Model of Familiarity Discrimination in the Perirhinal Cortex

Much evidence indicates that recognition memory involves two separable processes, recollection and familiarity discrimination, with familiarity discrimination being dependent on the perirhinal cortex of the temporal lobe. Here, we describe a new neural network model designed to mimic the response patterns of perirhinal neurons that signal information concerning the novelty or familiarity of stimuli. The model achieves very fast and accurate familiarity discrimination while employing biologically plausible parameters and Hebbian learning rules. The fact that the activity patterns of the model's simulated neurons are closely similar to those of neurons recorded from the primate perirhinal cortex indicates that this brain region could discriminate familiarity using principles akin to those of the model. If so, the capacity of the model establishes that the perirhinal cortex alone may discriminate the familiarity of many more stimuli than current neural network models indicate could be recalled (recollected) by all the remaining areas of the cerebral cortex. This efficiency and speed of detecting novelty provides an evolutionary advantage, thereby providing a reason for the existence of a familiarity discrimination network in addition to networks used for recollection.     

Activity in both hippocampus and perirhinal cortex predicts the memory strength of subsequently remembered information

It has been suggested that hippocampal activity predicts subsequent recognition success when recognition decisions are based disproportionately on recollection, whereas perirhinal activity predicts recognition success when decisions are based primarily on familiarity. Another perspective is that both hippocampal and perirhinal activity are predictive of overall memory strength. We tested the relationship between brain activity during learning and subsequent memory strength. Activity in a number of cortical regions (including regions within the "default network") was negatively correlated with subsequent memory strength, suggesting that this activity reflects inattention or mind wandering (and, consequently, poor memory). In contrast, activity in both hippocampus and perirhinal cortex positively correlated with the subsequent memory strength of remembered items. This finding suggests that both structures cooperate during learning to determine the memory strength of what is being learned.     

Perirhinal cortex supports encoding and familiarity-based recognition of novel associations

Results from imaging and lesion studies of item recognition memory have suggested that the hippocampus supports memory for the arbitrary associations that form the basis of episodic recollection, whereas the perirhinal cortex (PRc) supports familiarity for individual items. This view has been challenged, however, by findings showing that PRc may contribute to associative recognition, a task thought to measure relational or recollective memory. Here, using functional magnetic resonance imaging, we demonstrate that PRc activity is increased when pairs of items are processed as a single configuration or unit and that this activity predicts subsequent familiarity-based associative memory. These results explain the discrepancy in the literature by showing that novel associations can be encoded in a unitized manner, thereby allowing PRc to support associative recognition based on familiarity.     

Correlations of recognition memory performance with expression and methylation of brain-derived neurotrophic factor in rats

Object recognition memory allows discrimination between novel and familiar objects. This kind of memory consists of two components: recollection, which depends on the hippocampus, and familiarity, which depends on the perirhinal cortex (Pcx). The importance of brain-derived neurotrophic factor (BDNF) for recognition memory has already been recognized. Recent evidence suggests that DNA methylation regulates the expression of BDNF and memory. Behavioral and molecular approaches were used to understand the potential contribution of DNA methylation to recognition memory. To that end, rats were tested for their ability to distinguish novel from familiar objects by using a spontaneous object recognition task. Furthermore, the level of DNA methylation was estimated after trials with a methyl-sensitive PCR. We found a significant correlation between performance on the novel object task and the expression of BDNF, negatively in hippocampal slices and positively in perirhinal cortical slices. By contrast, methylation of DNA in CpG island 1 in the promoter of exon 1 in BDNF only correlated in hippocampal slices, but not in the Pxc cortical slices from trained animals. These results suggest that DNA methylation may be involved in the regulation of the BDNF gene during recognition memory, at least in the hippocampus.     

