Disrupting direct inputs from the dorsal subiculum to the granular retrosplenial cortex impairs flexible spatial memory in the rat.

In a changing environment, animals must process spatial signals in a flexible manner. The rat hippocampal formation projects directly upon the retrosplenial cortex, with most inputs arising from the dorsal subiculum and terminating in the granular retrosplenial cortex (area 29). The present study examined whether these same projections are required for spatial working memory and what happens when available spatial cues are altered. Consequently, injections of iDREADDs were made into the dorsal subiculum of rats. In a separate control group, GFP-expressing adeno-associated virus was injected into the dorsal subiculum. Both groups received intracerebral infusions within the retrosplenial cortex of clozapine, which in the iDREADDs rats should selectively disrupt the subiculum to retrosplenial projections. When tested on reinforced T-maze alternation, disruption of the subiculum to retrosplenial projections had no evident effect on the performance of those alternation trials when all spatial-cue types remained present and unchanged. However, the same iDREADDs manipulation impaired performance on all three alternation conditions when there was a conflict or selective removal of spatial cues. These findings reveal how the direct projections from the dorsal subiculum to the retrosplenial cortex support the flexible integration of different spatial cue types, helping the animal to adopt the spatial strategy that best meets current environmental demands.

Converging diencephalic and hippocampal supports for episodic memory.

To understand the neural basis of episodic memory it is necessary to appreciate the significance of the fornix. This pathway creates a direct link between those temporal lobe and medial diencephalic sites responsible for anterograde amnesia. A collaboration with Andrew Mayes made it possible to recruit and scan 38 patients with colloid cysts in the third ventricle, a condition associated with variable fornix damage. Complete fornix loss was seen in three patients, who suffered chronic long-term memory problems. Volumetric analyses involving all 38 patients then revealed a highly consistent relationship between mammillary body volume and the recall of episodic memory. That relationship was not seen for working memory or tests of recognition memory. Three different methods all supported a dissociation between recollective-based recognition (impaired) and familiarity-based recognition (spared). This dissociation helped to show how the mammillary body-anterior thalamic nuclei axis, as well as the hippocampus, is vital for episodic memory yet is not required for familiarity-based recognition. These findings set the scene for a reformulation of temporal lobe and diencephalic amnesia. In this revised model, these two regions converge on overlapping cortical areas, including retrosplenial cortex. The united actions of the hippocampal formation and the anterior thalamic nuclei on these cortical areas enable episodic memory encoding and consolidation, impacting on subsequent recall.

No evidence from complementary data sources of a direct glutamatergic projection from the mouse anterior cingulate area to the hippocampal formation.

The connectivity and interplay between the prefrontal cortex and hippocampus underpin various key cognitive processes, with changes in these interactions being implicated in both neurodevelopmental and neurodegenerative conditions. Understanding the precise cellular connections through which this circuit is organised is, therefore, vital for understanding these same processes. Overturning earlier findings, a recent study described a novel excitatory projection from anterior cingulate area to dorsal hippocampus. We sought to validate this unexpected finding using multiple, complementary methods: anterograde and retrograde anatomical tracing, using anterograde and retrograde adeno-associated viral vectors, monosynaptic rabies tracing, and the Fast Blue classical tracer. Additionally, an extensive data search of the Allen Projection Brain Atlas database was conducted to find the stated projection within any of the deposited anatomical studies as an independent verification of our own results. However, we failed to find any evidence of a direct, monosynaptic glutamatergic projection from mouse anterior cingulate cortex to the hippocampus proper.

Chemogenetics Reveal an Anterior Cingulate-Thalamic Pathway for Attending to Task-Relevant Information.

In a changing environment, organisms need to decide when to select items that resemble previously rewarded stimuli and when it is best to switch to other stimulus types. Here, we used chemogenetic techniques to provide causal evidence that activity in the rodent anterior cingulate cortex and its efferents to the anterior thalamic nuclei modulate the ability to attend to reliable predictors of important outcomes. Rats completed an attentional set-shifting paradigm that first measures the ability to master serial discriminations involving a constant stimulus dimension that reliably predicts reinforcement (intradimensional-shift), followed by the ability to shift attention to a previously irrelevant class of stimuli when reinforcement contingencies change (extradimensional-shift). Chemogenetic disruption of the anterior cingulate cortex (Experiment 1) as well as selective disruption of anterior cingulate efferents to the anterior thalamic nuclei (Experiment 2) impaired intradimensional learning but facilitated 2 sets of extradimensional-shifts. This pattern of results signals the loss of a corticothalamic system for cognitive control that preferentially processes stimuli resembling those previously associated with reward. Previous studies highlight a separate medial prefrontal system that promotes the converse pattern, that is, switching to hitherto inconsistent predictors of reward when contingencies change. Competition between these 2 systems regulates cognitive flexibility and choice.

