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.     

Qualitatively different modes of perirhinal–hippocampal engagement when rats explore novel vs. familiar objects as revealed by c‐Fos imaging

Expression of the immediate‐early gene c‐fos was used to test for different patterns of temporal lobe interactions when rats explore either novel or familiar objects. A new behavioural test of recognition memory was first devised to generate robust levels of novelty discrimination and to provide a matched control condition using familiar objects. Increased c‐Fos activity was found in caudal but not rostral portions of the perirhinal cortex (areas 35/36) and in area Te2 in rats showing object recognition, i.e. preferential exploration of novel vs. familiar objects. The findings are presented at a higher anatomical resolution than previous studies of immediate‐early gene expression and object novelty and, crucially, provide the first analyses when animals are actively discriminating the novel objects. Novel vs. familiar object comparisons also revealed altered c‐Fos patterns in hippocampal subfields, with relative increases in CA3 and CA1 and decreases in the dentate gyrus. These hippocampal changes match those previously reported for the automatic coding of object–spatial associations. Additional analyses of the c‐Fos data using structural equation modelling indicated the presence of pathways starting in the caudal perirhinal cortex that display a direction of effects from the entorhinal cortex to the CA1 field (temporo‐ammonic) when presented with familiar objects, but switch to the engagement of the direct entorhinal cortex pathway to the dentate gyrus (perforant) with novel object discrimination. This entorhinal switch provides a potential route by which the rhinal cortex can moderate hippocampal processing, with a dynamic change from temporo‐ammonic (familiar stimuli) to perforant pathway (novel stimuli) influences.     

Detecting and discriminating novel objects: The impact of perirhinal cortex disconnection on hippocampal activity patterns

Perirhinal cortex provides object‐based information and novelty/familiarity information for the hippocampus. The necessity of these inputs was tested by comparing hippocampal c‐fos expression in rats with or without perirhinal lesions. These rats either discriminated novel from familiar objects (Novel‐Familiar) or explored pairs of novel objects (Novel‐Novel). Despite impairing Novel‐Familiar discriminations, the perirhinal lesions did not affect novelty detection, as measured by overall object exploration levels (Novel‐Novel condition). The perirhinal lesions also largely spared a characteristic network of linked c‐fos expression associated with novel stimuli (entorhinal cortex→CA3→distal CA1→proximal subiculum). The findings show: I) that perirhinal lesions preserve behavioral sensitivity to novelty, whilst still impairing the spontaneous ability to discriminate novel from familiar objects, II) that the distinctive patterns of hippocampal c‐fos activity promoted by novel stimuli do not require perirhinal inputs, III) that entorhinal Fos counts (layers II and III) increase for novelty discriminations, IV) that hippocampal c‐fos networks reflect proximal‐distal connectivity differences, and V) that discriminating novelty creates different pathway interactions from merely detecting novelty, pointing to top‐down effects that help guide object selection. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

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.     

Finding and Not Finding Rat Perirhinal Neuronal Responses to Novelty

There is much evidence that the perirhinal cortex of both rats and monkeys is important for judging the relative familiarity of visual stimuli. In monkeys many studies have found that a proportion of perirhinal neurons respond more to novel than familiar stimuli. There are fewer studies of perirhinal neuronal responses in rats, and those studies based on exploration of objects, have raised into question the encoding of stimulus familiarity by rat perirhinal neurons. For this reason, recordings of single neuronal activity were made from the perirhinal cortex of rats so as to compare responsiveness to novel and familiar stimuli in two different behavioral situations. The first situation was based upon that used in “paired viewing” experiments that have established rat perirhinal differences in immediate early gene expression for novel and familiar visual stimuli displayed on computer monitors. The second situation was similar to that used in the spontaneous object recognition test that has been widely used to establish the involvement of rat perirhinal cortex in familiarity discrimination. In the first condition 30 (25%) of 120 perirhinal neurons were visually responsive; of these responsive neurons 19 (63%) responded significantly differently to novel and familiar stimuli. In the second condition eight (53%) of 15 perirhinal neurons changed activity significantly in the vicinity of objects (had “object fields”); however, for none (0%) of these was there a significant activity change related to the familiarity of an object, an incidence significantly lower than for the first condition. Possible reasons for the difference are discussed. It is argued that the failure to find recognition‐related neuronal responses while exploring objects is related to its detectability by the measures used, rather than the absence of all such signals in perirhinal cortex. Indeed, as shown by the results, such signals are found when a different methodology is used. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

