were severely impaired at discriminating a novel object from a simultaneously presented familiar object (direct test), yet displayed normal levels of exploration to novel objects presented on their own and showed normal declines in exploration times for familiar objects that were repeatedly presented (indirect tests). This effective reduction in the exploration of familiar objects after perirhinal cortex lesions points to the sparing of some recognition mechanisms. This possibility led us to determine whether rats with perirhinal cortex lesions can overcome their preferential exploration deficits when given multiple object familiarisation trials prior to that same (familiar) object being paired with a novel object. It was found that after multiple familiarisation trials, objects could now successfully be recognised as familiar by rats with perirhinal cortex lesions, both following a 90-min delay (the longest delay tested) and when object recognition was tested in the dark after familiarisation trials in the light. These latter findings reveal: (i) the presumed recruitment of other regions to solve recognition memory problems in the absence of perirhinal cortex tissue; and (ii) that these additional recognition mechanisms require more familiarisation trials than perirhinal-based recognition mechanisms.     

Bilateral NMDA lesions centered on the postrhinal cortex have minimal effects on hippocampal place cell firing

The postrhinal cortex (POR) receives input from parietal cortex and sends output to the hippocampus. It may, therefore, relay spatial information to the hippocampus and as a result, lesions of POR may disturb the spatial firing patterns of hippocampal place cells. To test this hypothesis, the firing of hippocampal CA1 place cells in rats with bilateral N-methyl-D-aspartic acid lesions centered on the POR (n = 83 cells) and rats with sham lesions (n = 77 cells) was compared, while animals foraged freely. The main effect of postrhinal lesions on the basic firing properties of hippocampal place cells was to decrease the coherence of their firing fields. In contrast to the previously reported effects of lesions of neighboring perirhinal cortex, however, there was no effect of postrhinal lesions on the location stability of the fields over time or in the response of these cells to the animal's movement. These data indicate that information originating from the POR has relatively little influence on hippocampal place cell firing while an animal is engaged in foraging behavior. This also suggests that perirhinal and postrhinal cortices make distinct contributions to hippocampal functioning.     

Memory for spatial location and object-place associations are differently processed by the hippocampal formation, parahippocampal areas TH/TF and perirhinal cortex

To clarify the specific contribution of the medial temporal lobe structures in spatial memory, we tested monkeys (Macaca mulatta) with sham operations and with lesions of either the hippocampal formation, areas TH/TF or perirhinal cortex on two versions of the visual-paired comparison task, measuring Spatial Location, and Object-in-Place associations. In the Spatial Location version, the comparison was between two identical objects presented simultaneously in a familiar and a novel location. In the Object-in-Place version, the comparison was between an image consisting of five objects and another image showing the same five objects, but with the position of 2, 3, or 4 of the objects rearranged. Finally, a VPC-Control task was given to animals with hippocampal and perirhinal lesions, in which the comparison was between an image consisting of five objects and another image showing four of the five familiar objects and a new one. Perirhinal lesions yielded no deficit in the Spatial Location task and a deficit in the Object-in-Place task associated with a deficit in the VPC-control task, suggesting that this cortical area does not participate in spatial memory unless the stimuli have overlapping features. Areas TH/TF lesions produced a deficit in both Spatial Location and Object-in-Place tasks, whereas the hippocampal lesions resulted in a deficit of Object-in-Place associations only. The data showed that the hippocampal formation, areas TH/TF, and perirhinal cortex appear to contribute interactively to object and spatial memory processes.     