Deconstructing the Direct Reciprocal Hippocampal-Anterior Thalamic Pathways for Spatial Learning.

The hippocampus is essential for normal memory but does not act in isolation. The anterior thalamic nuclei may represent one vital partner. Using DREADDs, the behavioral consequences of transiently disrupting anterior thalamic function were examined, followed by inactivation of the dorsal subiculum. Next, the anterograde transport of an adeno-associated virus expressing DREADDs was paired with localized intracerebral infusions of a ligand to target specific input pathways. In this way, the direct projections from the anterior thalamic nuclei to the dorsal hippocampal formation were inhibited, followed by separate inhibition of the dorsal subiculum projections to the anterior thalamic nuclei. To assay spatial working memory, all animals performed a reinforced T-maze alternation task, then a more challenging version that nullifies intramaze cues. Across all four experiments, deficits emerged on the spatial alternation task that precluded the use of intramaze cues. Inhibiting dorsal subiculum projections to the anterior thalamic nuclei produced the severest spatial working memory deficit. This deficit revealed the key contribution of dorsal subiculum projections to the anteromedial and anteroventral thalamic nuclei for the processing of allocentric information, projections not associated with head-direction information. The overall pattern of results provides consistent causal evidence of the two-way functional significance of direct hippocampal-anterior thalamic interactions for spatial processing. At the same time, these findings are consistent with hypotheses that these same, reciprocal interactions underlie the common core symptoms of temporal lobe and diencephalic anterograde amnesia.SIGNIFICANCE STATEMENT It has long been conjectured that the anterior thalamic nuclei might be key partners with the hippocampal formation and that, respectively, they are principally responsible for diencephalic and temporal lobe amnesia. However, direct causal evidence for this functional relationship is lacking. Here, we examined the behavioral consequences of transiently silencing the direct reciprocal interconnections between these two brain regions on tests of spatial learning. Disrupting information flow from the hippocampal formation to the anterior thalamic nuclei and vice versa impaired performance on tests of spatial learning. By revealing the conjoint importance of hippocampal-anterior thalamic pathways, these findings help explain why pathology in either the medial diencephalon or the medial temporal lobes can result in profound anterograde amnesic syndromes.

The retrosplenial cortex and object recency memory in the rat.

It has been proposed that the retrosplenial cortex forms part of a 'where/when' information network. The present study focussed on the related issue of whether retrosplenial cortex also contributes to 'what/when' information, by examining object recency memory. In Experiment 1, rats with retrosplenial lesions were found to be impaired at distinguishing the temporal order of objects presented in a continuous series ('Within-Block' condition). The same lesioned rats could, however, distinguish between objects that had been previously presented in one of two discrete blocks ('Between-Block' condition). Experiment 2 used intact rats to map the expression of the immediate-early gene c-fos in retrosplenial cortex following performance of a between-block, recency discrimination. Recency performance correlated positively with levels of c-fos expression in both granular and dysgranular retrosplenial cortex (areas 29 and 30). Expression of c-fos in the granular retrosplenial cortex also correlated with prelimbic cortex and ventral subiculum c-fos activity, the latter also correlating with recency memory performance. The combined findings from both experiments reveal an involvement of the retrosplenial cortex in temporal order memory, which includes both between-block and within-block problems. The current findings also suggest that the rat retrosplenial cortex comprises one of a group of closely interlinked regions that enable recency memory, including the hippocampal formation, medial diencephalon and medial frontal cortex. In view of the well-established importance of the retrosplenial cortex for spatial learning, the findings support the notion that, with its frontal and hippocampal connections, retrosplenial cortex has a key role for both what/when and where/when information.

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

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

Why do lesions in the rodent anterior thalamic nuclei cause such severe spatial deficits?

Lesions of the rodent anterior thalamic nuclei cause severe deficits to multiple spatial learning tasks. Possible explanations for these effects are examined, with particular reference to T-maze alternation. Anterior thalamic lesions not only impair allocentric place learning but also disrupt other spatial processes, including direction learning, path integration, and relative length discriminations, as well as aspects of nonspatial learning, e.g., temporal discriminations. Working memory tasks, such as T-maze alternation, appear particularly sensitive as they combine an array of these spatial and nonspatial demands. This sensitivity partly reflects the different functions supported by individual anterior thalamic nuclei, though it is argued that anterior thalamic lesion effects also arise from covert pathology in sites distal to the thalamus, most critically in the retrosplenial cortex and hippocampus. This two-level account, involving both local and distal lesion effects, explains the range and severity of the spatial deficits following anterior thalamic lesions. These findings highlight how the anterior thalamic nuclei form a key component in a series of interdependent systems that support multiple spatial functions.

