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.

Collateral rostral thalamic projections to prelimbic, infralimbic, anterior cingulate and retrosplenial cortices in the rat brain.

As the functional properties of a cortical area partly reflect its thalamic inputs, the present study compared collateral projections arising from various rostral thalamic nuclei that terminate across prefrontal (including anterior cingulate) and retrosplenial areas in the rat brain. Two retrograde tracers, fast blue and cholera toxin B, were injected in pairs to different combinations of cortical areas. The research focused on the individual anterior thalamic nuclei, including the interanteromedial nucleus, nucleus reuniens and the laterodorsal nucleus. Of the principal anterior thalamic nuclei, only the anteromedial nucleus contained neurons reaching both the anterior cingulate cortex and adjacent cortical areas (prefrontal or retrosplenial), though the numbers were modest. For these same cortical pairings (medial prefrontal/anterior cingulate and anterior cingulate/retrosplenial), the interanteromedial nucleus and nucleus reuniens contained slightly higher proportions of bifurcating neurons (up to 11% of labelled cells). A contrasting picture was seen for collaterals reaching different areas within retrosplenial cortex. Here, the anterodorsal nucleus, typically provided the greatest proportion of bifurcating neurons (up to 15% of labelled cells). While individual neurons that terminate in different retrosplenial areas were also found in the other thalamic nuclei, they were infrequent. Consequently, these thalamo-cortical projections predominantly arise from separate populations of neurons with discrete cortical termination zones, consistent with the transmission of segregated information and influence. Overall, two contrasting medial-lateral patterns of collateral projections emerged, with more midline nuclei, for example, nucleus reuniens and the interoanteromedial nucleus innervating prefrontal areas, while more dorsal and lateral anterior thalamic collaterals innervated retrosplenial cortex.

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.

Insulin resistance and idiopathic infertility: A potential possible link.

Among various health issues, infertility has been always considered as one of the major health problems. Idiopathic infertility is still a matter of debate since the underlying mechanisms stay obscure. Idiopathic infertility is related to expanded chance of metabolic syndrome components, obesity and increased risk of cardiovascular diseases. This study aimed to assess insulin resistance and serum levels of irisin as one of the adipokines in patients with idiopathic infertility. This study included 50 male patients aged 25-50 years old suffering from idiopathic infertility, together with 50 healthy individuals of matched age as controls. Patients showed significantly increased homeostasis model assessment for insulin resistance values than controls. For irisin results, idiopathic infertility patients had significantly decreased values than controls indicating the potential effect of irisin in development of insulin resistance in idiopathic infertility patients.

Separate cortical and hippocampal cell populations target the rat nucleus reuniens and mammillary bodies.

Nucleus reuniens receives dense projections from both the hippocampus and the frontal cortices. Reflecting these connections, this nucleus is thought to enable executive functions, including those involving spatial learning. The mammillary bodies, which also support spatial learning, again receive dense hippocampal inputs, as well as lighter projections from medial frontal areas. The present study, therefore, compared the sources of these inputs to nucleus reuniens and the mammillary bodies. Retrograde tracer injections in rats showed how these two diencephalic sites receive projections from separate cell populations, often from adjacent layers in the same cortical areas. In the subiculum, which projects strongly to both sites, the mammillary body inputs originate from a homogenous pyramidal cell population in more superficial levels, while the cells that target nucleus reuniens most often originate from cells positioned at a deeper level. In these deeper levels, a more morphologically diverse set of subiculum cells contributes to the thalamic projection, especially at septal levels. While both diencephalic sites also receive medial frontal inputs, those to nucleus reuniens are especially dense. The densest inputs to the mammillary bodies appear to arise from the dorsal peduncular cortex, where the cells are mostly separate from deeper neurons that project to nucleus reuniens. Again, in those other cortical regions that innervate both nucleus reuniens and the mammillary bodies, there was no evidence of collateral projections. The findings support the notion that these diencephalic nuclei represent components of distinct, but complementary, systems that support different aspects of cognition.

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.

Perirhinal cortex lesions impair tests of object recognition memory but spare novelty detection.

