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This review charts recent advances from a variety of disciplines that create a new perspective on why the multiple hippocampal–anterior thalamic interconnections are together vital for human episodic memory and rodent event memory. Evidence has emerged for the existence of a series of parallel temporal–diencephalic pathways that function in a reciprocal manner, both directly and indirectly, between the hippocampal formation and the anterior thalamic nuclei. These extended pathways also involve the mammillary bodies, the retrosplenial cortex and parts of the prefrontal cortex. Recent neuropsychological findings reveal the disproportionate importance of these hippocampal–anterior thalamic systems for recollective rather than familiarity-based recognition, while anatomical studies highlight the precise manner in which information streams are kept separate but can also converge at key points within these pathways. These latter findings are developed further by electrophysiological stimulation studies showing how the properties of the direct hippocampal–anterior thalamic projections are often opposed by the indirect hippocampal projections via the mammillary bodies to the thalamus. Just as these hippocampal–anterior thalamic interactions reflect an interdependent system, so it is also the case that pathology in one of the component sites within this system can induce dysfunctional changes to distal sites both directly and indirectly across the system. Such distal effects challenge more traditional views of neuropathology as they reveal how extensive covert pathology might accompany localised overt pathology, and so impair memory.

The rat retrosplenial cortex comprises two major subregions (granular and dysgranular) that differ in morphology and connectivity. Although the effects of selective dysgranular retrosplenial cortex (area 30) lesions and the effects of selective lesions within separate sub-areas of the granular retrosplenial cortex have been described, the effects of complete granular lesions (area 29) remain unknown. The present study, therefore, contrasted excitotoxic lesions of the total granular retrosplenial cortex with complete retrosplenial cortex lesions (dysgranular plus granular) using two spatial working memory tasks variably sensitive to complete retrosplenial damage. The granular retrosplenial and complete retrosplenial lesion groups were comparably impaired throughout most of radial-arm maze acquisition, including when subsequently challenged by having the maze rotated mid-trial or being tested in the dark. The other test, reinforced spatial alternation in a T-maze, provided a slightly different result as it was the rats with selective granular cortex lesions that were most impaired when the rats were tested in two, parallel mazes (one for the sample run, the other for the test run). These findings reveal the importance of the granular retrosplenial cortex for learning across a variety of different spatial tasks. Combining these findings with the results of previous functional and anatomical studies suggests that the granular and dysgranular retrosplenial subregions function in close conjunction to support spatial learning.

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.

This review brings together past and present achievements in memory research, ranging from molecular to psychological discoveries. Despite some false starts, major advances include our growing understanding of learning-related neural plasticity and the characterisation of different classes of memory. One striking example is the ability to reactivate targeted neuronal ensembles so that an animal will seemingly re-experience a particular memory, with the further potential to modify such memories. Meanwhile, human functional imaging studies can distinguish individual episodic memories based on voxel activation patterns. While the hippocampus continues to provide a rich source of information, future progress requires broadening our research to involve other sites. Related challenges include the need to understand better the role of glial–neuron interactions and to look beyond the synapse as the sole site of experience-dependent plasticity. Unmet goals include translating our neuroscientific knowledge in order to optimise learning and memory, especially among disadvantaged populations.

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 perirhinal cortex (areas 35/36) and in area Te2 in rats showing object recognition i.e. preferential exploration of novel versus 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 versus 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.

Rats with lesions of the perirhinal cortex, and a control group, were required to find a platform in one corner of a white rectangle, and in the reflection of this corner in a black rectangle. Test trials revealed that these groups were able to integrate information regarding the shape of the pool and the color of its walls (black or white) in order to identify the correct location of the platform. A clear effect of the perirhinal cortex lesions was, however, revealed using an object recognition task that involved the spontaneous exploration of novel objects. The results challenge the view that the perirhinal cortex enables rats to solve discriminations involving feature ambiguity.

In 3 habituation experiments, rats with excitotoxic lesions of the perirhinal cortex were found to be indistinguishable from control rats. Two of the habituation experiments examined the habituation of suppression of responding on an appetitive, instrumental baseline. One of those experiments used stimuli selected from the visual modality (lights), the other used auditory stimuli. The third experiment examined habituation of suppression of novel-flavored water consumption. In contrast to the null results on the habituation experiments, the perirhinal lesions disrupted transfer performance on a configural, visual discrimination, indicating the behavioral effectiveness of the lesions. Implications for comparator theories of habituation are considered, and it is concluded that others' demonstrations of the sensitivity of object recognition to perirhinal cortex damage is not the result of standard habituation.

