Perirhinal cortex learns a predictive map of the task environment.

Goal-directed tasks involve acquiring an internal model, known as a predictive map, of relevant stimuli and associated outcomes to guide behavior. Here, we identified neural signatures of a predictive map of task behavior in perirhinal cortex (Prh). Mice learned to perform a tactile working memory task by classifying sequential whisker stimuli over multiple training stages. Chronic two-photon calcium imaging, population analysis, and computational modeling revealed that Prh encodes stimulus features as sensory prediction errors. Prh forms stable stimulus-outcome associations that can progressively be decoded earlier in the trial as training advances and that generalize as animals learn new contingencies. Stimulus-outcome associations are linked to prospective network activity encoding possible expected outcomes. This link is mediated by cholinergic signaling to guide task performance, demonstrated by acetylcholine imaging and systemic pharmacological perturbation. We propose that Prh combines error-driven and map-like properties to acquire a predictive map of learned task behavior.

Subpopulations of neurons in the perirhinal cortex enable both modality-specific and modality-invariant recognition of objects.

The perirhinal cortex (PER) supports multimodal object recognition, but how multimodal information of objects is integrated within the PER remains unknown. Here, we recorded single units within the PER while rats performed a PER-dependent multimodal object-recognition task. In this task, audiovisual cues were presented simultaneously (multimodally) or separately (unimodally). We identified 2 types of object-selective neurons in the PER: crossmodal cells, showing constant firing patterns for an object irrespective of its modality, and unimodal cells, showing a preference for a specific modality. Unimodal cells further dissociated unimodal and multimodal versions of the object by modulating their firing rates according to the modality condition. A population-decoding analysis confirmed that the PER could perform both modality-invariant and modality-specific object decoding-the former for recognizing an object as the same in various conditions and the latter for remembering modality-specific experiences of the same object.

Temporal multiplexing of perception and memory codes in IT cortex.

A central assumption of neuroscience is that long-term memories are represented by the same brain areas that encode sensory stimuli1. Neurons in inferotemporal (IT) cortex represent the sensory percept of visual objects using a distributed axis code2-4. Whether and how the same IT neural population represents the long-term memory of visual objects remains unclear. Here we examined how familiar faces are encoded in the IT anterior medial face patch (AM), perirhinal face patch (PR) and temporal pole face patch (TP). In AM and PR we observed that the encoding axis for familiar faces is rotated relative to that for unfamiliar faces at long latency; in TP this memory-related rotation was much weaker. Contrary to previous claims, the relative response magnitude to familiar versus unfamiliar faces was not a stable indicator of familiarity in any patch5-11. The mechanism underlying the memory-related axis change is likely intrinsic to IT cortex, because inactivation of PR did not affect axis change dynamics in AM. Overall, our results suggest that memories of familiar faces are represented in AM and perirhinal cortex by a distinct long-latency code, explaining how the same cell population can encode both the percept and memory of faces.

Experience transforms crossmodal object representations in the anterior temporal lobes.

Combining information from multiple senses is essential to object recognition, core to the ability to learn concepts, make new inferences, and generalize across distinct entities. Yet how the mind combines sensory input into coherent crossmodal representations - the crossmodal binding problem - remains poorly understood. Here, we applied multi-echo fMRI across a 4-day paradigm, in which participants learned three-dimensional crossmodal representations created from well-characterized unimodal visual shape and sound features. Our novel paradigm decoupled the learned crossmodal object representations from their baseline unimodal shapes and sounds, thus allowing us to track the emergence of crossmodal object representations as they were learned by healthy adults. Critically, we found that two anterior temporal lobe structures - temporal pole and perirhinal cortex - differentiated learned from non-learned crossmodal objects, even when controlling for the unimodal features that composed those objects. These results provide evidence for integrated crossmodal object representations in the anterior temporal lobes that were different from the representations for the unimodal features. Furthermore, we found that perirhinal cortex representations were by default biased toward visual shape, but this initial visual bias was attenuated by crossmodal learning. Thus, crossmodal learning transformed perirhinal representations such that they were no longer predominantly grounded in the visual modality, which may be a mechanism by which object concepts gain their abstraction.