The present study examined why perirhinal cortex lesions in rats impair the spontaneous ability to select novel objects in preference to familiar objects, when both classes of object are presented simultaneously. The study began by repeating this standard finding, using a test of delayed object recognition memory. As expected, the perirhinal cortex lesions reduced the difference in exploration times for novel vs. familiar stimuli. In contrast, the same rats with perirhinal cortex lesions appeared to perform normally when the preferential exploration of novel vs. familiar objects was tested sequentially, i.e. when each trial consisted of only novel or only familiar objects. In addition, there was no indication that the perirhinal cortex lesions reduced total levels of object exploration for novel objects, as would be predicted if the lesions caused novel stimuli to appear familiar. Together, the results show that, in the absence of perirhinal cortex tissue, rats still receive signals of object novelty, although they may fail to link that information to the appropriate object. Consequently, these rats are impaired in discriminating the source of object novelty signals, leading to deficits on simultaneous choice tests of recognition.

Selective importance of the rat anterior thalamic nuclei for configural learning involving distal spatial cues.

To test potential parallels between hippocampal and anterior thalamic function, rats with anterior thalamic lesions were trained on a series of biconditional learning tasks. The anterior thalamic lesions did not disrupt learning two biconditional associations in operant chambers where a specific auditory stimulus (tone or click) had a differential outcome depending on whether it was paired with a particular visual context (spot or checkered wall-paper) or a particular thermal context (warm or cool). Likewise, rats with anterior thalamic lesions successfully learnt a biconditional task when they were reinforced for digging in one of two distinct cups (containing either beads or shredded paper), depending on the particular appearance of the local context on which the cup was placed (one of two textured floors). In contrast, the same rats were severely impaired at learning the biconditional rule to select a specific cup when in a particular location within the test room. Place learning was then tested with a series of go/no-go discriminations. Rats with anterior thalamic nuclei lesions could learn to discriminate between two locations when they were approached from a constant direction. They could not, however, use this acquired location information to solve a subsequent spatial biconditional task where those same places dictated the correct choice of digging cup. Anterior thalamic lesions produced a selective, but severe, biconditional learning deficit when the task incorporated distal spatial cues. This deficit mirrors that seen in rats with hippocampal lesions, so extending potential interdependencies between the two sites.

Impairments in the early consolidation of spatial memories via group II mGluR agonism in the mammillary bodies.

mGluR2 receptors are widely expressed in limbic brain regions associated with memory, including the hippocampal formation, retrosplenial and frontal cortices, as well as subcortical regions including the mammillary bodies. mGluR2/3 agonists have been proposed as potential therapeutics for neurological and psychiatric disorders, however, there is still little known about the role of these receptors in cognitive processes, including memory consolidation. To address this, we assessed the effect of the mGluR2/3 agonist, eglumetad, on spatial memory consolidation in both mice and rats. Using the novel place preference paradigm, we found that post-sample injections of eglumetad impaired subsequent spatial discrimination when tested 6 h later. Using the immediate early gene c-fos as a marker of neural activity, we showed that eglumetad injections reduced activity in a network of limbic brain regions including the hippocampus and mammillary bodies. To determine whether the systemic effects could be replicated with more targeted manipulations, we performed post-sample infusions of the mGluR2/3 agonist 2R,4R-APDC into the mammillary bodies. This impaired novelty discrimination on a place preference task and an object-in-place task, again highlighting the role of mGluR2/3 transmission in memory consolidation and demonstrating the crucial involvement of the mammillary bodies in post-encoding processing of spatial information.

Association rules for rat spatial learning: the importance of the hippocampus for binding item identity with item location.