Evidence concerning how neurons of the perirhinal cortex may effect familiarity discrimination

Many studies indicate that recognition memory involves at least two separable processes, familiarity discrimination and recollection. Aspects of what is known of potential neuronal substrates of familiarity discrimination are reviewed. Lesion studies have established that familiarity discrimination for individual visual stimuli is effected by a system centred on the perirhinal cortex of the temporal lobe. The fundamental change that encodes prior occurrence of such stimuli appears to be a reduction in the response of neurons in anterior inferior temporal (including perirhinal) cortex when a stimulus is repeated. The neuronal responses rapidly signal the presence of a novel stimulus, and are evidence of long-lasting learning after a single exposure. Computational modelling indicates that a neuronal network based on such a change in responsiveness is potentially highly efficient in information theoretic terms. Processes that occur in long-term depression within the perirhinal cortex provide candidate synaptic plastic mechanisms for that underlying the change, but such linkage remains to be experimentally established.     

Sleep-related hippocampo-cortical interplay during emotional memory recollection

Emotional events are usually better remembered than neutral ones. This effect is mediated in part by a modulation of the hippocampus by the amygdala. Sleep plays a role in the consolidation of declarative memory. We examined the impact of sleep and lack of sleep on the consolidation of emotional (negative and positive) memories at the macroscopic systems level. Using functional MRI (fMRI), we compared the neural correlates of successful recollection by humans of emotional and neutral stimuli, 72 h after encoding, with or without total sleep deprivation during the first post-encoding night. In contrast to recollection of neutral and positive stimuli, which was deteriorated by sleep deprivation, similar recollection levels were achieved for negative stimuli in both groups. Successful recollection of emotional stimuli elicited larger responses in the hippocampus and various cortical areas, including the medial prefrontal cortex, in the sleep group than in the sleep deprived group. This effect was consistent across subjects for negative items but depended linearly on individual memory performance for positive items. In addition, the hippocampus and medial prefrontal cortex were functionally more connected during recollection of either negative or positive than neutral items, and more so in sleeping than in sleep-deprived subjects. In the sleep-deprived group, recollection of negative items elicited larger responses in the amygdala and an occipital area than in the sleep group. In contrast, no such difference in brain responses between groups was associated with recollection of positive stimuli. The results suggest that the emotional significance of memories influences their sleep-dependent systems-level consolidation. The recruitment of hippocampo-neocortical networks during recollection is enhanced after sleep and is hindered by sleep deprivation. After sleep deprivation, recollection of negative, potentially dangerous, memories recruits an alternate amygdalo-cortical network, which would keep track of emotional information despite sleep deprivation.     

The hippocampus supports both the recollection and the familiarity components of recognition memory

The receiver operating characteristic (ROC) has been used to investigate the component processes of recognition memory. Some studies with this technique have been taken to indicate that the hippocampus selectively supports the process of recollection, whereas adjacent cortex in the parahippocampal gyrus supports the process of familiarity. We analyzed ROC data from young adults, memory-impaired patients with limited hippocampal lesions, and age-matched controls. The shape of the ROC changed in similar ways from asymmetric to symmetric, as a function of the strength of memory (strong to weak) in both the young adults and the patients. Moreover, once overall memory strength was similar, the shape of the patient ROC was asymmetric and matched the control ROC. These results suggest that the component processes that determine the shape of the ROC are operative in the absence of the hippocampus, and they argue against the idea that the hippocampus selectively supports the recollection process.     

Intact memory for irrelevant information impairs perception in amnesia

Memory and perception have long been considered separate cognitive processes, and amnesia resulting from medial temporal lobe (MTL) damage is thought to reflect damage to a dedicated memory system. Recent work has questioned these views, suggesting that amnesia can result from impoverished perceptual representations in the MTL, causing an increased susceptibility to interference. Using a perceptual matching task for which fMRI implicated a specific MTL structure, the perirhinal cortex, we show that amnesics with MTL damage including the perirhinal cortex, but not those with damage limited to the hippocampus, were vulnerable to object-based perceptual interference. Importantly, when we controlled such interference, their performance recovered to normal levels. These findings challenge prevailing conceptions of amnesia, suggesting that effects of damage to specific MTL regions are better understood not in terms of damage to a dedicated declarative memory system, but in terms of impoverished representations of the stimuli those regions maintain.     