Male rodent perirhinal cortex, but not ventral hippocampus, inhibition induces approach bias under object-based approach-avoidance conflict.

Neural models of approach-avoidance (AA) conflict behavior and its dysfunction have focused traditionally on the hippocampus, with the assumption that this medial temporal lobe (MTL) structure plays a ubiquitous role in arbitrating AA conflict. We challenge this perspective by using three different AA behavioral tasks in conjunction with optogenetics, to demonstrate that a neighboring region in male rats, perirhinal cortex, is also critically involved but only when conflicting motivational values are associated with objects and not contextual information. The ventral hippocampus, in contrast, was found not to be essential for object-associated AA conflict, suggesting its preferential involvement in context-associated conflict. We propose that stimulus type can impact MTL involvement during AA conflict and that a more nuanced understanding of MTL contributions to impaired AA behavior (e.g., anxiety) is required. These findings serve to expand upon the established functions of the perirhinal cortex while concurrently presenting innovative behavioral paradigms that permit the assessment of different facets of AA conflict behavior.

Hippocampal activity during memory and visual perception: The role of representational content.

The functional organisation of the medial temporal lobe (MTL) has long been described on the basis of cognitive processes such as recollection or familiarity. However, this view has recently been challenged, and researchers have proposed decomposing cognitive phenomena into representations and operations. According to the representational view, representations, such as scenes for the hippocampus and objects for the perirhinal cortex, are critical in understanding the role of MTL regions in cognition. In the present study, 51 healthy young participants underwent functional magnetic resonance imaging (fMRI) while completing a visual-discrimination task. Subsequently, half of the participants performed a patch-cue recognition procedure in which "Rec" responses are believed to reflect the operation of pattern completion, whereas the other half performed a whole-item remember/know procedure. We replicated the previously-reported demonstration that hippocampal involvement in pattern completion is preferential for scenes as compared with objects. In contrast, the perirhinal cortex was more recruited for object processing than for scene processing. We further extended these results to the operations of strength-signal memory and visual discrimination. Finally, the modulation of hippocampal engagement in pattern completion by representational content was found to be specific to its anterior segment. This observation is consistent with the proposal that this segment would process broad/global representations, whereas the posterior hippocampus would perform sharp/local representations. Taken together, these results favour the representational view of MTL functional organisation, but support that this specialisation differs along the hippocampal long-axis.

The Interaction of Cue Type and Its Associated Behavioral Response Dissociates the Neural Activity between the Perirhinal and Postrhinal Cortices.

The perirhinal cortex (PER) and postrhinal cortex (POR) in the medial temporal lobe are commonly described as two distinct systems that process nonspatial and spatial information, respectively. Recent findings suggest that the two regions exhibit functional overlap when processing stimulus information, especially when associative responses are required in goal-directed behavior. However, we lack the neural correlates of this. In the current study, we recorded spiking activities for single units of the PER and POR as rats were required to choose a response associated with the identity of a visual object or scene stimulus. We found that similar proportions of cells fired selectively for either scene or object between the two regions. In the PER and POR, response-selective neurons showed higher contrast for different responses than stimulus-selective cells did for stimuli. More cells fired selectively for specific choice response in the POR than in the PER. The differential firing patterns of the PER and POR were best explained when the stimulus and response components were considered together: Stimulus-selective cells were modulated more by the response in the POR than in the PER, whereas response-selective cells in the PER were modulated more by object information than by scenes. Our results suggest that in a goal-directed memory task, the information processing in the PER and POR may be dynamically modulated not only by input stimulus information but also by the associated choice behavior and stimulus-response interaction.

Noncanonical projections to the hippocampal CA3 regulate spatial learning and memory by modulating the feedforward hippocampal trisynaptic pathway.