Three cohorts of rats with extensive hippocampal lesions received multiple tests to examine the relationships between particular forms of associative learning and an influential account of hippocampal function (the cognitive map hypothesis). Hippocampal lesions spared both the ability to discriminate two different digging media and to discriminate two different room locations in a go/no-go task when each location was approached from a single direction. Hippocampal lesions had, however, differential effects on a more complex task (biconditional discrimination) where the correct response was signaled by the presence or absence of specific cues. For all biconditional tasks, digging in one medium (A) was rewarded in the presence of cue C, while digging in medium B was rewarded in the presences of cue D. Such biconditional tasks are "configural" as no individual cue or element predicts the solution (AC+, AD-, BD+, and BC-). When proximal context cues signaled the correct digging choice, biconditional learning was seemingly unaffected by hippocampal lesions. Severe deficits occurred, however, when the correct digging choice was signaled by distal room cues. Also, impaired was the ability to discriminate two locations when each location was approached from two directions. A task demand that predicted those tasks impaired by hippocampal damage was the need to combine specific cues with their relative spatial positions ("structural learning"). This ability makes it possible to distinguish the same cues set in different spatial arrays. Thus, the hippocampus appears necessary for configural discriminations involving structure, discriminations that potentially underlie the creation of cognitive maps.

The effects of a self-learning package on mothers' knowledge and practices towards caring for their children with phenylketonuria.

The objective of this study was to evaluate the effect of a self-learning package on mothers' knowledge and practices towards caring for their children with phenylketonuria. A pre/post quasi-experimental study was conducted, including 128 mothers of children diagnosed with phenylketonuria. A specifically designed and validated questionnaire was used to evaluate mothers' knowledge and reported practices toward their children before and after participating in the educational program. There was a highly positive association between knowledge and reported practice (.674 and .398). The self-learning package had a positive impact on mothers' knowledge and practices. Consequently, educational programs should be provided to all mothers of newly diagnosed cases to improve their children's adherence to the therapeutic regimen.

Separate but interacting recognition memory systems for different senses: the role of the rat perirhinal cortex.

Two different models (convergent and parallel) potentially describe how recognition memory, the ability to detect the re-occurrence of a stimulus, is organized across different senses. To contrast these two models, rats with or without perirhinal cortex lesions were compared across various conditions that controlled available information from specific sensory modalities. Intact rats not only showed visual, tactile, and olfactory recognition, but also overcame changes in the types of sensory information available between object sampling and subsequent object recognition, e.g., between sampling in the light and recognition in the dark, or vice versa. Perirhinal lesions severely impaired object recognition whenever visual cues were available, but spared olfactory recognition and tactile-based object recognition when tested in the dark. The perirhinal lesions also blocked the ability to recognize an object sampled in the light and then tested for recognition in the dark, or vice versa. The findings reveal parallel recognition systems for different senses reliant on distinct brain areas, e.g., perirhinal cortex for vision, but also show that: (1) recognition memory for multisensory stimuli involves competition between sensory systems and (2) perirhinal cortex lesions produce a bias to rely on vision, despite the presence of intact recognition memory systems serving other senses.

Perirhinal cortex lesions uncover subsidiary systems in the rat for the detection of novel and familiar objects.

The present study compared the impact of perirhinal cortex lesions on tests of object recognition. Object recognition was tested directly by looking at the preferential exploration of novel objects over simultaneously presented familiar objects. Object recognition was also tested indirectly by presenting just novel objects or just familiar objects, and recording exploration levels. Rats with perirhinal cortex lesions were severely impaired at discriminating a novel object from a simultaneously presented familiar object (direct test), yet displayed normal levels of exploration to novel objects presented on their own and showed normal declines in exploration times for familiar objects that were repeatedly presented (indirect tests). This effective reduction in the exploration of familiar objects after perirhinal cortex lesions points to the sparing of some recognition mechanisms. This possibility led us to determine whether rats with perirhinal cortex lesions can overcome their preferential exploration deficits when given multiple object familiarisation trials prior to that same (familiar) object being paired with a novel object. It was found that after multiple familiarisation trials, objects could now successfully be recognised as familiar by rats with perirhinal cortex lesions, both following a 90-min delay (the longest delay tested) and when object recognition was tested in the dark after familiarisation trials in the light. These latter findings reveal: (i) the presumed recruitment of other regions to solve recognition memory problems in the absence of perirhinal cortex tissue; and (ii) that these additional recognition mechanisms require more familiarisation trials than perirhinal-based recognition mechanisms.

New behavioral protocols to extend our knowledge of rodent object recognition memory.