Advances in the behavioural testing and network imaging of rodent recognition memory.

Research into object recognition memory has been galvanised by the introduction of spontaneous preference tests for rodents. The standard task, however, contains a number of inherent shortcomings that reduce its power. Particular issues include the problem that individual trials are time consuming, so limiting the total number of trials in any condition. In addition, the spontaneous nature of the behaviour and the variability between test objects add unwanted noise. To combat these issues, the 'bow-tie maze' was introduced. Although still based on the spontaneous preference of novel over familiar stimuli, the ability to give multiple trials within a session without handling the rodents, as well as using the same objects as both novel and familiar samples on different trials, overcomes key limitations in the standard task. Giving multiple trials within a single session also creates new opportunities for functional imaging of object recognition memory. A series of studies are described that examine the expression of the immediate-early gene, c-fos. Object recognition memory is associated with increases in perirhinal cortex and area Te2 c-fos activity. When rats explore novel objects the pathway from the perirhinal cortex to lateral entorhinal cortex, and then to the dentate gyrus and CA3, is engaged. In contrast, when familiar objects are explored the pathway from the perirhinal cortex to lateral entorhinal cortex, and then to CA1, takes precedence. The switch to the perforant pathway (novel stimuli) from the temporoammonic pathway (familiar stimuli) may assist the enhanced associative learning promoted by novel stimuli.

The irregular firing properties of thalamic head direction cells mediate turn-specific modulation of the directional tuning curve.

Head direction cells encode an animal's heading in the horizontal plane. However, it is not clear why the directionality of a cell's mean firing rate differs for clockwise, compared with counterclockwise, head turns (this difference is known as the "separation angle") in anterior thalamus. Here we investigated in freely behaving rats whether intrinsic neuronal firing properties are linked to this phenomenon. We found a positive correlation between the separation angle and the spiking variability of thalamic head direction cells. To test whether this link is driven by hyperpolarization-inducing currents, we investigated the effect of thalamic reticular inhibition during high-voltage spindles on directional spiking. While the selective directional firing of thalamic neurons was preserved, we found no evidence for entrainment of thalamic head direction cells by high-voltage spindle oscillations. We then examined the role of depolarization-inducing currents in the formation of separation angle. Using a single-compartment Hodgkin-Huxley model, we show that modeled neurons fire with higher frequencies during the ascending phase of sinusoidal current injection (mimicking the head direction tuning curve) when simulated with higher high-threshold calcium channel conductance. These findings demonstrate that the turn-specific encoding of directional signal strongly depends on the ability of thalamic neurons to fire irregularly in response to sinusoidal excitatory activation. Another crucial factor for inducing phase lead to sinusoidal current injection was the presence of spike-frequency adaptation current in the modeled neurons. Our data support a model in which intrinsic biophysical properties of thalamic neurons mediate the physiological encoding of directional information.

Contrasting networks for recognition memory and recency memory revealed by immediate-early gene imaging in the rat.

The expression of the immediate-early gene c-fos was used to compare networks of activity associated with recency memory (temporal order memory) and recognition memory. In Experiment 1, rats were first familiarized with sets of objects and then given pairs of different, familiar objects to explore. For the recency test group, each object in a pair was separated by 110 min in the time between their previous presentations. For the recency control test, each object in a pair was separated by less than a 1 min between their prior presentations. Temporal discrimination of the objects correlated with c-fos activity in the recency test group in several sites, including area Te2, the perirhinal cortex, lateral entorhinal cortex, as well as the dentate gyrus, hippocampal fields CA3 and CA1. For both the test and control conditions, network models were derived using structural equation modeling. The recency test model emphasized serial connections from the perirhinal cortex to lateral entorhinal cortex and then to the CA1 subfield. The recency control condition involved more parallel pathways, but again highlighted CA1 within the hippocampus. Both models contrasted with those derived from tests of object recognition (Experiment 2), because stimulus novelty was associated with pathways from the perirhinal cortex to lateral entorhinal cortex that then involved both the dentate gyrus (and CA3) and CA1 in parallel. The present findings implicate CA1 for the processing of familiar stimuli, including recency discriminations, while the dentate gyrus and CA3 pathways are recruited when the perirhinal cortex signals novel stimuli.

The neural basis of nonvisual object recognition memory in the rat.