False positives to confusable objects predict medial temporal lobe atrophy

Animal models agree that the perirhinal cortex plays a critical role in object recognition memory, but qualitative aspects of this mnemonic function are still debated. A recent model claims that the perirhinal cortex is required to recognize the novelty of confusable distractor stimuli, and that damage here results in an increased propensity to judge confusable novel objects as familiar (i.e., false positives). We tested this model in healthy participants and patients with varying degrees of perirhinal cortex damage, i.e., amnestic mild cognitive impairment and very early Alzheimer's disease (AD), with a recognition memory task with confusable and less confusable realistic object pictures, and from whom we acquired high‐resolution anatomic MRI scans. Logistic mixed‐model behavioral analyses revealed that both patient groups committed more false positives with confusable than less confusable distractors, whereas healthy participants performed comparably in both conditions. A voxel‐based morphometry analysis demonstrated that this effect was associated with atrophy of the anteromedial temporal lobe, including the perirhinal cortex. These findings suggest that also the human perirhinal cortex recognizes the novelty of confusable objects, consistent with its border position between the hierarchical visual object processing and medial temporal lobe memory systems, and explains why AD patients exhibit a heightened propensity to commit false positive responses with inherently confusable stimuli. © The Authors. Hippocampus Published by Wiley Periodicals, 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 cortex neuronal activity related to long-term familiarity memory in the macaque

Lesion studies suggest that the perirhinal cortex plays a role in object recognition memory. To analyse its role, the activity of single neurons in the perirhinal cortex was recorded in three rhesus monkeys (Macaca mulatta) performing a delayed matching-to-sample task with up to three intervening stimuli. A set of familiar visual stimuli was used. Some neurons had activity related to working memory, in that they responded more to the sample than to the match image within a trial, as shown previously. However, when a novel set of stimuli was introduced, the neuronal responses were on average only 47% of the magnitude of the responses to the familiar set of stimuli. Moreover, it was shown in eight different replications in three monkeys that the responses of the perirhinal cortex neurons gradually increased over hundreds of presentations of the new set of (initially novel) stimuli to become as large as with the already familiar stimuli. The mean number of 1.3-s presentations to induce this effect was 400 occurring over 7-13 days. These results show that perirhinal cortex neurons represent the very long-term familiarity of visual stimuli. A representation of the long-term familiarity of visual stimuli may be important for many aspects of social behaviour, and part of the impairment in temporal lobe amnesia may be related to the difficulty of building representations of the degree of familiarity of stimuli.     

A role for the CAMKK pathway in visual object recognition memory

The role of the CAMKK pathway in object recognition memory was investigated. Rats' performance in a preferential object recognition test was examined after local infusion into the perirhinal cortex of the CAMKK inhibitor STO-609. STO-609 infused either before or immediately after acquisition impaired memory tested after a 24 h but not a 20-min delay. Memory was not impaired when STO-609 was infused 20 min after acquisition. The expression of a downstream reaction product of CAMKK was measured by immunohistochemical staining for phospho-CAMKI(Thr177) at 10, 40, 70, and 100 min following the viewing of novel and familiar images of objects. Processing familiar images resulted in more pCAMKI stained neurons in the perirhinal cortex than processing novel images at the 10- and 40-min delays. Prior infusion of STO-609 caused a reduction in pCAMKI stained neurons in response to viewing either novel or familiar images, consistent with its role as an inhibitor of CAMKK. The results establish that the CAMKK pathway within the perirhinal cortex is important for the consolidation of object recognition memory. The activation of pCAMKI after acquisition is earlier than previously reported for pCAMKII.     

Differential contributions of hippocampus, amygdala and perirhinal cortex to recognition of novel objects, contextual stimuli and stimulus relationships

This study examined contributions of the hippocampus, amygdala and perirhinal cortex to memory. Rats performed a cover task, and changes to stimulus identity or relationships were used to test incidental memory. Rats with hippocampal damage showed deficient responses to relationship changes, but demonstrated knowledge of the position and identity of the target object. They over-focused on the most predictive stimuli, and failed to acquire associations including surrounding cues. Rats with amygdala damage responded to changes involving distal stimuli, and showed deficient responses to novel objects and object relationships. These rats may be highly reliant on relational representations, resulting in a reduced salience for individual novel stimuli. Rats with perirhinal damaged responded to novel stimulus relationships and distal cues, but showed deficient responses to novel objects, suggesting that changes in identity had reduced salience. Implications for declarative and conjunctive hippocampal theories are discussed.     

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.     

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.     

Impaired object recognition with increasing levels of feature ambiguity in rats with perirhinal cortex lesions

It has been proposed that the perirhinal cortex is involved in the representation of the characteristics of objects. In particular it has been proposed that it is critical for discriminating between stimuli which have some features in common and thus it has been described as being involved in resolving feature ambiguity. The present experiments demonstrate that lesions of perirhinal cortex in the rat cause impairments in object recognition which increase with the level of feature ambiguity present in the discrimination. Although increasing feature ambiguity increases the overall difficulty of discriminations, lesions of the perirhinal cortex resulted in a disproportionate impairment when feature ambiguity was increased and not when the difficulty of the discrimination was increased through enlargement of the stimulus set. The present experiments therefore support the view that perirhinal cortex in the rat is critical to resolution of feature ambiguity in stimulus specification.     

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.     