Animals often show an innate preference for novelty. This preference facilitates spontaneous exploration tasks of novelty discrimination (recognition memory). In response to limitations with standard spontaneous object recognition procedures for rodents, a new task ("bow-tie maze") was devised. This task combines features of delayed nonmatching-to-sample with spontaneous exploration. The present study explored aspects of object recognition in the bow-tie maze not amenable to standard procedures. Two rat strains (Lister Hooded, Dark Agouti) displayed very reliable object recognition in both the light and dark, with the Lister Hooded strain showing superior performance (Experiment 1). These findings reveal the potential contribution of tactile and odor cues in object recognition. As the bow-tie maze task permits multiple trials within a session, it was possible to derive forgetting curves both within-session and between-sessions (Experiment 1). In Experiment 2, rats with hippocampal or fornix lesions performed at normal levels on the basic version of the recognition task, contrasting with the marked deficits previously seen after perirhinal cortex lesions. Next, the training protocol was adapted (Experiment 3), and this modified version was used successfully with mice (Experiment 4). The overall findings demonstrate the efficacy of this new behavioral task and advance our understanding of object recognition.

A Direct Comparison of Afferents to the Rat Anterior Thalamic Nuclei and Nucleus Reuniens: Overlapping But Different.

Both nucleus reuniens and the anterior thalamic nuclei are densely interconnected with medial cortical and hippocampal areas, connections that reflect their respective contributions to learning and memory. To better appreciate their comparative roles, pairs of different retrograde tracers were placed in these two thalamic sites in adult rats. Both thalamic sites receive modest cortical inputs from layer V that contrasted with much denser projections from layer VI. Despite frequent overlap in layer VI, ventral prefrontal and anterior cingulate inputs to nucleus reuniens were concentrated in the deepest sublayer (VIb). Meanwhile, inputs to the anterior thalamic nuclei originated more evenly from both sublayers VIa and VIb, with the result that they were often located more superficially than the projections to nucleus reuniens. Again, while the many hippocampal (subiculum) neurons projecting to nucleus reuniens and the anterior thalamic nuclei were partially intermingled within the deep cellular parts of the subiculum, cells projecting to nucleus reuniens consistently tended to lie even deeper (i.e., immediately adjacent to the alveus). Variable numbers of double-labeled cells were present in those cortical and subicular portions where the two cell populations intermingled, though they remained in a minority. Our data also show how projections to these two thalamic sites are organized in opposing dorsal/ventral and rostral/caudal gradients across both the cortex and hippocampal formation. While the anterior thalamic nuclei are preferentially innervated by dorsal cortical sites, more ventral frontal sites preferentially reach nucleus reuniens. These anatomic differences may underpin the complementary cognitive functions of these two thalamic areas.

Qualitatively different hippocampal subfield engagement emerges with mastery of a spatial memory task by rats.

The parallel, entorhinal cortex projections to different hippocampal regions potentially support separate mnemonic functions. To examine this possibility, rats were trained in a radial-arm maze task so that hippocampal activity could be compared after "early" (two sessions) or "late" (five sessions) learning. Induction of the immediate-early gene Zif268 was then measured, so revealing possible activity differences across hippocampal subfields and the parahippocampal cortices. Each rat in the two experimental groups (early, late) was also yoked to a control rat that obtained the same number of rewards, visited the same number of maze arms, and spent a comparable amount of time in the maze. Although overall Zif268 levels did not distinguish the four groups, significant correlations were found between spatial memory performance and levels of dentate gyrus Zif268 expression in the early but not the late training group. Conversely, hippocampal fields CA3 and CA1 Zif268 expression correlated with performance in the late but not the early training group. This reversal in the correlation pattern was echoed by structural equation modeling, which revealed dynamic changes in effective network connectivity. With early training, the dentate gyrus appeared to help determine CA1 activity, but by late training the dentate gyrus reduced its neural influence. Furthermore, CA1 was distinguished from CA3, each subfield developing opposite relations with task mastery. Thus, functional entorhinal cortex coupling with CA1 activity became more direct with additional training, so producing a trisynaptic circuit bypass. The present study reveals qualitatively different patterns of hippocampal subfield engagement dependent on task demands and mastery.

Do the rat anterior thalamic nuclei contribute to behavioural flexibility?