The past decade has seen a transformation in research on the retrosplenial cortex (RSC). This cortical area has emerged as a key member of a core network of brain regions that underpins a range of cognitive functions, including episodic memory, navigation, imagination and planning for the future. It is now also evident that the RSC is consistently compromised in the most common neurological disorders that impair memory. Here we review advances on multiple fronts, most notably in neuroanatomy, animal studies and neuroimaging, that have highlighted the importance of the RSC for cognition, and consider why specifying its precise functions remains problematic.

Four experiments examined the disruptive effects of selective lesions in limbic thalamic nuclei on retrosplenial cortex function, as characterized by striking changes in immediate-early gene activity. Major goals were to test the specificity of these retrosplenial changes, to define better their time course, and to assess the spread of retrosplenial dysfunction with time post-surgery. Experiment 1 examined the activity of two immediate-early genes (c-Fos, Zif268) in the retrosplenial cortex after unilateral anterior thalamic nuclei lesions (1, 2, or 8 weeks post-surgery). Marked immediate-early gene hypoactivity in the hemisphere ipsilateral to the thalamic lesion was consistent across these different post-surgical intervals and, hence, across different rat strains. Concurrent processing of brain tissues from rats either 4 weeks or 1 year after anterior thalamic lesions (Experiments 2 and 3) enabled direct comparisons across very different survival times. The results confirmed that over time the immediate-early gene disruption expanded from the superficial laminae to the deep laminae of granular b cortex and to the dysgranular subregion, indicative of more global disruptions to retrosplenial cortex with extended survival. Associated, subtle changes to cell morphometry (size and sphericity) were found in the retrosplenial cortex. In contrast, unilateral lesions in the adjacent laterodorsal thalamic nucleus (Experiment 4) did not significantly alter retrosplenial cortex c-Fos activity, so highlighting the anatomical specificity of the anterior thalamic lesion effects. These findings not only indicate that the impact of anterior thalamic lesions on cognition could be enhanced by retrosplenial cortex dysfunction but they also show that the effects could increase with longer post-insult survival.

Recent, convergent evidence places the anterior thalamic nuclei at the heart of diencephalic amnesia. However, the reasons for the severe memory loss in diencephalic amnesia remain unknown. A potential clue comes from the dense, reciprocal connections between the anterior thalamic nuclei and retrosplenial cortex, another region vital for memory. We now report a loss of synaptic plasticity [long-term depression (LTD)] in rat retrosplenial cortex slices months following an anterior thalamic lesion. The loss of LTD was lamina-specific, occurring only in superficial layers of the cortex and was associated with a decrease in GABA(A)-mediated inhibitory transmission. As retrosplenial cortex is itself vital for memory, this distal lesion effect will amplify the impact of anterior thalamic lesions. These findings not only provide novel insights into the functional pathology of diencephalic amnesia and have implications for the aetiology of the posterior cingulate hypoactivity in Alzheimer's disease, but also show how distal changes in plasticity could contribute to diaschisis.

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.

The present study used 2 different discrimination tasks designed to isolate distinct components of visuospatial learning: structural learning and geometric learning. Structural learning refers to the ability to learn the precise combination of stimulus identity with stimulus location. Rats with anterior thalamic lesions and fornix lesions were unimpaired on a configural learning task in which the rats learned 3 concurrent mirror-image discriminations (structural learning). Indeed, both lesions led to facilitated learning. In contrast, anterior thalamic lesions impaired the geometric discrimination (e.g., swim to the corner with the short wall to the right of the long wall). Finally, both the fornix and anterior thalamic lesions severely impaired T-maze alternation, a task that taxes an array of spatial strategies including allocentric learning. This pattern of dissociations and double dissociations highlights how distinct classes of spatial learning rely on different systems, even though they may converge on the hippocampus. Consequently, the findings suggest that structural learning is heavily dependent on cortico-hippocampal interactions. In contrast, subcortical inputs (such as those from the anterior thalamus) contribute to geometric learning.