Perception and conception: temporal lobe activity during complex discriminations of familiar and novel faces and objects

Recent studies indicate that medial-temporal lobe (MTL) damage, either from focal lesions or neurodegenerative disease (e.g., semantic dementia), impairs perception as well as long-term declarative memory. Notably, however, these two patient groups show different performance for meaningful versus unfamiliar stimuli. In amnesics with nonprogressive MTL lesions, the use of meaningful stimuli, compared with unfamiliar items, boosted discrimination performance. In semantic dementia, a condition characterized by progressive deterioration of conceptual knowledge in the context of anterolateral temporal lobe damage, performance for meaningful stimuli was equivalent to that for unfamiliar items. To further investigate these findings, we scanned healthy volunteers while they performed odd-one-out discriminations involving familiar (i.e., meaningful/famous) and unfamiliar (i.e., novel) objects and faces and a baseline task of size oddity. Outside the scanner, volunteers' recognition memory was assessed. We found above baseline activity in the perirhinal cortex and hippocampus for all object and face discriminations and above baseline activity in the temporal pole for all face discriminations. The comparison of meaningful, relative to novel, faces and objects, revealed increased activity in the perirhinal cortex and hippocampus. In the temporal pole, we also found activity related to meaningfulness for faces but not for objects. Importantly, these meaningfulness effects were evident even for discriminations that were not subsequently well remembered, suggesting that the difference between meaningful and novel stimuli reflects perceptual or conceptual processes rather than solely incidental encoding into long-term memory. The results provide further evidence that the MTL is recruited during complex perceptual discrimination and additionally suggest that these structures are recruited in semantic processing of objects and faces.     

A Preferential Role for Ventromedial Prefrontal Cortex in Assessing “the Value of the Whole” in Multiattribute Object Evaluation

Everyday decision-making commonly involves assigning values to complex objects with multiple value-relevant attributes. Drawing on object recognition theories, we hypothesized two routes to multiattribute evaluation: assessing the value of the whole object based on holistic attribute configuration or summing individual attribute values. In two samples of healthy human male and female participants undergoing eye tracking and functional magnetic resonance imaging (fMRI) while evaluating novel pseudo objects, we found evidence for both forms of evaluation. Fixations to and transitions between attributes differed systematically when the value of pseudo objects was associated with individual attributes or attribute configurations. Ventromedial prefrontal cortex (vmPFC) and perirhinal cortex were engaged when configural processing was required. These results converge with our recent findings that individuals with vmPFC lesions were impaired in decisions requiring configural evaluation but not when evaluating the sum of the parts. This suggests that multiattribute decision-making engages distinct evaluation mechanisms relying on partially dissociable neural substrates, depending on the relationship between attributes and value.SIGNIFICANCE STATEMENT Decision neuroscience has only recently begun to address how multiple choice-relevant attributes are brought together during evaluation and choice among complex options. Object recognition research makes a crucial distinction between individual attribute and holistic/configural object processing, but how the brain evaluates attributes and whole objects remains unclear. Using fMRI and eye tracking, we found that the vmPFC and the perirhinal cortex contribute to value estimation specifically when value was related to whole objects, that is, predicted by the unique configuration of attributes and not when value was predicted by the sum of individual attribute values. This perspective on the interactions between subjective value and object processing mechanisms provides a novel bridge between the study of object recognition and reward-guided decision-making.     

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.     

Hippocampal output area CA1 broadcasts a generalized novelty signal during an object‐place recognition task

Animals display an innate preference for novelty, spending more time exploring both novel objects and familiar objects in novel locations. This increase in exploration is thought to allow the animal to gather the information necessary to encode new experiences. Despite extensive evidence that increased exploration following spatial change requires the hippocampus, the pattern of hippocampal activity that supports this behavior remains unknown. We examined activity in hippocampal output area CA1 and one synapse upstream in area CA3 while freely behaving rats performed an object‐place recognition task. We found that the presence of novelty substantially altered activity in CA1, but not in CA3. During exploration of displaced familiar objects and novel objects in unexpected locations, CA1 place cells showed robust increases in firing rate. These firing rate increases persisted during sharp wave ripples, when place cell representations of previous experiences are replayed. Unexpectedly, increases in CA1 activity were not spatially restricted to regions of the environment that underwent change, indicating a generalized novelty signal. We suggest that hippocampal area CA1 broadcasts the presence of novelty, rather than signaling what is novel, and simultaneously becomes more plastic, allowing the integration of new information into previously stored memories. © 2014 Wiley Periodicals, Inc.     

Elemental and configural visual discrimination learning following lesions to perirhinal cortex in the rat.

Rats were tested in a series of two-choice visual discrimination tasks in a computer-controlled testing apparatus. The discriminations used a range of discriminanda, which varied in complexity. The discriminations included relatively simple form discriminations, more complex form discriminations and discriminations between compound stimuli that shared many features. It was found that rats with perirhinal cortex lesions were unimpaired in all discriminations except those that involved the compound stimuli with overlapping features. Using these stimuli, rats with perirhinal cortex lesions were unimpaired when the stage of learning did not necessitate discriminating stimuli on the basis of more than one feature. However, when efficient performance of the task needed the configuration of more than one feature to be taken into account, perirhinal lesioned rats were impaired. These results are interpreted as revealing the role of the perirhinal cortex in providing multifeature information about the properties of visual objects.     

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.