Perirhinal Cortex: Neural Representations

Perirhinal Cortex: Neural Representations

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Perirhinal Cortex: Neural Representations M W Brown and M Eldridge, University of Bristol, Bristol, UK ã 2009 Elsevier Ltd. All rights reserved.

Introduction This article primarily concerns what is known of the neural representations in the perirhinal cortex that relate to the identification of stimuli and their associations, and to judgments about prior occurrence. After some background anatomical information, a summary is given of the results of ablation experiments that indicate the functions of the perirhinal cortex. These functions include roles in perception, particularly for object-related information, and in memory, notably but not exclusively recognition memory and paired-associate learning. A brief overview of recent attempts to find synaptic plastic substrates for the memory functions of the perirhinal cortex is also included. The article does not include the results of human brain imaging, except when mentioned in passing when of particular pertinence.

Perirhinal Cortex In the last 20 years, the perirhinal cortex has received increasing scientific attention because of its important roles in perception and learning. The perirhinal cortex is located in the anterior and medial portion of the inferior aspect of the medial temporal lobe of primates (Figure 1). Although in the past there has been considerable variation in the definition of the boundaries of the perirhinal cortex, there is now broad agreement that in the monkey it extends immediately lateral to the full extent of the rhinal sulcus and includes the cortex corresponding to both areas 35 and 36 of Brodmann. In the rat, the perirhinal cortex (areas 35 and 36) is located on either side of the caudal part of the rhinal sulcus. The precise extent of the corresponding region in the human brain remains uncertain. Overview of Connections

The perirhinal cortex is highly interconnected with many other brain regions. It receives highly processed sensory information of all modalities and provides an important route for transferring information to and from the hippocampus. Its position at the top of the sensory processing hierarchy and at the gateway to the limbic system means that it is ideally placed to play important roles in sensory perception and memory. Once a stimulus may be identified, the

perirhinal cortex processes aspects of its past history and associations. In the monkey, the most prominent input arises from the inferior temporal cortex (unimodal visual areas TE and TEO), although it also receives input from the auditory, olfactory, and somatosensory association areas of cortex (Figure 1(a)). Further substantial inputs arise from polymodal association areas, including the prefrontal and cingulate cortices, entorhinal cortex (and, thereby, indirectly from the hippocampus), parahippocampal cortex (areas TH and TF), and cortex of the dorsal bank of the superior temporal sulcus. Perirhinal outputs largely mirror their inputs with strong connections to the entorhinal cortex (again, therefore indirectly connecting to the hippocampus), parahippocampal gyrus, prefrontal cortex, and unimodal and polymodal sensory association areas. The perirhinal cortex also has reciprocal connections with the amygdala and thalamus (mediodorsal and midline nuclei) and sends outputs to the tail of the caudate nucleus and ventral putamen. In addition, it receives input from brain stem monaminergic cell groups and cholinergic input from the basal forebrain. A parallel, similarly widespread pattern of connectivity is found in the rat (Figure 1(b)). The perirhinal cortex is juxtallocortex, cortex of a type that is transitional between the neocortex and the archicortex and paleocortex of the hippocampal and entorhinal regions. Unlike the neocortex, area 35 lacks an inner granular layer (layer 4) and this layer is very narrow in area 36. Again, in contrast to the neocortex, the perirhinal cortex does not have an obviously columnar organization. Overview of Functions

There is a very large body of evidence indicating that the perirhinal cortex plays a central role in certain aspects of recognition memory. The evidence is clearest for familiarity discrimination for single items. There is also much evidence of a role in perceptual functions, although this role is not universally accepted. In addition, the perirhinal cortex is involved in other types of memory linked to learned associations made with items (notably reinforcement learning and paired-associate learning). Details of the neuronal responses related to such functions are given later. Overall, ablation studies provide strong evidence for a role for the perirhinal cortex in object identification, although some findings have challenged this conclusion. Monkeys with perirhinal lesions have been shown to be impaired in a series of tasks designed to test object identification. Thus, there is

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Figure 1 Position and some major connections of the perirhinal and neighboring cortices: (a) in the monkey (ventral view); (b) in the rat (lateral view). Below each brain image, routes are shown by which sensory information may reach the perirhinal cortex and the connections from the perirhinal cortex to the hippocampus. The arrow thickness indicates the relative size of the projections. 35 and 36, perirhinal cortex areas; C, caudal; D, dorsal; DG, dentate gyrus; EC, entorhinal cortex; POR, postrhinal cortex; R, rostal; rs, rhinal sulcus; STG, superior temporal gyrus; STS, superior temporal sulcus; SUBIC, subicular complex; TE, TEO, Te2, Te3, visual association cortex areas; TH and TF, parahippocampal cortex areas; STSV, superior temporal sulcus ventral. From Witter MP, Groenewegen HJ, Lopes da Silva FH, and Lohman AHM (1989) Functional organization of the extrinsic and intrinsic circuitry of the parahippocampal region. Progress in Neurobiology 33: 161–253.