Research into the neural basis of recognition memory has traditionally focused on the remembrance of visual stimuli. The present study examined the neural basis of object recognition memory in the dark, with a view to determining the extent to which it shares common pathways with visual-based object recognition. Experiment 1 assessed the expression of the immediate-early gene c-fos in rats that discriminated novel from familiar objects in the dark (Group Novel). Comparisons made with a control group that explored only familiar objects (Group Familiar) showed that Group Novel had higher c-fos activity in the rostral perirhinal cortex and the lateral entorhinal cortex. Outside the temporal region, Group Novel showed relatively increased c-fos activity in the anterior medial thalamic nucleus and the anterior cingulate cortex. Both the hippocampal CA fields and the granular retrosplenial cortex showed borderline increases in c-fos activity with object novelty. The hippocampal findings prompted Experiment 2. Here, rats with hippocampal lesions were tested in the dark for object recognition memory at different retention delays. Across two replications, no evidence was found that hippocampal lesions impair nonvisual object recognition. The results indicate that in the dark, as in the light, interrelated parahippocampal sites are activated when rats explore novel stimuli. These findings reveal a network of linked c-fos activations that share superficial features with those associated with visual recognition but differ in the fine details; for example, in the locus of the perirhinal cortex activation. While there may also be a relative increase in c-fos activation in the extended-hippocampal system to object recognition in the dark, there was no evidence that this recognition memory problem required an intact hippocampus.

Lesions of the rat perirhinal cortex spare the acquisition of a complex configural visual discrimination yet impair object recognition.

Rats with perirhinal cortex lesions were sequentially trained in a rectangular water tank on a series of 3 visual discriminations, each between mirror-imaged stimuli. When these same discriminations were tested concurrently, the rats were forced to use a configural strategy to solve the problems effectively. There was no evidence that lesions of the perirhinal cortex disrupted the ability to learn the concurrent configural discrimination task, which required the rats to learn the precise combination of stimulus identity with stimulus placement ("structural" learning). The same rats with perirhinal cortex lesions were also unimpaired on a test of spatial working memory (reinforced T maze alternation), although they were markedly impaired on a new test of spontaneous object recognition. For the recognition test, rats received multiple trials within a single session in which on every trial, they were allowed to explore 2 objects, 1 familiar, the other novel. On the basis of their differential exploration times, rats with perirhinal cortex lesions showed very poor discrimination of the novel objects, thereby confirming the effectiveness of the surgery. The discovery that bilateral lesions of the perirhinal cortex can leave configural (structural) learning seemingly unaffected points to a need to refine those models of perirhinal cortex function that emphasize its role in representing conjunctions of stimulus features.

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

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

Granular and dysgranular retrosplenial cortices provide qualitatively different contributions to spatial working memory: evidence from immediate-early gene imaging in rats.

The present study revealed striking task-dependent differences in immediate-early gene activity in the two main subregions (granular and dysgranular) of the retrosplenial cortex. In addition, there were activity differences along the rostro-caudal axis of both subregions. Two groups of rats were trained on a working memory task in a radial-arm maze, one group in the light, the other in the dark. Each working memory group had two sets of yoked controls. Working memory consistently increased retrosplenial immediate-early gene activity (c-fos and zif268 ), although systematic differences occurred in the granular and dysgranular subregions. Both c-fos and zif268 expression increased in granular cortex irrespective of whether the spatial memory task was in the light or dark. In contrast, only in the light did spatial memory increase dysgranular cortex activation. Correlations based on the counts of Fos-positive cells helped to reinforce the particular association between the dysgranular retrosplenial cortex and radial-arm maze performance in the light. These results provide clear evidence for proposed functional differences between the major retrosplenial subregions: the granular cortex contributes to spatial learning and navigation based on both internal and external cues (light and dark), while dysgranular cortex is more selectively involved when distal visual cues control performance (light only).

Impaired recollection but spared familiarity in patients with extended hippocampal system damage revealed by 3 convergent methods.

To understand recognition memory, the detection of stimulus repetition, it first is necessary to resolve the debate between 2 fundamentally different models of recognition. Contemporary single-process models assume that recognition memory relies solely on the neural system required for the recall of prior events. Dual-process models assume that recognition comprises 2 independent forms of memory: one supports recall, and the other detects repeated stimuli by signaling their familiarity, the feeling of previous occurrence without the recall of any associated information. These 2 models were contrasted in patients who had undergone surgical removal of a colloid cyst, a condition associated with memory loss when accompanied by fornix and/or mammillary body atrophy. Comparisons were made between 2 groups of 9 patients that differed only with respect to the extent of mammillary body atrophy. Only the more atrophied group was impaired on tests of recall, but both groups showed normal recognition levels on a task that equates recall and recognition performance in normal participants. To explore the nature of this spared recognition, we estimated recall-based recognition and familiarity-based recognition using 3 distinct methods: self-report, receiver operating characteristics, and structural equation modeling. All 3 methods showed impaired recall-based recognition accompanied by intact familiarity in the most atrophied group, as predicted only by dual-process models. When structural equation modeling was applied to all 62 colloid cyst patients, the recall/familiarity dual-process model best explained the patients' memory pattern. The convergent evidence that mammillary body atrophy impairs recall but spares familiarity-based recognition appears irreconcilable with single-process models.