The hippocampal formation (HF) is well documented as having a feedforward, unidirectional circuit organization termed the trisynaptic pathway. This circuit organization exists along the septotemporal axis of the HF, but the circuit connectivity across septal to temporal regions is less well described. The emergence of viral genetic mapping techniques enhances our ability to determine the detailed complexity of HF circuitry. In earlier work, we mapped a subiculum (SUB) back projection to CA1 prompted by the discovery of theta wave back propagation from the SUB to CA1 and CA3. We reason that this circuitry may represent multiple extended noncanonical pathways involving the subicular complex and hippocampal subregions CA1 and CA3. In the present study, multiple retrograde viral tracing approaches produced robust mapping results, which supports this prediction. We find significant noncanonical synaptic inputs to dorsal hippocampal CA3 from ventral CA1 (vCA1), perirhinal cortex (Prh), and the subicular complex. Thus, CA1 inputs to CA3 run opposite the trisynaptic pathway and in a temporal to septal direction. Our retrograde viral tracing results are confirmed by anterograde-directed viral mapping of projections from input mapped regions to hippocampal dorsal CA3 (dCA3). We find that genetic inactivation of the projection of vCA1 to dCA3 impairs object-related spatial learning and memory but does not modulate anxiety-related behaviors. Our data provide a circuit foundation to explore novel functional roles contributed by these noncanonical hippocampal circuit connections to hippocampal circuit dynamics and learning and memory behaviors.

Lesion of the hippocampus selectively enhances LEC's activity during recognition memory based on familiarity.

The sense of familiarity for events is crucial for successful recognition memory. However, the neural substrate and mechanisms supporting familiarity remain unclear. A major controversy in memory research is whether the parahippocampal areas, especially the lateral entorhinal (LEC) and the perirhinal (PER) cortices, support familiarity or whether the hippocampus (HIP) does. In addition, it is unclear if LEC, PER and HIP interact within this frame. Here, we especially investigate if LEC and PER's contribution to familiarity depends on hippocampal integrity. To do so, we compare LEC and PER neural activity between rats with intact hippocampus performing on a human to rat translational task relying on both recollection and familiarity and rats with hippocampal lesions that have been shown to then rely on familiarity to perform the same task. Using high resolution Immediate Early Gene imaging, we report that hippocampal lesions enhance activity in LEC during familiarity judgments but not PER's. These findings suggest that different mechanisms support familiarity in LEC and PER and led to the hypothesis that HIP might exert a tonic inhibition on LEC during recognition memory that is released when HIP is compromised, possibly constituting a compensatory mechanism in aging and amnesic patients.

When the ventral visual stream is not enough: A deep learning account of medial temporal lobe involvement in perception.

The medial temporal lobe (MTL) supports a constellation of memory-related behaviors. Its involvement in perceptual processing, however, has been subject to enduring debate. This debate centers on perirhinal cortex (PRC), an MTL structure at the apex of the ventral visual stream (VVS). Here we leverage a deep learning framework that approximates visual behaviors supported by the VVS (i.e., lacking PRC). We first apply this approach retroactively, modeling 30 published visual discrimination experiments: excluding non-diagnostic stimulus sets, there is a striking correspondence between VVS-modeled and PRC-lesioned behavior, while each is outperformed by PRC-intact participants. We corroborate and extend these results with a novel experiment, directly comparing PRC-intact human performance to electrophysiological recordings from the macaque VVS: PRC-intact participants outperform a linear readout of high-level visual cortex. By situating lesion, electrophysiological, and behavioral results within a shared computational framework, this work resolves decades of seemingly inconsistent findings surrounding PRC involvement in perception.

Perirhinal damage produces modality-dependent deficits in fear learning.

The perirhinal cortex (PER) receives multimodal and unimodal sensory information from all modalities. In addition, the PER is anatomically connected with several brain regions that support fear learning. Several studies suggest that the PER is involved in fear conditioning to discontinuous auditory cues but not to continuous auditory cues. To date, studies examining the role of the PER in fear conditioning has largely focused on auditory and contextual stimuli. The present study assessed whether the role of the PER in fear conditioning would extend to visual modalities. Rodents were randomly assigned to one of four conditioned stimuli, which consisted of either a tone or a light stimulus that was either continuous or discontinuous. Pre-training excitotoxic lesions to the PER significantly reduced freezing to auditory and visual cues during the acquisition phase regardless of stimulus continuity. During subsequent testing, perirhinal lesions produced significant decreases in freezing levels to both continuous and discontinuous tones but not to either of the light CS groups. These results suggest that the PER is involved in the acquisition of fear across multiple cue modalities. However, the PER may have a more limited role in the retrieval of the fear memory dependent upon the cue modality.