Identifying cortical inputs to the rat hippocampus that subserve allocentric spatial processes: a simple problem with a complex answer

A consideration of the cortical projections to the hippocampus provides a number of candidate regions that might provide distal sensory information needed for allocentric processing. Prominent among the input regions are the entorhinal cortex, the perirhinal cortex, the postrhinal cortex, and the retrosplenial cortex. A review of these sites reveals the surprising fact that in spite of their anatomical connections, removal of the perirhinal and postrhinal cortices has little or no effect on spatial tasks and hence does not functionally disconnect the hippocampus. Extensive retrosplenial lesions have only mild effects, and even lesions of the entorhinal cortex only partially mimic the effects of hippocampal lesions upon tests of spatial memory. In contrast, studies using c-fos imaging support the involvement of the entorhinal, postrhinal, and retrosplenial cortices, but not the perirhinal cortex. It is argued that there exist multiple aspects of spatial memory, and this is reflected in the multiple routes by which cortical information can reach the hippocampus. One consequence is that lesions in a single site often have surprisingly mild effects on standard spatial tests.     

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.     

Excitotoxic lesion of the perirhinal cortex impairs spatial working memory in a delayed-alternation task

The perirhinal cortex (PRh) is strategically located between the neocortex and memory-related structures such as the entorhinal cortex and the hippocampal formation. The pattern of strong reciprocal connections between these areas, together with experimental evidence that PRh damage induces specific memory deficits, has placed this cortical region at the center of a growing interest for its role in learning and memory mechanisms. The aim of the present study is to clarify the involvement of PRh in learning and retention in a novel experimental model of spatial working memory, the water T-maze. The data show that pre-acquisition neurotoxic PRh lesions caused task-learning deficits. This impairment was observed during the acquisition phase as well as the retrieval phase. On the other hand, a post-acquisition PRh neurotoxic lesion failed to impair the acquisition and the retrieval of the water T-maze task performed 32 day after lesion. These results suggest a possible key role of PRh in the acquisition but not in the retention of a working memory task. Furthermore, these results show that the water T-maze may be a suitable learning paradigm to study different components of learning and memory.     

Visual presentation of novel objects and new spatial arrangements of objects differentially activates the medial temporal lobe subareas in humans

A number of studies in rodents and monkeys report a distinction between the contributions of the hippocampus and perirhinal cortex to memory, such that the hippocampus is crucial for spatial memory whereas the perirhinal cortex has a pivotal role in perception and memory for visual objects. To determine if there is such a distinction in humans, we conducted a functional magnetic resonance imaging study to compare the medial temporal lobe responses to changes in object identity and spatial configurations of objects. We found evidence for the predicted distinction between hippocampal and perirhinal cortical activations, although part of the hippocampus was also activated by identification of novel objects. Additionally, an anterior-posterior activation gradient emerged inside the hippocampus and parahippocampal cortex. The anterior hippocampus, perirhinal cortex and anterior parahippocampal cortex are involved in perception of contextually novel objects, whereas the posterior hippocampus and posterior parahippocampal cortex are involved in processing of novel arrangements of familiar objects. These results demonstrate that there is a functional dissociation between processing of novel object identities and new spatial locations of objects among the subregions of medial temporal lobe structures in humans also.     

Mapping parahippocampal systems for recognition and recency memory in the absence of the rat hippocampus

The present study examined immediate‐early gene expression in the perirhinal cortex of rats with hippocampal lesions. The goal was to test those models of recognition memory which assume that the perirhinal cortex can function independently of the hippocampus. The c‐fos gene was targeted, as its expression in the perirhinal cortex is strongly associated with recognition memory. Four groups of rats were examined. Rats with hippocampal lesions and their surgical controls were given either a recognition memory task (novel vs. familiar objects) or a relative recency task (objects with differing degrees of familiarity). Perirhinal Fos expression in the hippocampal‐lesioned groups correlated with both recognition and recency performance. The hippocampal lesions, however, had no apparent effect on overall levels of perirhinal or entorhinal cortex c‐fos expression in response to novel objects, with only restricted effects being seen in the recency condition. Network analyses showed that whereas the patterns of parahippocampal interactions were differentially affected by novel or familiar objects, these correlated networks were not altered by hippocampal lesions. Additional analyses in control rats revealed two modes of correlated medial temporal activation. Novel stimuli recruited the pathway from the lateral entorhinal cortex (cortical layer II or III) to hippocampal field CA3, and thence to CA1. Familiar stimuli recruited the direct pathway from the lateral entorhinal cortex (principally layer III) to CA1. The present findings not only reveal the independence from the hippocampus of some perirhinal systems associated with recognition memory, but also show how novel stimuli engage hippocampal subfields in qualitatively different ways from familiar stimuli.     