Perirhinal contributions to human visual perception

Medial temporal lobe (MTL) structures including the hippocampus, entorhinal cortex, and perirhinal cortex are thought to be part of a unitary system dedicated to memory [1, 2], although recent studies suggest that at least one component-perirhinal cortex-might also contribute to perceptual processing [3, 4, 5, 6]. To date, the strongest evidence for this comes from animal lesion studies [7, 8, 9, 10, 11, 12, 13, 14]. In contrast, the findings from human patients with naturally occurring MTL lesions are less clear and suggest a possible functional difference between species [15, 16, 17, 18, 19, 20]. Here, both these issues were addressed with functional neuroimaging in healthy volunteers performing a perceptual discrimination task originally developed for monkeys [7]. This revealed perirhinal activation when the task required the integration of visual features into a view-invariant representation but not when it could be accomplished on the basis of simple features (e.g., color and shape). This activation pattern matched lateral inferotemporal regions classically associated with visual processing but differed from entorhinal cortex associated with memory encoding. The results demonstrate a specific role for the perirhinal cortex in visual perception and establish a functional homology for perirhinal cortex between species, although we propose that in humans, the region contributes to a wider behavioral repertoire including mnemonic, perceptual, and linguistic processes.     

Expression of long-term depression underlies visual recognition memory

The modifications occurring in the brain during learning and memory are still poorly understood but may involve long-lasting changes in synaptic transmission (synaptic plasticity). In perirhinal cortex, a lasting decrement in neuronal responsiveness is associated with visual familiarity discrimination, leading to the hypothesis that long-term depression (LTD)-like synaptic plasticity may underlie recognition memory. LTD relies on internalization of AMPA receptors (AMPARs) through interaction between their GluR2 subunits and AP2, the clathrin adaptor protein required for endocytosis. We demonstrate that a peptide that blocks interactions between GluR2 and AP2 blocks LTD in perirhinal cortex in vitro. Viral transduction of this peptide in perirhinal cortex produced striking deficits in visual recognition memory. Furthermore, there was a deficit of LTD in perirhinal cortex slices from virally transduced, recognition memory-deficient animals. These results suggest that internalization of AMPA receptors, a process critical for the expression of LTD in perirhinal cortex, underlies visual recognition memory.     

The role of acetylcholine in learning and memory

Pharmacological data clearly indicate that both muscarinic and nicotinic acetylcholine receptors have a role in the encoding of new memories. Localized lesions and antagonist infusions demonstrate the anatomical locus of these cholinergic effects, and computational modeling links the function of cholinergic modulation to specific cellular effects within these regions. Acetylcholine has been shown to increase the strength of afferent input relative to feedback, to contribute to theta rhythm oscillations, activate intrinsic mechanisms for persistent spiking, and increase the modification of synapses. These effects might enhance different types of encoding in different cortical structures. In particular, the effects in entorhinal and perirhinal cortex and hippocampus might be important for encoding new episodic memories.     

How emotion strengthens the recollective experience: a time-dependent hippocampal process

Emotion significantly strengthens the subjective recollective experience even when objective accuracy of the memory is not improved. Here, we examine if this modulation is related to the effect of emotion on hippocampal-dependent memory consolidation. Two critical predictions follow from this hypothesis. First, since consolidation is assumed to take time, the enhancement in the recollective experience for emotional compared to neutral memories should become more apparent following a delay. Second, if the emotion advantage is critically dependent on the hippocampus, then the effects should be reduced in amnesic patients with hippocampal damage. To test these predictions we examined the recollective experience for emotional and neutral photos at two retention intervals (Experiment 1), and in amnesics and controls (Experiment 2). Emotional memories were associated with an enhancement in the recollective experience that was greatest after a delay, whereas familiarity was not influenced by emotion. In amnesics with hippocampal damage the emotion effect on recollective experience was reduced. Surprisingly, however, these patients still showed a general memory advantage for emotional compared to neutral items, but this effect was manifest primarily as a facilitation of familiarity. The results support the consolidation hypothesis of recollective experience, but suggest that the effects of emotion on episodic memory are not exclusively hippocampally mediated. Rather, emotion may enhance recognition by facilitating familiarity when recollection is impaired due to hippocampal damage.     