Perirhinal cortex and the recognition of relative familiarity.

Spontaneous object recognition (SOR) is a widely used task of recognition memory in rodents which relies on their propensity to explore novel (or relatively novel) objects. Network models typically define perirhinal cortex as a region required for recognition of previously seen objects largely based on findings that lesions or inactivations of this area produce SOR deficits. However, relatively little is understood about the relationship between the activity of cells in the perirhinal cortex that signal novelty and familiarity and the behavioural responses of animals in the SOR task. Previous studies have used objects that are either highly familiar or absolutely novel, but everyday memory is for objects that sit on a spectrum of familiarity which includes objects that have been seen only a few times, or objects that are similar to objects which have been previously experienced. We present two studies that explore cellular activity (through c-fos imaging) within perirhinal cortex of rats performing SOR where the familiarity of objects has been manipulated. Despite robust recognition memory performance, we show no significant changes in perirhinal activity related to the level of familiarity of the objects. Reasons for this lack of familiarity-related modulation in perirhinal cortex activity are discussed. The current findings support emerging evidence that perirhinal responses to novelty are complex and that task demands are critical to the involvement of perirhinal cortex in the control of object recognition memory.

Rodent mnemonic similarity task performance requires the prefrontal cortex.

Mnemonic similarity task performance, in which a known target stimulus must be distinguished from similar lures, is supported by the hippocampus and perirhinal cortex. Impairments on this task are known to manifest with advancing age. Interestingly, disrupting hippocampal activity leads to mnemonic discrimination impairments when lures are novel, but not when they are familiar. This observation suggests that other brain structures support discrimination abilities as stimuli are learned. The prefrontal cortex (PFC) is critical for retrieval of remote events and executive functions, such as working memory, and is also particularly vulnerable to dysfunction in aging. Importantly, the medial PFC is reciprocally connected to the perirhinal cortex and neuron firing in this region coordinates communication between lateral entorhinal and perirhinal cortices to presumably modulate hippocampal activity. This anatomical organization and function of the medial PFC suggests that it contributes to mnemonic discrimination; however, this notion has not been empirically tested. In the current study, rats were trained on a LEGO object-based mnemonic similarity task adapted for rodents, and surgically implanted with guide cannulae targeting prelimbic and infralimbic regions of the medial PFC. Prior to mnemonic discrimination tests, rats received PFC infusions of the GABAA agonist muscimol. Analyses of expression of the neuronal activity-dependent immediate-early gene Arc in medial PFC and adjacent cortical regions confirmed muscimol infusions led to neuronal inactivation in the infralimbic and prelimbic cortices. Moreover, muscimol infusions in PFC impaired mnemonic discrimination performance relative to the vehicle control across all testing blocks when lures shared 50-90% feature overlap with the target. Thus, in contrast hippocampal infusions, PFC inactivation impaired target-lure discrimination regardless of the novelty or familiarity of the lures. These findings indicate the PFC plays a critical role in mnemonic similarity task performance, but the time course of PFC involvement is dissociable from that of the hippocampus.

Perirhinal Cortex is Involved in the Resolution of Learned Approach-Avoidance Conflict Associated with Discrete Objects.