The expression of two immediate-early genes (IEGs), Zif268 and c-Fos, was quantified in hippocampal subregions and related structures following spatial learning in the Morris water-maze. A critical feature was the novel control protocol alongside more standard controls, the purpose of which was to test whether hippocampal activity is set automatically when traversing an environment or whether it is dependent on reaching a specific goal using learning that requires the hippocampus (i.e. task dependent). The new control protocol (Procedural Task) made it possible to match swim time, swim distance and learning to escape from water with that of the experimental (Working Memory) group. Unlike the Working Memory group, the Procedural Task animals showed no evidence of learning the absolute platform location during the test session. While the Working Memory rats showed c-Fos increases relative to the Procedural Task controls in the frontal and parahippocampal cortices, hippocampal levels did not differ. Again, for Zif268 there was no evidence of a relative increase of hippocampal activity in the Working Memory group. In fact, hippocampal Zif268 showed evidence of a relative decrease, even though the spatial working memory task is hippocampal dependent. The study not only highlighted the shortcomings of other control procedures used in water-maze studies (free-swimming or home cage control), but also indicated that the expression of these IEGs in the hippocampus is not a direct predictor of explicit spatial location learning. Rather, the activity in combinations of regions, including prefrontal cortex, provides a stronger correlate of water-maze learning.

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.

Mammillary body neurons projecting to the thalamus were identified by injecting retrograde tracers into the medial thalamus of macaque monkeys. The source of the thalamic projections from the medial mammillary nucleus showed strikingly different patterns of organization depending on the site of the injection within the two anterior thalamic nuclei, anterior medialis and anterior ventralis. These data reveal at least two distinct modes by which the primate medial mammillary bodies can regulate anterior thalamic function. Projections to the thalamic nucleus anterior medialis arise mainly from the pars lateralis of the medial mammillary nucleus. A particularly dense source is the dorsal cap in the posterior half of the pars lateralis, a subregion that has not previously been distinguished. In contrast, neurons spread evenly across the medial mammillary nucleus gave rise to projections more laterally in the anterior thalamic nuclei. A third pattern of medial mammillary neurons appeared to provide the source of projections to the rostral midline thalamic nuclei. In contrast, the labeled cells in the lateral mammillary nucleus were evenly spread across that nucleus, irrespective of injection site. In addition to the established projection to anterior dorsalis, the lateral mammillary nucleus appears to project lightly to a number of other thalamic nuclei, including lateralis dorsalis, anterior medialis, anterior ventralis, and the rostral midline nuclei, e.g. nucleus reuniens. These anatomical findings not only reveal novel ways of grouping the neurons within the medial mammillary nucleus, but also indicate that the mammillothalamic connections support cognition in multiple ways.

The present study examined whether hippocampal lesions disrupt retrosplenial cortex function. The immediate–early genesc-fos and zif268 provided markers of cellular activity, and their levels were compared in different cytoarchitectonic subregions (dysgranular, granular a and granular b) and different layers (superficial or deep) within retrosplenial cortex. Experiments 1–3 examined the impact of hippocampal lesions on retrosplenial cortex function, with the variations in protocol (e.g. lesion method, rat strain, behaviour prior to gene activity measurement) testing the generality of the findings. Experiment 1 showed that radio-frequency hippocampus lesions result in very striking losses of Fos and Zif268 activity in both superficial and deep laminae of all retrosplenial subregions. This pattern of results was repeated for Fos in experiments 2 and 3. Despite the loss of Fos and Zif268, there was no evidence of retrosplenial cortex atrophy as measured by Nissl counts (experiments 1–3) or NeuN-positive cell counts (experiment 3). Likewise, there was little evidence of any overt changes in cellular size, shape or appearance. The specificity of these hippocampal lesion effects was confirmed in experiment 4 as entorhinal cortex lesions did not change retrosplenial Fos levels. These results provide strong support for the notion that the retrosplenial cortex is unusually sensitive to deafferentation from some of its inputs, so that hippocampal damage might produce permanent ‘covert pathology’ in the retrosplenial cortex. Such dysfunctions could contribute to the pattern of cognitive changes associated with hippocampal lesions and also help to explain the functional interdependency of these two structures.