Item, context and relational episodic encoding in humans

Recent functional imaging work supports the view that item and relational memory depend upon distinct encoding operations within the medial temporal lobe. Specifically, emerging findings demonstrate that the level of engagement of perirhinal cortex predicts later memory for individual items, whereas the level of hippocampal processing correlates with later relational memory, or recovery of additional episodic details. Furthermore, recent functional magnetic resonance imaging evidence in humans suggests that medial temporal lobe cortical input structures, the perirhinal and posterior parahippocampal cortices, differentially participate in the encoding of objects and their context, providing domain-specific input to the hippocampus. Taken together, these data help to construct a working model of how distinct medial temporal lobe structures participate in episodic memory formation with domain-general relational binding mechanisms supported by the hippocampus and provide emerging evidence for domain-specificity within the perirhinal and parahippocampal cortices.     

A biphasic and brain-region selective down-regulation of cyclic adenosine monophosphate concentrations supports object recognition in the rat

Background

We aimed to further understand the relationship between cAMP concentration and mnesic performance.

Methods and Findings

Rats were injected with milrinone (PDE3 inhibitor, 0.3 mg/kg, i.p.), rolipram (PDE4 inhibitor, 0.3 mg/kg, i.p.) and/or the selective 5-HT4R agonist RS 67333 (1 mg/kg, i.p.) before testing in the object recognition paradigm. Cyclic AMP concentrations were measured in brain structures linked to episodic-like memory (i.e. hippocampus, prefrontal and perirhinal cortices) before or after either the sample or the testing phase. Except in the hippocampus of rolipram treated-rats, all treatment increased cAMP levels in each brain sub-region studied before the sample phase. After the sample phase, cAMP levels were significantly increased in hippocampus (1.8 fold), prefrontal (1.3 fold) and perirhinal (1.3 fold) cortices from controls rat while decreased in prefrontal cortex (∼0.83 to 0.62 fold) from drug-treated rats (except for milrinone+RS 67333 treatment). After the testing phase, cAMP concentrations were still increased in both the hippocampus (2.76 fold) and the perirhinal cortex (2.1 fold) from controls animals. Minor increase were reported in hippocampus and perirhinal cortex from both rolipram (respectively, 1.44 fold and 1.70 fold) and milrinone (respectively 1.46 fold and 1.56 fold)-treated rat. Following the paradigm, cAMP levels were significantly lower in the hippocampus, prefrontal and perirhinal cortices from drug-treated rat when compared to controls animals, however, only drug-treated rats spent longer time exploring the novel object during the testing phase (inter-phase interval of 4 h).

Conclusions

Our results strongly suggest that a “pre-sample” early increase in cAMP levels followed by a specific lowering of cAMP concentrations in each brain sub-region linked to the object recognition paradigm support learning efficacy after a middle-term delay.     

Remembrance of odors past: human olfactory cortex in cross-modal recognition memory

Episodic memory is often imbued with multisensory richness, such that the recall of an event can be endowed with the sights, sounds, and smells of its prior occurrence. While hippocampus and related medial temporal structures are implicated in episodic memory retrieval, the participation of sensory-specific cortex in representing the qualities of an episode is less well established. We combined functional magnetic resonance imaging (fMRI) with a cross-modal paradigm, where objects were presented with odors during memory encoding. We then examined the effect of odor context on neural responses at retrieval when these same objects were presented alone. Primary olfactory (piriform) cortex, as well as anterior hippocampus, was activated during the successful retrieval of old (compared to new) objects. Our findings indicate that sensory features of the original engram are preserved in unimodal olfactory cortex. We suggest that reactivation of memory traces distributed across modality-specific brain areas underpins the sensory qualities of episodic memories.     