impairment in perceptual oddity tasks, in which the odd one of a set of images must be chosen; tasks requiring object identification from different views or partial views of the same object; and tasks in which an object previously experienced only by touch must be selected using vision. In addition, monkeys with perirhinal lesions are particularly impaired on tasks requiring discrimination between visual stimuli with a high level of feature ambiguity. It has been argued that, when perceptual deficits have not been found, the tasks may have been solved using discrimination based on individual features rather than whole objects as entities in themselves. When test has been made, the evidence indicates that it is possible to dissociate the mnemonic and perceptual functions of the perirhinal cortex. The ability to recognize the novelty or familiarity of individual items is an important aspect of recognition memory. Such recognition memory relies not

only on identification (perception) but also on judgment of prior occurrence (memory). The involvement of the perirhinal cortex in the judgment of prior occurrence for individual items is widely agreed on. In one view it forms part of a unified medial temporal lobe memory system; an alternative view is that its role is differentiable from that of the hippocampus (the hippocampus is concerned with recollective, complex associational, and spatial aspects of recognition memory, whereas the perirhinal cortex is concerned with single-item familiarity discrimination and simple associations). The pattern of impairments after perirhinal cortex lesions has been doubly dissociated from neighboring areas such as the middle temporal gyrus, which corresponds to the dorsal part of visual area TE; hippocampus; and amygdala. Thus, whereas lesions of the middle temporal gyrus impair color discrimination but spare recognition memory, lesions of the perirhinal cortex impair object

Perirhinal Cortex: Neural Representations

recognition memory but not color discrimination. Further, in both monkeys and rats, hippocampal or fornix lesions lead to marked impairment in spatial tasks with relatively mild or no effect on recognition memory, whereas perirhinal cortex lesions result in the opposite pattern of deficits. Amygdalar lesions impair food preference learning but not delayed matching to sample with infrequently repeated stimuli, whereas perirhinal lesions result in the opposite pattern of impairment. These double dissociations demonstrate that the perirhinal cortex is necessary for visual recognition memory even when functionally isolated from structures to which it is connected both in the ventral visual processing stream and in the medial temporal lobe. In addition to these results for visual tasks, perirhinal lesions impair tactile recognition memory in monkeys and olfactory recognition memory in rats, although auditory recognition memory seems to be spared. Ablation studies also indicate that the perirhinal cortex is necessary for making certain (although not all) associations involving objects. Such work has shown that perirhinal lesions impair tasks involving associations of objects with other objects, odors, tastes, and tactile or auditory information. Such associations may also be abstract. Monkeys with perirhinal lesions are impaired in a task in which they must respond to a sequence of discriminations to obtain a reward; the results suggest a role of the perirhinal cortex in forming associations between objects and position in a series or proximity to reward in a sequence. In addition, perirhinal lesions in rats produce impairments in conditioned avoidance tasks, notably contextual fear conditioning; the impairment relates to processing of the conditioned stimulus rather than the spatial context of the task.

Neural Responses Related to Stimulus Identification and Linked Associational Functions Stimulus Identification

Visual information processing is largely divided between two pathways: a dorsal visual stream primarily associated with spatial perception and sensorimotor output, and a ventral visual stream primarily associated with object identification. The latter pathway runs in the posterior–anterior direction through successive processing areas from the primary visual cortex, via area V4, to the inferior temporal cortex, including area TE, which supplies strong projections to the perirhinal cortex. Electrophysiological evidence indicates that neurons in the anterior regions of the ventral visual stream code more complex visual

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representations than do neurons in the more caudal regions. The perirhinal cortex can be considered to be at the top of the hierarchy of the processing regions, and it has been suggested that it is necessary for the perception of objects as entities as opposed to the identification of their individual features. Most studies of neuronal response properties concerning stimulus identification in the anterior temporal lobe have concerned visual stimuli and the inferior temporal cortex. Although it is clear that some such studies have included perirhinal neurons, the sensory response properties of perirhinal neurons have rarely been distinguished from those of other anterior inferior temporal neurons. (Past uncertainties about the boundaries of the perirhinal cortex have not assisted in making such distinctions.) Indeed, only a few distinctions have been described between the responses of neurons in anterior TE and in the perirhinal cortex, and these chiefly relate to associative or mnemonic properties (see the sections titled ‘Correlates of long-term memory and learned associations of frequently repeated stimuli,’ ‘Neuronal responses related to paired-associate learning,’ and ‘Neural responses related to judgment of prior occurrence’). In conscious monkeys, typically more than half of recorded perirhinal neurons are reported as being visually responsive. When reported, more than half of these visually responsive neurons respond to the majority of complex stimuli tested, although by no means with equal vigor to every stimulus. Nevertheless, some perirhinal neurons respond only to restricted classes of stimuli, such as faces or stimuli of a particular color. Accordingly, the responses of perirhinal neurons signal information about the physical features of visual stimuli. It has been reported that a higher proportion of neurons are stimulus selective in the perirhinal cortex than in area TE. Unfortunately, in spite of the suggestion that the perirhinal cortex is critical to object identification, no recordings examining this issue have included the perirhinal cortex. As in TE, when single stimuli are viewed, perirhinal receptive fields are large and may encompass a region extending into both visual hemifields. There has been little study of perirhinal responses in relation to stimulus constancy, but again evidence indicates that it is similar to that found in TE, with similar responses being found when stimuli are shown across different positions or at different sizes. Although some tendency for clustering of similar perirhinal responses has been reported, there is no strong anatomical or physiological evidence that the perirhinal cortex has a columnar organization. Anatomical connectivity indicates that the perirhinal cortex is a polymodal area, yet there is still

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no published major study of polymodal perirhinal responses (although commonly perirhinal neuronal activity in both monkeys and rats is found to vary with all aspects of the behavioral task during which recordings are made and not merely to the presentation of sensory stimuli). Studies of neuronal responses in rats indicate that the responses of perirhinal neurons encode stimulus-specific visual and olfactory information but do not encode detailed spatial information.