Perirhinal and postrhinal cortices of the rat: Interconnectivity and connections with the entorhinal cortex

The cortical regions dorsally adjacent to the posterior rhinal sulcus in the rat can be divided into a rostral region, the perirhinal cortex, which shares features of the monkey perirhinal cortex, and a caudal region, the postrhinal cortex, which has connectional attributes similar to the monkey parahippocampal cortex. We examined the connectivity among the rat perirhinal (areas 35 and 36), postrhinal, and entorhinal cortices by placing anterograde and retrograde tracers in all three regions. There is a dorsal-to-ventral cascade of connections in the perirhinal and entorhinal cortices. Dorsal area 36 projects strongly to ventral area 36, and ventral area 36 projects strongly to area 35. The return projections are substantially weaker. The cascade continues with the perirhinal to entorhinal connections. Area 35 is more strongly interconnected with the entorhinal cortex, ventral area 36 somewhat less strongly, and dorsal area 36 projects only weakly to the entorhinal cortex. The postrhinal-to-perirhinal connections also follow this general pattern. The postrhinal cortex is more heavily connected with dorsal area 36 than with ventral area 36 and is more heavily connected with area 36 than with area 35. The rostral portion of the postrhinal cortex has the strongest connections with the perirhinal cortex. Like in the monkey, the perirhinal and postrhinal cortices have different patterns of projections to the entorhinal cortex. The perirhinal cortex is preferentially connected with the rostrolateral portion of the entorhinal cortex. The postrhinal cortex projects to a part of this same region but is also connected to caudal and medial portions of the entorhinal cortex. The perirhinal and postrhinal projections to the entorhinal cortex originate in layers III and V and terminate preferentially in layers II and III. J. Comp. Neurol. 391:293–321, 1998. © 1998 Wiley-Liss, Inc.     

Dissociation in retrograde memory for object discriminations and object recognition in rats with perirhinal cortex damage

This experiment examined the effects of perirhinal cortex (PeRh) lesions on rats' retrograde memory for object-discriminations and retrograde object recognition. Rats learned one discrimination problem or five concurrent discrimination problems 4 weeks before surgery, and a new problem or five new problems during the week preceding surgery. Each rat was also familiarized with a sample object in an open field, 5, 3, or 1 week before surgery. PeRh-lesioned rats displayed normal retention of the object discrimination problems, but on a test of novelty preference they showed evidence of impaired recognition of the sample objects. A similar dissociation was observed on anterograde tests of object-discrimination learning and object recognition. The findings suggest the perirhinal cortex plays an essential role in rats' ability to discriminate the familiarity of objects previously encountered either before or after surgery, but this ability may not be essential for accurate performance of a simple object-discrimination task.     

Perirhinal and hippocampal contributions to visual recognition memory can be distinguished from those of occipito-temporal structures based on conscious awareness of prior occurrence