The fornix and hippocampus are critical to recollection in the healthy human brain. Fornix degeneration is a feature of aging and Alzheimer's disease. In the presence of fornix damage in mild cognitive impairment (MCI), a recognized prodrome of Alzheimer's disease, recall shows greater dependence on other tracts, notably the parahippocampal cingulum (PHC). The current aims were to determine whether this shift is adaptive and to probe its relationship to cholinergic signaling, which is also compromised in Alzheimer's disease. Twenty-five human participants with MCI and 20 matched healthy volunteers underwent diffusion MRI, behavioral assessment, and volumetric measurement of the basal forebrain. In a regression model for recall, there was a significant group × fornix interaction, indicating that the association between recall and fornix structure was weaker in patients. The opposite trend was present for the left PHC. To further investigate this pattern, two regression models were generated to account for recall performance: one based on fornix microstructure and the other on both fornix and left PHC. The realignment to PHC was positively correlated with free recall but not non-memory measures, implying a reconfiguration that is beneficial to residual memory. There was a positive relationship between realignment to PHC and basal forebrain gray matter volume despite this region demonstrating atrophy at a group level, i.e., the cognitive realignment to left PHC was most apparent when cholinergic areas were relatively spared. Therefore, cholinergic systems appear to enable adaptation to injury even as they degenerate, which has implications for functional restoration.

While descriptions of the subiculum often emphasize its role as a recipient of hippocampal inputs, the area also has particular importance as a source of hippocampal projections. The extrinsic projections from the subiculum not only parallel those from hippocampal fields CA1–4 but also terminate in sites that do not receive direct inputs from the rest of the hippocampus. Both electrophysiological and lesion studies reveal how, despite its very dense CA1 inputs, the subiculum has functional properties seemingly independent from the rest of the hippocampus. In understanding the subiculum, it is necessary to appreciate that its connections are topographically organized along all three planes (longitudinal, transverse, and depth). These topographies may enable the subiculum to separate multiple information types and, hence, support multiple functions. The particular significance of the subiculum for learning and memory is underlined by its importance as a source of hippocampal projections to nuclei in the medial diencephalon, which are themselves vital for human memory and rodent spatial learning. Of particular note are its reciprocal connections with the anterior thalamic nuclei, which are not shared by the rest of the hippocampus (CA1–4). These thalamosubiculum connections may be of especial significance for resolving memory problems that suffer high interference and require the flexible use of stimulus representations.

Changes in limbic brain activity in response to novel configurations of visual stimuli were assessed by quantifying two immediate-early genes, c-fos and zif268. Rats were first trained to use distal, visual cues to support radial-arm maze performance. Two separate sets of visual cues were used, one in the morning (Set A) and the other in the afternoon (Set B). On the final day the experimental group was tested with a novel configuration created by combining four of the eight visual cues from Set A with four of the eight visual cues from Set B. Although each individual cue was in a familiar location, the combination of cues was novel. Comparisons with a control group revealed discrete decreases in Fos centred in the hippocampus and retrosplenial cortex. The hippocampal c-fos findings produced a dissociation with the perirhinal cortex, where no change was observed. Other regions seemingly unaffected by the novel stimulus configuration included the postrhinal, entorhinal and parietal cortices. Zif268 levels in the experimental group increased in the anterior ventral thalamic nucleus. Although previous studies have shown how the rat hippocampus is involved in responding to the spatial rearrangement of visual stimuli, the present study examined temporal rearrangement. The selective immediate-early gene changes in the hippocampus and two closely related sites (retrosplenial cortex and anterior ventral thalamic nucleus) when processing the new stimulus configuration support the notion that the hippocampus is important for learning the ‘relational’ or ‘structural’ features of arrays of elements, be they spatial or temporal.

It has been assumed that the integrity of the rodent hippocampus is required for learning the spatial distribution of visual elements in an array. Formally assessing this assumption is, however, far from straightforward as standard tests are amenable to alternative strategies. In order to provide a stringent test of this ability rats were trained on three concurrent visual discriminations in a water tank in which the stimuli in each pair of discriminations contained exactly the same elements but they differed in their spatial arrangement e.g. A|B vs. its mirror image B/A. Such 'structural' discriminations are a specific subtype of 'configural' or 'nonlinear' tasks. Following acquisition half of the rats received hippocampal lesions and all rats were retrained on the structural discriminations. Hippocampal lesions impaired the ability to relearn these 'structural' discriminations. In contrast, two other groups of rats with similar hippocampal lesions showed no impairment on relearning two non-structural, configural discriminations: transverse patterning and biconditional learning. All three tasks used the same apparatus, the same stimulus elements, and similar training regimes. Superior performance by the rats with hippocampal lesions during a generalization decrement probe showed that hippocampal lesions had diminished sensitivity to 'structural' features on the biconditional task. While the rat hippocampus need not be required for all configural learning, it is important for the special case when the spatial arrangements of the elements are critical. This ability may be a prerequisite for the creation of mental snapshots, which underlie episodic memory.