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Correlates of Attention and Short-Term Memory

Correlates of Long-Term Memory and Learned Associations of Frequently Repeated Stimuli

A number of different types of long-term change have been reported in the responses of perirhinal neurons trained on different tasks in which stimuli are seen many times and associated with reward. The findings emphasize the plasticity of the perirhinal cortex in relation to different processing demands. This plasticity and adaptation to specific learning situations may explain what are, at first, apparent inconsistencies in some reported findings. Let us review information available about perirhinal neuronal responses related to examples of such long-term changes and learned

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Two types of neuronal activity that occur in many brain regions in relation to attentional and short-term memory tasks are also found in the perirhinal cortex: response suppression and delay activity. When monkeys are trained to select a target stimulus presented among nontarget stimuli, neural responses to the behaviorally irrelevant stimuli are suppressed, whereas the response to the behaviorally relevant target stimulus remains unchanged (see Figure 2). This change in responsiveness reflects a neural mechanism encoding the learned salience of a given stimulus. Delay activity is found during the interval between stimulus presentations in short-term or working memory tasks such as delayed matching to sample. In such tasks, a stimulus is presented in an acquisition phase and, after a possibly variable but relatively brief (<1 min) delay interval, there follows a choice phase in which a decision must be made on the basis of the stimulus presented in the acquisition phase. For many perirhinal neurons, the activity in the delay period carries information concerning the stimulus presented during the acquisition phase (i.e., it is stimulus specific). Such activity maintains a representation of that stimulus online and may be a correlate of the stimulus being held in mind. In certain cases, the response of the neuron to the stimulus may then be enhanced when it is repeated on match trials. Again, the activity change shows that perirhinal activity is modulated by attentive and mnemonic factors.

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Figure 2 Differential delay activity and response suppression: (a) experiment design; (b) graph of population response for 22 monkey inferior temporal (including perirhinal) neurons. For each neuron, one stimulus that evoked a strong response and one that evoked a weak response were chosen. As shown in (a), either stimulus was presented as the cue (first bar on time scale in (b)), and after a delay, the cue stimulus had to be selected (by making a saccadic eye movement to it; second bar in (b)) from a display of both stimuli in the choice phase. Thus, whichever stimulus was the cue, the display during the choice phase was of both stimuli. The activity was averaged for each neuron for trials using the good and poor stimuli and then across neurons to produce a population response. Note that the delay activity between the end of the cue stimulus presentation and the appearance of the choice stimuli is greater for the good than for the poor stimuli. Also note that the response to the display of both stimuli during the choice phase is rapidly suppressed when the poor stimulus is the target. Thus, across the population of neurons only those that respond strongly to the target are strongly active during the delay and the choice phases. The responses of other neurons are rapidly (
200 ms) suppressed in the choice phase. * indicates the start of saccadic eye movement (note that this is later than start of suppression). From Desimone R (1996) Neural mechanisms for visual memory and their role in attention. Proceedings of the National Academy of Sciences of the United States of America 93: 13494–13499.

associations that are concerned with frequently presented stimuli. First, the response change that has been reported most often is found in delayed matching tasks using small stimulus sets in which the stimuli are frequently repeated. In such experiments, the response to a stimulus changes (becoming variously either stronger or weaker for different neurons) according to whether it occurs as the choice stimulus on a match or mismatch trial. Such response changes establish that perirhinal neuronal responses can be determined

Perirhinal Cortex: Neural Representations

Neuronal Responses Related to Paired-Associate Learning Correlates of the Sequential Pairing of Stimuli

Both recording and lesion experiments in monkeys have established the importance of the perirhinal cortex for visual paired-associate learning. In this task, the animal learns across many trials to associate arbitrarily assigned pairs of complex visual stimuli, so that, after a delay following an initial (cue) stimulus presentation, the animal selects (e.g., by touching) the other stimulus of the pair (its paired associate). Two

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neural substrates of this form of associative learning have been identified in perirhinal cortex: (1) stimulusspecific delay activity and (2) the occurrence of strong responses to both of the stimuli that have been paired (such paired responsiveness occurs more frequently than expected by chance; see Figure 3). Thus, the learning results in single neurons that can code for both of a pair of stimuli; that is, information from both stimuli has converged on individual perirhinal neurons. Such pairs have not been found in TE; there, neurons are responsive only to individual stimuli. Although sensory information is fed forward from TE to the perirhinal cortex, memory retrieval is fed

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by more than the physical characteristics of the presented stimulus; the responses can also reflect the behavioral context in which the stimulus is presented. In one description, such responses therefore contain information about the learned associations of the stimulus and, hence, may be said to convey information concerning the behavioral meaning of the stimulus. In another description, the responses contain information about the recent occurrence or nonoccurrence of the stimulus and, hence, are related to a temporal rather than any more abstract context and therefore to judgment of prior occurrence. Second, sequence learning provides stronger evidence that perirhinal neurons can respond on the basis of the behavioral meaning of a stimulus (its abstract associations) rather than solely according to the physical characteristics of the stimulus. Consider findings from experiments in which a monkey has been trained in a task in which different length sequences of stimulus presentations occur before the availability of reward. The animal learns that certain stimuli signal the position in the sequence (e.g., first or last). Certain perirhinal neurons respond according to the position in the sequence leading to reward that is signaled by a stimulus rather than according to the physical attributes of the particular stimulus. This type of response to a stimulus’ implication rather than its appearance was not observed for neurons in TE. Recent results indicate that the development of such perirhinal responses can be blocked by local infusion of an oligonucleotide that interrupts dopaminergic transmission. Third, when the same stimuli are used repeatedly for tens or hundreds of trials and the animal must attend to these stimuli to gain reward, the responses to these highly familiar stimuli show a gradual increase in magnitude. This finding (along with others) indicates that perirhinal neuronal representations of stimuli are plastic even in the adult. They adapt to experience, presumably to optimize the processing of behaviorally important information.