The rodent ventral and primate anterior hippocampus have been implicated in approach-avoidance (AA) conflict processing. It is unclear, however, whether this structure contributes to AA conflict detection and/or resolution, and if its involvement extends to conditions of AA conflict devoid of spatial/contextual information. To investigate this, neurologically healthy human participants first learned to approach or avoid single novel visual objects with the goal of maximizing earned points. Approaching led to point gain and loss for positive and negative objects, respectively, whereas avoidance had no impact on score. Pairs of these objects, each possessing nonconflicting (positive-positive/negative-negative) or conflicting (positive-negative) valences, were then presented during functional magnetic resonance imaging. Participants either made an AA decision to score points (Decision task), indicated whether the objects had identical or differing valences (Memory task), or followed a visual instruction to approach or avoid (Action task). Converging multivariate and univariate results revealed that within the medial temporal lobe, perirhinal cortex, rather than the anterior hippocampus, was predominantly associated with object-based AA conflict resolution. We suggest the anterior hippocampus may not contribute equally to all learned AA conflict scenarios and that stimulus information type may be a critical and overlooked determinant of the neural mechanisms underlying AA conflict behavior.

Goal-directed interaction of stimulus and task demand in the parahippocampal region.

The hippocampus and parahippocampal region are essential for representing episodic memories involving various spatial locations and objects, and for using those memories for future adaptive behavior. The "dual-stream model" was initially formulated based on anatomical characteristics of the medial temporal lobe, dividing the parahippocampal region into two streams that separately process and relay spatial and nonspatial information to the hippocampus. Despite its significance, the dual-stream model in its original form cannot explain recent experimental results, and many researchers have recognized the need for a modification of the model. Here, we argue that dividing the parahippocampal region into spatial and nonspatial streams a priori may be too simplistic, particularly in light of ambiguous situations in which a sensory cue alone (e.g., visual scene) may not allow such a definitive categorization. Upon reviewing evidence, including our own, that reveals the importance of goal-directed behavioral responses in determining the relative involvement of the parahippocampal processing streams, we propose the Goal-directed Interaction of Stimulus and Task-demand (GIST) model. In the GIST model, input stimuli such as visual scenes and objects are first processed by both the postrhinal and perirhinal cortices-the postrhinal cortex more heavily involved with visual scenes and perirhinal cortex with objects-with relatively little dependence on behavioral task demand. However, once perceptual ambiguities are resolved and the scenes and objects are identified and recognized, the information is then processed through the medial or lateral entorhinal cortex, depending on whether it is used to fulfill navigational or non-navigational goals, respectively. As complex sensory stimuli are utilized for both navigational and non-navigational purposes in an intermixed fashion in naturalistic settings, the hippocampus may be required to then put together these experiences into a coherent map to allow flexible cognitive operations for adaptive behavior to occur.

Perirhinal input to neocortical layer 1 controls learning.

Hippocampal output influences memory formation in the neocortex, but this process is poorly understood because the precise anatomical location and the underlying cellular mechanisms remain elusive. Here, we show that perirhinal input, predominantly to sensory cortical layer 1 (L1), controls hippocampal-dependent associative learning in rodents. This process was marked by the emergence of distinct firing responses in defined subpopulations of layer 5 (L5) pyramidal neurons whose tuft dendrites receive perirhinal inputs in L1. Learning correlated with burst firing and the enhancement of dendritic excitability, and it was suppressed by disruption of dendritic activity. Furthermore, bursts, but not regular spike trains, were sufficient to retrieve learned behavior. We conclude that hippocampal information arriving at L5 tuft dendrites in neocortical L1 mediates memory formation in the neocortex.

Fluctuating NMDA Receptor Subunit Levels in Perirhinal Cortex Relate to Their Dynamic Roles in Object Memory Destabilization and Reconsolidation.

Reminder cues can destabilize consolidated memories, rendering them modifiable before they return to a stable state through the process of reconsolidation. Older and stronger memories resist this process and require the presentation of reminders along with salient novel information in order to destabilize. Previously, we demonstrated in rats that novelty-induced object memory destabilization requires acetylcholine (ACh) activity at M1 muscarinic receptors. Other research predominantly has focused on glutamate, which modulates fear memory destabilization and reconsolidation through GluN2B- and GluN2A-containing NMDARs, respectively. In the current study, we demonstrate the same dissociable roles of GluN2B- and N2A-containing NMDARs in perirhinal cortex (PRh) for object memory destabilization and reconsolidation when boundary conditions are absent. However, neither GluN2 receptor subtype was required for novelty-induced destabilization of remote, resistant memories. Furthermore, GluN2B and GluN2A subunit proteins were upregulated selectively in PRh 24 h after learning, but returned to baseline by 48 h, suggesting that NMDARs, unlike muscarinic receptors, have only a temporary role in object memory destabilization. Indeed, activation of M1 receptors in PRh at the time of reactivation effectively destabilized remote memories despite inhibition of GluN2B-containing NMDARs. These findings suggest that cholinergic activity at M1 receptors overrides boundary conditions to destabilize resistant memories when other established mechanisms are insufficient.