"What-Where-Which" Episodic Retrieval Requires Conscious Recollection and Is Promoted by Semantic Knowledge

Episodic memory is defined as the conscious retrieval of specific past events. Whether accurate episodic retrieval requires a recollective experience or if a feeling of knowing is sufficient remains unresolved. We recently devised an ecological approach to investigate the controlled cued-retrieval of episodes composed of unnamable odors (What) located spatially (Where) within a visual context (Which context). By combining the Remember/Know procedure with our laboratory-ecological approach in an original way, the present study demonstrated that the accurate odor-evoked retrieval of complex and multimodal episodes overwhelmingly required conscious recollection. A feeling of knowing, even when associated with a high level of confidence, was not sufficient to generate accurate episodic retrieval. Interestingly, we demonstrated that the recollection of accurate episodic memories was promoted by odor retrieval-cue familiarity and describability. In conclusion, our study suggested that semantic knowledge about retrieval-cues increased the recollection which is the state of awareness required for the accurate retrieval of complex episodic memories.     

Components of episodic memory: the contribution of recollection and familiarity

The examination of recognition memory confidence judgements indicates that there are two separate components or processes underlying episodic memory. A model that accounts for these results is described in which a recollection process and a familiarity process are assumed to contribute to recognition memory performance. Recollection is assumed to reflect a threshold process whereby qualitative information about the study event is retrieved, whereas familiarity reflects a classical signal-detection process whereby items exceeding a familiarity response criterion are accepted as having been studied. Evidence from cognitive, neuropsychological and neuroimaging studies indicate that the model is in agreement with the existing recognition results, and indicate that recollection and familiarity are behaviourally, neurally and phenomenologically distinct memory retrieval processes.     

A hippocampal marker of recollection memory ability among healthy young adults: contributions of posterior and anterior segments

The hippocampus is known to support recollection memory, but the relation between its structure and recollection in healthy adults has not been established. Here we show that the hippocampus (including subiculum, DG, and CA1-CA4), when separated into posterior and anterior segments, can reliably predict recollection in healthy young adults. Better memory was associated with larger posterior and smaller anterior segments, as evaluated relative to the uncal apex. Overall hippocampal volume, however, did not predict memory. This pattern was confirmed in four separate data sets from different studies and laboratories. The relationship between the posterior hippocampus and memory was mediated by the structure's functional connectivity with a neocortical network identified during a postencoding resting-state scan. The relationship was also weakest in an experiment involving no appreciable study-test interval. These findings suggest that enhanced posterior-hippocampal postencoding processes may account for the memory benefit associated with larger posterior hippocampi.     

Hippocampus and neocortex: recognition and spatial memory

Recognition and spatial memory are typically associated with the perirhinal cortex and hippocampal formation, respectively. Solely focusing on these structures for these specific mnemonic functions may, however, be limiting progress in the field. The distinction between these subdivisions of memory is becoming less defined as, for example, hippocampal cells traditionally considered to encode locations also encode place-object associations. There is increasing evidence for the involvement of overlapping networks of brain structures for aspects of both spatial and recognition memory. Future models of spatial and recognition memory will have to extend beyond the hippocampus and perirhinal cortex to incorporate a wider network of cortical and subcortical structures.     

Cholecystokinin from the entorhinal cortex enables neural plasticity in the auditory cortex

Patients with damage to the medial temporal lobe show deficits in forming new declarative memories but can still recall older memories, suggesting that the medial temporal lobe is necessary for encoding memories in the neocortex. Here, we found that cortical projection neurons in the perirhinal and entorhinal cortices were mostly immunopositive for cholecystokinin (CCK). Local infusion of CCK in the auditory cortex of anesthetized rats induced plastic changes that enabled cortical neurons to potentiate their responses or to start responding to an auditory stimulus that was paired with a tone that robustly triggered action potentials. CCK infusion also enabled auditory neurons to start responding to a light stimulus that was paired with a noise burst. In vivo intracellular recordings in the auditory cortex showed that synaptic strength was potentiated after two pairings of presynaptic and postsynaptic activity in the presence of CCK. Infusion of a CCK_B antagonist in the auditory cortex prevented the formation of a visuo-auditory association in awake rats. Finally, activation of the entorhinal cortex potentiated neuronal responses in the auditory cortex, which was suppressed by infusion of a CCK_B antagonist. Together, these findings suggest that the medial temporal lobe influences neocortical plasticity via CCK-positive cortical projection neurons in the entorhinal cortex.