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Figure 3 Example stimulus-selective neuronal response for learned paired-associate stimuli: (a) Raster display and peristimulus time histogram for the trials; (b) mean (þ SEM) discharge rates during the cue period (60–320 ms from the cue onset) for each of 12 learned pairs of stimuli. The example monkey perirhinal neuron was strongly activated by both members of a particular pair of associated stimuli. In contrast, its responses were negligible when presented with members of any of the 11 other stimulus pairs. In (a) the response to the preferred stimulus as the cue stimulus is indicated by the thick black line and the response to its paired associate is indicated by the gray line. The thin black line denotes the averaged responses in the trials in which other stimuli were used as the cue. The horizontal gray bar indicates the cue presentation period. Note the continuing (delay) activity for the preferred stimuli after the cue stimulus is turned off. Note in (b) that the responses to both members of pair 4 are much greater than the response to any member of the other 11 paired associates. PCI, pair-coding index. Reproduced from Naya Y, Yoshida M, and Miyashita Y (2003) Forward processing of long-term associative memory in monkey inferotemporal cortex. Journal of Neuroscience 23: 2861–2871, copyright ã 2003, with permission from the Society for Neuroscience.

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back from the perirhinal cortex to TE. Figure 4 illustrates the firing rate of a perirhinal neuron and that of a neuron from area TE in response to the stimulus to which they both respond preferentially. Memoryretrieval signals appear first in the perirhinal cortex, after which TE neurons are gradually recruited to represent the sought target. It has been established that the perirhinal changes involve and are dependent on the immediate early gene Zif268. Anatomical tracing indicates that paired-associate learning is associated with changes in the pattern of axonal connectivity between TE and the perirhinal cortex. Such alterations in the functional architecture of the perirhinal cortex may facilitate the reactivation of newly formed object representations and, moreover, may form a neural basis for the process of memory retrieval.

representation of the pair appears to have become more differentiated. This differential response develops across trials in which the two stimuli are paired when the pairing is repeated many times. The alteration of the representation of the pair of stimuli in the cortex is presumably a result of the altered effectiveness of interconnections within the cortex. Moreover, measured across a range of stimuli, two neighboring perirhinal neurons tend to respond more similarly if the stimuli are familiar (presented many times on the previous day) than if they are relatively novel (not seen before the day of recording). The finding suggests that as a result of repeated experience perirhinal neurons that respond similarly to particular stimuli tend to become grouped.

Correlates of the Simultaneous Pairing of Stimuli

Neural Responses Related to Judgment of Prior Occurrence

In contrast to findings for paired stimuli presented sequentially, when pairs of stimuli are shown simultaneously, inferior temporal (including perirhinal) neuronal responses to the stimuli shown individually appear to be unchanged even after many such pairings. However, responses to the stimuli shown as a pair are slowly changed by learning. In such experiments, the animal learns to respond (saccade) to whichever one of the two stimuli has been previously shown as a cue. After training, when both stimuli are displayed simultaneously the neuronal response is enhanced if the animal must saccade to the stimulus to which the neuron responds better, but it is reduced when the neuron must respond to the stimulus to which it responds more weakly. Thus, the cortical

In addition to the changes detailed in previous sections, the responses of certain neurons in the perirhinal and neighboring cortices signal information concerning the previous occurrence of infrequently encountered stimuli. Most strikingly, responses of such neurons are strong for stimuli that have not been seen previously and weak once these stimuli appear again. We term such responses repetition sensitive. They have characteristics necessary for making judgments of prior occurrence, and they have been related to the recency and familiarity discrimination aspects of recognition memory. These response changes have also been called stimulus-specific adaptation and response suppression; however, these phrases carry implications concerning the underlying mechanisms or functionality of the changes that cannot

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Figure 4 Neuronal activity during paired associate memory retrieval in monkey for a neuron: (a) in the perirhinal cortex (A36); (b) in area TE. Shown for each neuron are raster displays and peristimulus time histograms for trials in which the preferred stimulus (upper graphs) or its paired associate (lower graphs) were presented as the cue stimulus. The black lines indicate responses to the preferred cue stimulus (upper graphs) or its paired associate (lower graphs); the gray lines indicate the mean responses to all 24 stimuli. Note that for the paired associate of the preferred stimulus, the delay activity in the perirhinal cortex is high from the time that stimulus presentation ends, whereas there is a delay before such activity appears in TE. The delay activity in TE is dependent on a signal fed back from the perirhinal cortex. From Naya Y, Yoshida M, and Miyashita Y (2001) Backward spreading of memory retrieval signal in primate temporal cortex. Science 291: 661–664.

Perirhinal Cortex: Neural Representations

currently be justified. In particular, to date no evidence has been found that the response reductions (decrements) are dependent on an active suppressive or inhibitory mechanism. Moreover, the term response suppression is used in relation to attentional processes; the use of the same term for a different process involved in familiarity discrimination is inappropriate. Most information about repetition-sensitive responses comes from monkeys and visual stimulation. Next, we present the characteristics of these neuronal responses, with generalizations across modalities and species (discussed later).

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Response Characteristics

Up to 25% of perirhinal neurons have a reduced response to familiar (compared to novel) visual stimuli, representing approximately 60% of the visually responsive neurons (Figure 5). Note that such change divides perirhinal neurons into two classes: those that have repetition-sensitive responses signaling information concerning even a single prior occurrence of a stimulus and the remainder that do not. The overall tendency to response reduction on repetition is sufficiently large that it is readily seen in population

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b Figure 5 Example of repetition-sensitive monkey perirhinal neuronal response: (a) first appearance of ten initially novel pictures; (b) repeat appearance of the ten pictures. Responses are stronger to first than for the repeat appearances. One stimulus was shown (bars above the histograms) on each trial of a serial recognition memory task. To be rewarded, the monkey had to press left (L) for the first appearance and right (R) for a repeat appearance of the stimulus. The first and repeat trials have been grouped in this display, but were intermixed when presented. Controls (not shown) established that the difference in activity was not due to the different behavioral responses. Note also that the neuron does not respond equally strongly to the first presentations of the ten different pictures; that is, its activity carries information about stimulus features as well as prior occurrence. From Brown MW (1990) Why does the cortex have a hippocampus? In: Gabriel M and Moore J (eds.) Learning and Computational Neuroscience: Foundations of Adaptive Networks, pp. 233–282. Cambridge, MA: MIT Press.