Disconnection of the perirhinal and insular cortices severely disrupts taste neophobia.

It is well known that the perirhinal (Prh) and insular (IC) cortices are reciprocally connected, mainly through ipsilateral projections. Although some studies have demonstrated that excitotoxic lesions to these regions, each separately, disrupt taste neophobia, it is not yet known whether the two regions have functional interactions with one another. To find out if they form a functional unit, we examined the effects of crossed excitotoxic lesions to the Prh and the contralateral IC (contralateral group). This group's performance was compared to that of rats with ipsilateral Prh and IC lesions (ipsilateral group) and to that of control-operated rats. All the animals received a 0.3% saccharin solution for fifteen minutes on five consecutive days. Rats with contralateral Prh-IC lesions drank significantly higher amounts of saccharin than the other groups during the first encounter with the novel taste, indicating a disruption in neophobia. However, the lesions did not disrupt attenuation of neophobia, with the contralateral group reaching asymptote in trial 2 and the rest of the groups after 3-5 days of exposure to the saccharin. These findings suggest that both Prh and IC play a necessary role in taste neophobia. Additionally, the two cortices function interdependently and their interaction is critical for normal expression of taste neophobia.

Retrieval of allocentric spatial memories is preserved up to thirty days and does not require higher brain metabolic demands.

Spatial orientation is a cognitive ability that is indispensable for survival. Several visual distal cues present in the context can be integrated, establishing a cognitive map. Although there is cumulative evidence about the neural substrate involved in spatial memory acquisition, the brain networks mediating the processes involved in the retrieval of allocentric spatial memories have been studied less. Here, we aimed to explore the role of neuronal oxidative metabolism in the retrieval of allocentric spatial memories through cytochrome c oxidase (CCO) histochemistry seven, 15, 30, 45, and 60 days after task acquisition. Our behavioural results show that spatial memory retrieval in male and female rats is preserved seven, 15, and 30 days post-acquisition, but there is forgetfulness after this time, with subjects not being able to remember the position of the hidden platform after 45 and 60 dfearays. Regarding the study of male brain metabolism, we observed reduced CCO activity in the medial prefrontal cortex, the parietal, retrosplenial, rhinal cortex, and the hippocampal regions in all the groups that failed to solve the task. Similar results were found for female brain oxidative metabolism, in addition to certain differences between succefearssful-retrieval female groups. In conclusion, our work adds information about the behavioural retrieval of an allocentric spatial reference task, suggesting that recovering spatial information seven, 15, and 30days after acquisition is a simple task that does not require a high metabolic demand, in both male and female rats.

Dynamic coordination of the perirhinal cortical neurons supports coherent representations between task epochs.

Cortical neurons show distinct firing patterns across multiple task epochs characterized by different computations. Recent studies suggest that such distinct patterns underlie dynamic population code achieving computational flexibility, whereas neurons in some cortical areas often show coherent firing patterns across epochs. To understand how coherent single-neuron code contributes to dynamic population code, we analyzed neural responses in the rat perirhinal cortex (PRC) during cue and reward epochs of a two-alternative forced-choice task. We found that the PRC neurons often encoded the opposite choice directions between those epochs. By using principal component analysis as a population-level analysis, we identified neural subspaces associated with each epoch, which reflected coordination across the neurons. The cue and reward epochs shared neural dimensions where the choice directions were consistently discriminated. Interestingly, those dimensions were supported by dynamically changing contributions of the individual neurons. These results demonstrated heterogeneity of coherent single-neuron representations in their contributions to population code.