EPS Mid-Career Award 2006. Understanding anterograde amnesia: disconnections and hidden lesions.

Three emerging strands of evidence are helping to resolve the causes of the anterograde amnesia associated with damage to the diencephalon. First, new anatomical studies have refined our understanding of the links between diencephalic and temporal brain regions associated with amnesia. These studies direct attention to the limited numbers of routes linking the two regions. Second, neuropsychological studies of patients with colloid cysts confirm the importance of at least one of these routes, the fornix, for episodic memory. By combining these anatomical and neuropsychological data strong evidence emerges for the view that damage to hippocampal-mammillary body-anterior thalamic interactions is sufficient to induce amnesia. A third development is the possibility that the retrosplenial cortex provides an integrating link in this functional system. Furthermore, recent evidence indicates that the retrosplenial cortex may suffer "covert" pathology (i.e., it is functionally lesioned) following damage to the anterior thalamic nuclei or hippocampus. This shared indirect "lesion" effect on the retrosplenial cortex not only broadens our concept of the neural basis of amnesia but may also help to explain the many similarities between temporal lobe and diencephalic amnesia.

A disproportionate role for the fornix and mammillary bodies in recall versus recognition memory.

Uncovering the functional relationship between temporal lobe amnesia and diencephalic amnesia depends on determining the role of the fornix, the major interlinking fiber tract. In this study relating fornix volume with memory, we made magnetic resonance imaging-based volume estimates of 13 brain structures in 38 individuals with surgically removed colloid cysts. Fornix status was assessed directly by overall volume and indirectly by mammillary body volume (which atrophies after fornix damage). Mammillary body volume significantly correlated with 13 out of 14 tests of episodic memory recall, but correlated poorly with recognition memory. Furthermore, as the volumes of the left fornix and the left mammillary bodies decreased, the difference between recall and recognition scores increased. No other structure was consistently associated with memory. These findings support models of diencephalic memory mechanisms that require hippocampal inputs for recall, but not for key elements of recognition.

Contrasting hippocampal and perirhinal cortex function using immediate early gene imaging.

The perirhinal cortex and hippocampus have close anatomical links, and it might, therefore, be predicted that they have close, interlinked roles in memory. Lesion studies have, however, often failed to support this prediction, providing dissociations and double dissociations between the two regions on tests of object recognition and spatial memory. In a series of rat studies we have compared these two regions using the expression of the immediate early gene c-fos as a marker of neuronal activity. This gene imaging approach makes it possible to assess the relative involvement of different brain regions and avoids many of the limitations of the lesion approach. A very consistent pattern of results was found as the various hippocampal subfields but not the perirhinal cortex show increased c-fos activity following tests of spatial learning. In contrast, the perirhinal cortex but none of the hippocampal subfields show increased c-fos activity when presented with novel rather than familiar visual objects. When novel scenes are created by the spatial rearrangement of familiar objects it is the hippocampus and not the perirhinal cortex that shows c-fos changes. This double dissociation for gene expression accords with that found from lesion studies and highlights the different contributions of the perirhinal cortex and hippocampus to memory.

cAMP responsive element-binding protein phosphorylation is necessary for perirhinal long-term potentiation and recognition memory.

We established the importance of phosphorylation of cAMP responsive element-binding protein (CREB) to both the familiarity discrimination component of long-term recognition memory and plasticity within the perirhinal cortex of the temporal lobe. Adenoviral transduction of perirhinal cortex (and adjacent visual association cortex) with a dominant-negative inhibitor of CREB impaired the preferential exploration of novel over familiar objects at a long (24 h) but not a short (15 min) delay, disrupted the normal reduced activation of perirhinal neurons to familiar compared with novel pictures, and impaired long-term potentiation of synaptic transmission in perirhinal slices. The consistency of these effects across the behavioral, systems, and cellular levels of analysis provides strong evidence for involvement of CREB phosphorylation in synaptic plastic processes within perirhinal cortex necessary for long-term recognition memory.