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measures of neuronal activity from this cortex. Except under specific circumstances (see next section), response increases with stimulus repetition occur at a level below that expected by chance. Response reductions with repetition have been described for threedimensional objects and two-dimensional pictures of objects, faces, patterns, and scenes. Repetitionsensitive responses also encode information concerning the physical features of the stimuli, just as do responses that are not repetition sensitive. Thus, for example, some neurons respond only to novel faces and not novel objects or only to novel stimuli of a certain color. Similar response changes are found in the perirhinal cortex (areas 35 and 36), adjacent visual association cortex (anterior TE), and neighboring lateral entorhinal cortex. In experiments in which both novel and highly familiar stimuli have been repeated, it has been possible to show that there is more than one pattern of response change on stimulus repetition. Under the conditions of the original experiments, these response types were termed novelty, recency, and familiarity because of the type of information signaled. Novelty responses were strong to first presentations of novel stimuli and weak when these stimuli were repeated or already familiar stimuli were shown; the responses gave out a novelty signal. Recency responses were strong for novel stimuli and for highly familiar stimuli that had not been seen for some time (e.g., 24 h) but weak when either type of stimulus had been seen recently; accordingly, such response changes contained information about the recency of presentation of stimuli. In contrast, familiarity responses were strong for novel stimuli even when they were seen for a second time after a brief interval (e.g., <5 min) but weak for highly familiar stimuli even if they had not been seen for a long time (e.g., 24 h); accordingly, such response changes contained information about the relative familiarity of stimuli. Significantly, these different patterns of response change indicated that information about recency of occurrence could be encoded separably from that about relative familiarity. Collectively, perirhinal neurons signaled information about both familiarity and recency. Further study of the properties of the response changes indicated that the term ‘familiarity response’ was potentially misleading. A better description is that they are slow-change responses because such responses are reduced when an initially novel stimulus is shown for a second time if the interval between its presentations is sufficiently long (e.g., > 10 min). They are not reduced if the interval is brief. In contrast, the novelty and recency responses are reduced even when an initially novel stimulus is repeated after an interval of <1 s; correspondingly, such

responses are fast change (Figure 6). This new designation does not alter the fact that more than one type of information is being signaled and that there must be more than one type of underlying synaptic change (see the section titled ‘Synaptic plasticity and modeling of perirhinal neuronal response changes’). Evidence of Relationship to Recognition Memory

The findings of a large number of ablation studies in both rats and monkeys are in agreement that lesions involving the perirhinal cortex cause major impairment of recognition memory tasks that can be solved using familiarity discrimination for single items. The perirhinal cortex is thus necessary for the solution of such tasks. Repetition-sensitive perirhinal responses provide sufficient information to solve such tasks. First, they signal information concerning stimulus novelty or familiarity and recency of occurrence. Second, the responses are changed by a single occurrence of a new stimulus; they therefore evidence single-exposure learning, as does animal and human recognition memory. Third, the system appears to have a very large capacity; even after a monkey has been shown many hundreds of stimuli, the neurons still respond on the basis of whether an individual stimulus has been seen before. The responses are in this way highly stimulus selective. This property also has an important corollary, namely, that the neurons do not respond weakly to a repeated stimulus because of response fatigue; they continue to respond strongly to a subsequent new stimulus. Fourth, the response changes show access to information held in long-term memory. In particular, the response to the second appearance of a stimulus is reduced even when many other stimuli have been seen and a long time has elapsed since the stimulus was first seen. For many such perirhinal neurons (
70%, compared to
45% in anterior TE), responses are reduced even when a stimulus has not been seen for 24 h (Figure 6). Neuronal memory spans (the length of time during which reduced responses are still found) of a few days have also been reported, but longer delays have not been tested. These properties establish that the underlying mechanism differs from that of simple habituation produced by a monotonously repeated stimulus. Moreover, the change is not a simple analog of adaptation to prolonged sensory stimulation. Although the fast-change responses might be related to priming mechanisms, evidence from human lesion and psychological studies makes this unlikely. Slow-change responses do not have the characteristics necessary to explain priming. It should be noted that, for many neurons, response reductions fade with the passage of time and that this provides information within the network concerning how recently a stimulus was presented. In addition, response

Perirhinal Cortex: Neural Representations

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Number of intervening trials Figure 6 Mean population memory spans for neurons in the monkey anterior inferior temporal cortex: (a) recency neurons; (b) familiarity neurons; (c) novelty neurons. Mean population responses (averaged within neurons and then across neurons) are shown for first presentations (N) and second presentations after different intervals (numbers of intervening trials in a serial recognition memory task or 24 h). For these intervals, memory across the population increased with time elapsed for familiarity neurons but decreased for novelty and recency neurons. The decrement developed rapidly (<10 s) for recency and novelty neurons but took more than 5 min to become significant for the population of familiarity neurons. * indicates P < 0.05 difference in mean response to second presentations compared to first presentations. From Brown MW (2000) Neuronal correlates of recognition memory. In: Bolhuis JJ (ed.) Brain, Perception and Memory, pp.185–208. Oxford: Oxford University Press.