The rodent anterior thalamic nuclei (ATN) are vital for spatial memory. A consideration of their extensive frontal connections suggests that these nuclei may also subserve non-spatial functions. The current experiments explored the importance of the ATN for different aspects of behavioural flexibility, including their contribution to tasks typically associated with frontal cortex. In Experiment 1, rats with ATN lesions were tested on a series of response and visual discriminations in an operant box and, subsequently, in a water tank. The tasks included assessments of reversal learning as well switches between each discrimination dimension. Results revealed a mild and transient deficit on the operant task that was not specific to any stage of the procedure. In the water tank, the lesion animals were impaired on the reversal of a spatial discrimination but did not differ from controls on any other measure. Experiment 2 examined the impact of ATN damage on a rodent analogue of the 'Stroop', which assesses response choice during stimulus conflict. The lesion animals successfully acquired this task and were able to use contextual information to disambiguate conflicting cue information. However, responding during the initial presentation of conflicting cue information was affected by the lesion. Taken together, these results suggest that the ATN are not required for aspects of behavioural flexibility (discrimination learning, reversals or high-order switches) typically associated with the rat medial prefrontal cortex. The results from Experiment 2 suggest that the non-spatial functions of the ATN may be more aligned with those of the anterior cingulate cortex.

Lesions of retrosplenial cortex spare immediate-early gene activity in related limbic regions in the rat.

The retrosplenial cortex forms part of a network of cortical and subcortical structures that have particular importance for spatial learning and navigation in rodents. This study examined how retrosplenial lesions affect activity in this network by visualising the expression of the immediate-early genes c-fos and zif268 after exposure to a novel location. Groups of rats with extensive cytotoxic lesions (areas 29 and 30) and rats with lesions largely confined to area 30 (dysgranular cortex) were compared with their respective control animals for levels of c-fos expression measured by immunohistochemistry. These cortical lesions had very limited effects on distal c-fos activity. Evidence of a restricted reduction in c-fos activity was seen in the septal dentate gyrus (superior blade) but not in other hippocampal and parahippocampal subareas, nor in the anterior cingulate and prelimbic cortices. Related studies examined zif268 activity in those cases with combined area 29 and 30 lesions. The only clear evidence for reduced zif268 activity following retrosplenial cell loss came from the septal CA3 area. The confined impact of retrosplenial tissue loss is notable as, by the same immediate-early gene measures, retrosplenial cortex is itself highly sensitive to damage in related limbic areas, showing a marked c-fos and zif268 hypoactivity across all of its subareas. This asymmetry in covert pathology may help to explain the apparent disparity between the severity of learning deficits after retrosplenial cortex lesions and after lesions in either the hippocampus or the anterior thalamic nuclei.

Medial temporal pathways for contextual learning: Network c-fos mapping in rats with or without perirhinal cortex lesions.

BACKGROUND: In the rat brain, context information is thought to engage network interactions between the postrhinal cortex, medial entorhinal cortex, and the hippocampus. In contrast, object information is thought to be more reliant on perirhinal cortex and lateral entorhinal cortex interactions with the hippocampus. METHOD: The 'context network' was explored by mapping expression of the immediate-early gene, c-fos, after exposure to a new spatial environment. RESULTS: Structural equation modelling of Fos counts produced networks of good fit that closely matched prior predictions based on anatomically-grounded functional models. These same models did not, however, fit the Fos data from home-cage controls nor did they fit the corresponding data from a previous study exploring object recognition. These additional analyses highlight the specificity of the context network. The home-cage controls, meanwhile, showed raised levels of inter-area Fos correlations between the many sites examined, i.e., their changes in Fos levels lacked anatomical specificity. Two additional groups of rats received perirhinal cortex lesions. While the loss of perirhinal cortex reduced lateral entorhinal c-fos activity, it did not affect mean levels of hippocampal c-fos expression. Similarly, overall c-fos expression in the prelimbic cortex, retrosplenial cortex and nucleus reuniens of the thalamus appeared unaffected by the perirhinal cortex lesions. CONCLUSION: The perirhinal cortex lesions disrupted network interactions involving the medial entorhinal cortex and the hippocampus, highlighting ways in which perirhinal cortex might affect specific aspects of context learning.