The ability of humans to distinguish consciously between new and previously encountered objects can be probed with visual recognition memory tasks that require explicit old-new discriminations. Medial temporal-lobe (MTL) lesions impair performance on such tasks. Within the MTL, both perirhinal cortex and the hippocampus have been implicated. Cognitive processes can also be affected by past object encounters in the absence of conscious recognition, as in repetition priming tasks. Past functional neuroimaging findings in healthy individuals suggest that even in tasks that require conscious recognition decisions for visual stimuli, posterior cortical structures in the ventral visual pathway distinguish between old and new objects at a nonconscious level. Conclusive evidence that differentiates the neural underpinnings of conscious from nonconscious processes in recognition memory, however, is still missing. In particular, functional magnetic resonance imaging (fMRI) findings for the MTL have been inconsistent towards this end. In the present fMRI study, we tested whether perirhinal and hippocampal contributions to recognition memory can be distinguished from those of occipito-temporal structures in the ventral visual pathway based on the participants' reported conscious awareness of prior occurrence. Images of objects with a large degree of feature overlap served as stimuli; they were selected to ensure an involvement of perirhinal cortex in the present recognition task, based on evidence from past lesion-based research. We found that both perirhinal cortex and occipito-temporal cortex showed a differential old-new response that reflected a repetition-related decrease in activity (i.e., new > old). Whereas in perirhinal cortex this decrease was observed with respect to whether subjects reported objects to be old or new, irrespective of the true item status, in occipito-temporal cortex it occurred in relation to whether objects were truly old or new, irrespective of the participants' conscious reports. Hippocampal responses differed in their exact pattern from those of perirhinal cortex, but were also related to the conscious recognition reports. These results indicate that both perirhinal and hippocampal contributions can be distinguished from those of occipito-temporal structures in the ventral visual pathway based on the participants' reported conscious awareness of prior occurrence.     

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.     

Spared place and object-place learning but limited spatial working memory capacity in rats with selective lesions of the dentate gyrus

We studied the cognitive performance of rats with colchicine-induced lesions of the hippocampal dentate gyrus (DG) on a range of spatial, non-spatial and mixed spatial/procedural tasks. Rats were assigned to three experimental groups receiving large colchicine lesions (7 microg per hippocampus), small colchicine lesions (1.75 microg per hippocampus) or sham lesions. Stereological estimates of cell density indicated that the colchicine treatments induced dose-dependent damage to the DG, while sparing in large part other hippocampal subfields. Remarkably, the behavioural results showed that the colchicine lesions did not affect the performance of rats in an object discrimination task, in an object-place associative task in which a familiar object was displaced from a given position nor in a spontaneous spatial discrimination task performed in the T-maze. However, rats in both lesion groups were severely impaired in a reinforced non-matching-to-position working memory task conducted in the T-maze. Importantly, performance in the working memory task correlated strongly with cell density in the DG but not with cell density in the CA1 and CA3 areas. Only rats with large-lesions showed a transient deficit in a reinforced rule-based conditional discrimination task. These data demonstrated that rats with selective lesions of the DG readily acquire and retain neural representations relative to objects and places but are specifically impaired in their ability to update rapidly and flexibly spatial information that is essential to guide goal-directed actions.     

Dense amnesia in the monkey after transection of fornix, amygdala and anterior temporal stem

The traditional explanation of dense amnesia after medial temporal lesions is that the amnesia is caused by damage to the hippocampus and related structures. An alternative view is that dense amnesia after medial temporal lesions is caused by the interruption of afferents to the temporal cortex from the basal forebrain. These afferents travel to the temporal cortex through three pathways, namely the anterior temporal stem, the amygdala and the fornix-fimbria, and all these three pathways are damaged in dense medial temporal amnesia. In four experiments using different memory tasks, we tested the effects on memory of sectioning some or all of these three pathways in macaque monkeys. In a test of scene-specific memory for objects, which is analogous in some ways to human episodic memory, section of fornix alone, or section of amygdala and anterior temporal stem sparing the fornix, each produced a significant but mild impairment. When fornix section was added to the section of anterior temporal stem and amygdala in this task, however, a very severe impairment resulted. In an object recognition memory task (delayed matching-to-sample) a severe impairment was seen after section of anterior temporal stem and amygdala alone, with or without the addition of fornix section; this impairment was significantly more severe than that which was seen in the same task after amygdalectomy leaving the temporal stem intact, with or without fornix section. Animals with combined section of anterior temporal stem, amygdala and fornix were also impaired in object-reward association learning. However, the retention of pre-operatively acquired object-reward associations was at a high level. These results show that the pattern of impairments after section of anterior temporal stem, amygdala and fornix in the monkey, leaving hippocampus intact, resembles human dense amnesia and is different from the effects of hippocampal lesions in the monkey.