reductions with stimulus repetition are found both when stimuli are presented within a recognition memory task (so that the animal must use its relative familiarity to gain reward) and when they are presented without the animal being trained in familiarity discrimination. The response changes are therefore automatic and endogenous; they are not solely induced by training. Three other types of perirhinal neuronal response change may also be observed during delayed matching to sample tasks in which judgments about the prior occurrence of a target stimulus have to be made in a choice phase following a delay. They signal information of importance to the solution of particular types of

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delayed matching to sample tasks, but do not have the properties necessary to explain the behavioral features of general familiarity discrimination for infrequently repeated individual visual stimuli. First, when only one stimulus needs be held in mind at a time and a decision related to its prior occurrence made within a short period (seconds rather than many minutes), increased firing (delay activity) is found between the initial stimulus presentation and the subsequent presentation of the choice (match or nonmatch) stimulus. Such delay activity is not observed when more than one stimulus must be held in mind and the interval before the decision is long, so delay activity cannot provide the substrate for general familiarity discrimination. Second, if a monkey is trained to distinguish between a repeated, unrewarded and a repeated rewarded stimulus, some perirhinal neurons show an increase in response to the repeated rewarded stimulus; however, such increases have been found only when there is a single repeated target stimulus and after training on the specific task. Thus, again, the mechanism appears to be specific to a particular type of task. Third, in delayed matching tasks using frequently repeating stimuli, many perirhinal neurons respond differently to the choice stimulus on match and nonmatch trials. However, it has been shown that for many neurons (notably those outside the perirhinal cortex in, for example, the hippocampus) that these match/nonmatch differences are the same for novel as for familiar stimuli; hence, such differences do not signal the novelty or familiarity of a stimulus. Match/nonmatch differences therefore cannot provide a substrate for general familiarity discrimination, although they may provide information important to judging the recency of occurrence of the stimulus. One other aspect of perirhinal neuronal activity must also play an important role in familiarity discrimination – the correlated firing of action potentials of neurons within local and distal networks. There is still relatively little known about such interactions or the makeup of such networks in the perirhinal cortex. Nevertheless, it has been established that when the activity of synchronously recorded pairs of perirhinal neurons is studied, the firing of one neuron is quite commonly correlated with that of the other. So far, the evidence from such pairs indicates that synchronized firing (when the two neurons fire at approximately the same time) carries less information about the relative familiarity of stimuli than does the firing rate of the neurons. Evidence for the Local Generation of the Response Changes

Neuronal response changes with the repetition of infrequently repeated stimuli are also found in areas

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other than the perirhinal and its neighboring cortices. For example, such changes are found in parts of prefrontal cortex and the striatum, and a small number (
1%) are found in the hippocampus. (Note that neuronal response changes with frequently repeating stimuli are found in even more regions, including the many that demonstrate habituation.) Nevertheless, there is good evidence that response changes with the necessary properties to underlie the familiarity discrimination component of visual recognition memory are initially generated in the perirhinal cortex, although also possibly in the neighboring anterior inferior temporal cortex. More posteriorly, and earlier in the visual processing pathway, repetition-sensitive response changes have memory spans that last for only a minute or so and are disrupted by one or two intervening stimuli. Such changes cannot explain those found in the perirhinal cortex. Therefore, perirhinal response changes are not merely passive reflections of responses earlier in the visual pathway. There is also evidence that the changes are not passive reflections of those occurring in subsequent processing areas. This evidence comes from the very fast latencies of the response changes found in the monkey perirhinal cortex and neighboring area TE. In the fastest cases, the change between the response to a novel stimulus and that to a familiar stimulus occurs within milliseconds (measurements are accurate to only 10–20 ms) of the response to the visual stimulus itself (70–80 ms). Accordingly, there is no time for feedback from areas further on in the processing hierarchy. Indeed, when such latencies have been measured in the hippocampus, prefrontal cortex, and striatum, they are significantly longer than in the perirhinal cortex. The conclusion is that at least the initial response change must be first generated in the perirhinal cortex (and/or anterior TE). This conclusion receives support from experiments in which drugs have been infused locally into the rat perirhinal cortex. Local infusions of different glutamate receptor antagonists block the acquisition of longer- or shorter-term recognition memory, and no other brain region is able to substitute for the perirhinal cortex for either type of delay period (see the section titled ‘Synaptic plasticity and modeling of perirhinal neuronal response changes’). The recording experiments in which repetitionsensitive response changes have been found have employed many controls to establish that the changes are not explicable by behavioral or motivational changes, including changes in alertness, eye movements, and pupil diameter. The speed of the response changes further establishes that they are not artifactually generated because they occur too soon to be explicable as secondary to ocular or attentional

changes. It also establishes that these neurons provide a very rapid signal indicating the presence of a novel stimulus. It has been argued that the evolutionary advantage conveyed by the capacity to attend early to novelty provides a reason for the existence of such a network. Generalization across Modalities and Species

Similar neuronal response changes on stimulus repetition have been described in both the monkey and rat perirhinal cortex. Moreover, recent functional magnetic resonance imaging (fMRI) studies have indicated that signals in the analogous human cortical region are also weaker for familiar than for novel stimuli. Thus, there is a strong indication that the same type of repetition-sensitive response reductions are likely to occur generally across mammalian species. Such response changes have been largely studied using visual stimuli because of the availability of such stimuli in the very large numbers necessary for such experiments. Because the connections of the perirhinal cortex indicate that it should be a multimodal area, it might be expected that similar results will be found whichever modality is used. Indeed, findings in the rat for olfactory stimuli are consistent with those for visual stimuli. Neuronal activity measurements have not been made with somatosensory stimuli, although perirhinal lesions impair tactile familiarity discrimination. However, lesion experiments suggest that the perirhinal cortex may not be necessary for auditory familiarity discrimination. When neuronal activity is imaged using Fos (which has proved to be a useful marker for imaging activity changes related to visual recognition memory), activity is higher for novel than familiar sounds in the auditory association cortex (as it is for visual stimuli in visual association cortex) adjacent to the perirhinal cortex but not in the perirhinal cortex itself. The implication is that either another region performs the role of the perirhinal cortex for auditory stimuli or that there is a difference in the nature or complexity of the auditory and visual stimuli being employed. The latter suggestion relates to the proposed role of the perirhinal cortex in the perception of objects and the question as to whether the particular auditory stimuli employed are processed as objects. If they are not, this could explain the lack of differential activation of the perirhinal cortex by the novel and familiar sounds.

Synaptic Plasticity and Modeling of Perirhinal Neuronal Response Changes Descriptions of different types of perirhinal neuronal response changes related to learning have already been presented. It is possible to list these under the

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following headings: (1) feature extraction (perceptual categorization), (2) familiarity/recency discrimination (potentially several different mechanisms), (3) pairedassociate learning, and (4) reward-association learning. Yet other changes, thought to be related to attentional and/or short-term memory mechanisms, have also been described, such as delay activity and response suppression. It is already clear that there are also developmental changes. The interrelationships and independencies of these different response changes and their underlying synaptic plastic mechanisms are largely unknown, but in the list there are at least eight types of activity change, all of which are observable in the activity of perirhinal neurons under different conditions. The changes observed are dependent on the particular conditions of the experiment and on the particular perirhinal neuron under study. Not all perirhinal neurons show all types of changes, although some may show more than one; again information here is limited. The perirhinal cortex provides a promising region for the investigation of neural substrates of memory. In recent years, increasing efforts have been made to relate perirhinal neuronal response changes to underlying synaptic plastic changes. This work has variously encompassed paired-associate learning, reward learning, developmental changes, and familiarity discrimination. It has also involved the study of synaptic plasticity mechanisms in slices of the perirhinal cortex. Perirhinal Plasticity Studied in Brain Slices

In vitro studies have established that both long-term potentiation (LTP) and long-term depression (LTD) can be evoked in the perirhinal cortex by suitable stimulation. The induction of both LTP and LTD are dependent on N-methyl-D-aspartate (NMDA) glutamate receptors in the perirhinal cortex, as elsewhere. However, LTD has been shown to have an unusual dependency on activation of metabotropic glutamate receptors. Moreover, in the adult perirhinal cortex LTP is dependent on the activation of NMDA receptors containing NR2A subunits, whereas LTD (and depotentiation) is dependent on NMDA receptors containing NR2B subunits. Again, as in other regions, there are differences between the adult and immature cortices in NMDA glutamate receptor composition and LTD induction mechanisms. Indeed, recently, it has been shown that visual experience triggers such a change between immature and adult perirhinal LTD induction mechanisms. Signaling Mechanisms Related to Paired-Associate and Reward Sequence Learning

As already mentioned, studies of paired-associate learning in the monkey have established that

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underlying perirhinal changes involve and are dependent on the immediate early gene Zif268. Similarly, reward-sequence learning in the monkey involves dopaminergic mechanisms because perirhinal neuronal response changes are blocked by local infusion of an oligonucleotide that downregulates the expression of D2 dopaminergic receptors. Interestingly, antagonism of the NMDA receptors did not prevent the development of the response changes. Signaling Mechanisms Related to Recognition Memory

Several studies have been carried out that look at potential substrates of familiarity discrimination in the rat. This work has established that recognition memory is impaired following local infusions into the perirhinal cortex of the muscarinic receptor antagonist scopolamine or of selective antagonists of a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), NMDA, kainate, and metabotropic glutamate receptors. When AMPA receptors are blocked, both acquisition and retrieval are impaired. Otherwise, all the studied drug actions involve acquisition and not retrieval. Interestingly, blockade of NMDA and metabotropic glutamate receptors produces recognition memory impairment only when the memory has to be held across a long (24 h) and not shorter (20 min) delay. In contrast and most unusually, kainate receptor antagonism impairs recognition memory after a 20 min but not after a 24 h delay. These results parallel the evidence provided by perirhinal neuronal responses that there must be more than one substrate underlying familiarity discrimination. The indication is that there must be a rapidly induced shorter-term process that is dependent on kainate receptor activation and one or more longerterm processes, more slowly induced and dependent on NMDA and/or metabotropic glutamate receptor activation. In addition, viral transduction of the perirhinal cortex has shown that phosphorylation of cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB) is necessary for both perirhinal LTP and long-term (24-h) recognition memory, a dependency that parallels findings elsewhere (e.g., in the hippocampus). Theoretical Models and Plasticity Mechanisms

There are now several theoretical neuronal models both of networks designed to extract features and thereby achieve stimulus categorizations leading to perception and of networks designed to achieve familiarity discrimination. None of these models yet uses specific details of perirhinal circuitry (about which there is still relatively little information). Most of the models have employed synaptic enhancement

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(i.e., LTP-like mechanisms) as their primary synaptic plasticity mechanism. One way of achieving the reduced neuronal responses for familiar compared to novel stimuli in such models is by increasing inhibition, but experimental evidence of such increased inhibition is lacking. Recently, it has been argued that models that use separate (but interlinked) networks for feature extraction and familiarity discrimination are more economical. The idea of separate networks is consistent with the observation that perirhinal neurons have responses that are either repetition-sensitive or not, rather than some mixture of the two. Moreover, the calculations indicate that the use of synaptic weakening as the primary mechanism is considerably more efficient than synaptic enhancement. Heuristically, this is because when features repeat across different stimuli, synaptic enhancement leads to certain synapses being successively strengthened so that the neurons with these synapses come to fire selectively strongly for these features (i.e., they signal the presence of such features). In contrast, synaptic weakening has the opposite effect; it emphasizes what is not common rather than what is common across stimuli – but this is what is required for novelty detection. Hence, neuronal modeling has provided an explanation for why perirhinal responses are weaker for familiar than novel stimuli. Under this hypothesis, the synapses that are most strongly activated by a novel stimulus are weakened; when the stimulus occurs again (i.e., when it is familiar), the weakened synapses give rise to a weaker response.

Summary The position of the perirhinal cortex at the top of the hierarchy of sensory processing areas and at the gateway to the limbic system means that it is ideally placed to play important roles in sensory perception and memory. Ablation evidence indicates that the perirhinal cortex is indeed involved in both perceptual (stimulus categorization) and mnemonic functions. The results of recording studies established that the responses of perirhinal cortical neurons carry information about complex stimuli and relate to stimulus identity, but they have yet to provide evidence for the categorization of objects as entities (as suggested by certain lesion studies). There is much evidence from recording studies that perirhinal neurons are involved in attentive and short-term memory, as well as multiple long-term memory tasks including sequence learning for reward, paired-associate learning, and recognition memory. A variety of different neuronal response changes have been related to these different memory tasks, and studies of their underlying synaptic plastic mechanisms are underway.

See also: Adult Cortical Plasticity; Cortical Plasticity and Learning: Mechanisms and Models; Hippocampus and Neural Representations; Memory Representation; Neural Patterning: Arealization of the Cortex; Neural Coding of Spatial Representations; Neuronal Plasticity after Cortical Damage; Perceptual Learning: Neural Mechanisms; Perceptual Learning and Sensory Plasticity; Perirhinal Cortex; Recognition Memory; Shape Representation in Inferotemporal Cortex; Synaptic Plasticity: Learning and Memory in Normal Aging; Synaptic Mechanisms of Learning; Visual Associative Memory.

Further Reading Barker GRI, Warburton EC, Koder T, et al. (2006) The different effects on recognition memory of perirhinal kainate and NMDA glutamate receptor antagonism: Implications for Underlying plasticity mechanisms. Journal of Neuroscience 26: 3561–3566. Brown MW (1990) Why does the cortex have a hippocampus? In: Gabriel M and Moore J (eds.) Learning and Computational Neuroscience: Foundations of Adaptive Networks, pp. 233– 282. Cambridge, MA: MIT Press Brown MW (2000) Neuronal correlates of recognition memory. In: Bolhuis JJ (ed.) Brain, Perception and Memory, pp.185–208. Oxford: Oxford University Press Brown MW and Aggleton JP (2001) Recognition memory: What are the roles of the perirhinal cortex and hippocampus? Nature Reviews Neuroscience 2: 51–61. Brown MW and Bashir ZI (2002) Evidence concerning how neurons of the perirhinal cortex may effect familiarity discrimination. Philosophical Transactions of the Royal Society of London B 357: 1083–1095. Brown MW and Xiang JZ (1998) Recognition memory: Neuronal substrates of the judgement of prior occurrence. Progress in Neurobiology 55: 149–189. Desimone R (1996) Neural mechanisms for visual memory and their role in attention. Proceedings of the National Academy of Sciences of the United States of America 93: 13494–13499. Eichenbaum H (2000) A cortical-hippocampal system for declarative memory. Nature Reviews Neuroscience 1: 41–50. Henson RN, Cansino S, Herron JE, Robb WG, and Rugg MD (2003) A familiarity signal in human anterior medial temporal cortex? Hippocampus 13: 301–304. Massey PV, Johnson BE, Moult PR, et al. (2004) Differential roles of NR2a and NR2b-containing NMDA receptors in cortical long-term potentiation and long-term depression. Journal of Neuroscience 24: 7821–7828. Miyashita Y (2004) Neural mechanisms of cognitive memory. Keio Journal of Medicine 53: 59–68. Murray EA and Bussey TJ (1999) Perceptual-mnemonic functions of the perirhinal cortex. Trends in Cognitive Neuroscience 3: 142–151. Murray EA and Richmond BJ (2001) Role of perirhinal cortex in object perception, memory, and associations. Current Opinion in Neurobiology 11: 188–193. Naya Y, Yoshida M, and Miyashita Y (2001) Backward spreading of memory retrieval signal in primate temporal cortex. Science 291: 661–664 Naya Y, Yoshida M, and Miyashita Y (2003) Forward processing of long-term associative memory in monkey inferotemporal cortex. Journal of Neuroscience 23: 2861–2871

Perirhinal Cortex: Neural Representations Rugg MD and Yonelinas AP (2003) Human recognition memory: A cognitive neuroscience perspective. Trends in Cognitive Sciences 7: 313–319. Squire LR, Stark CE, and Clark RE (2004) The medial temporal lobe. Annual Review of Neuroscience 27: 279–306. Suzuki WA and Eichenbaum H (2000) The neurophysiology of memory. Annals of the New York Academy of Sciences 911: 175–191.

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Witter MP, Groenewegen HJ, Lopes da Silva FH, and Lohman AHM (1989) Functional organization of the extrinsic and intrinsic circuitry of the parahippocampal region Progress in Neurobiology 33: 161–253. Witter MP, Naber PA, VanHaeften T, et al. (2000) Cortico-hippocampal communication by way of parallel parahippocampalsubicular pathways. Hippocampus 10: 398–410.