Activity of the immediate early genes c-fos and zif268 was compared across hemispheres in rats with unilateral, excitotoxic lesions of the hippocampus (dentate gyrus and CA fields 1-4). Counts of the protein products of these genes were made shortly after rats performed a test of spatial working memory in the radial-arm maze, a task that is sensitive to bilateral lesions of the hippocampus. Unilateral hippocampal lesions produced evidence of widespread hypoactivity. Significant reductions in immediate early gene counts were observed within all three anterior thalamic nuclei, as well as the entorhinal, perirhinal, and postrhinal cortices, and much of the subicular complex. In contrast, no observable changes were detected in the anterior cingulate, infralimbic or prelimbic cortices, as well as several amygdala nuclei, even though many of these regions receive projections from the subiculum. Instead, the immediate early gene changes were closely linked to sites that are thought to be required for successful task performance, with both immediate early genes giving similar patterns of results. The findings support the notion that the anterior thalamic nuclei, hippocampus, and parahippocampal cortices form the key components of an interdependent neuronal network involved in spatial mnemonic processing.

The present study provides the 1st report on the effects of selective lesions of the dysgranular portion of the retrosplenial cortex in rats. Excitotoxic lesions of the dysgranular area were sufficient to impair behavior in the radial-arm maze by biasing the strategy used to solve the task. In particular, rats with dysgranular retrosplenial lesions were less reliant on distal visual cues to control performance of a working memory task in the radial-arm maze. Instead, they were more reliant on using a motor turning strategy to solve the task. This change in strategy is consistent with anatomical data showing that the dysgranular region is the primary recipient of visual inputs to the rat retrosplenial cortex.

The present study: (1) tested the importance of the retrosplenial cortex for learning a specific heading direction and distance and, (2) determined if lesion size could explain apparent inconsistencies in the results of different research groups. Dark agouti rats received either 'complete' cytotoxic retrosplenial cortex lesions or 'standard' lesions, the latter sparing the caudal retrosplenial cortex. Animals were first tested on two versions of a "landmark" task in a water maze. In condition 1 animals could use both heading direction and allocentric position, while in condition 2 only heading direction was effective. In condition 1, animals with complete retrosplenial lesions were impaired by the end of training, their profile of performance being consistent with a failure to use allocentric position information. When the water maze task changed (condition 2) so that allocentric cues became redundant, the animals with complete retrosplenial lesions were able to head in the appropriate direction although they showed longer swim paths. Subsequent testing in the radial-arm maze provided more evidence that retrosplenial lesions can disrupt the use of distal (allocentric) room cues. The impairments seen with retrosplenial lesions were often mild but throughout the study performance of rats with 'complete' lesions was more disrupted than those with 'standard' lesions, who often did not differ from the controls. These findings show that lesion size is a critical factor and may explain why some studies have failed to find comparable deficits after retrosplenial cortex lesions.

The perirhinal cortex and hippocampus have close anatomical links and it has, therefore, been proposed that they have important, coordinated roles in memory. This review examines the relative role of these structures in spatial memory tasks that are known to be hippocampal-dependent. The published lesion data gives a mixed picture, as only some studies detect spatial deficits after perirhinal cortex lesions. The possible reasons for these inconsistencies are reviewed, along with electrophysiological data that indicate how perirhinal cortex lesions may alter neuronal activity in the hippocampus. Overall, the disruptive effects of perirhinal lesions on spatial memory performance are, when they occur, typically transient and never as severe as those seen after hippocampal lesions. It is argued that parallel cortical routes provide key, sensory data to the hippocampus such that in the absence of the perirhinal cortex alternative information is available. The deficits associated with perirhinal damage may then reflect difficulties that arise when task performance requires the use of ambiguous distal cues, for example, those containing overlapping visual features.

Benzodiazepines, including lorazepam, are widely used in human medicine as anxiolytics or sedatives, and at higher doses can produce amnesia. Here we demonstrate that in rats lorazepam impairs both recognition memory and synaptic plastic processes (long-term depression and long-term potentiation). Both impairments are produced by actions in perirhinal cortex. The findings thus establish a mechanism by means of which benzodiazepines impair recognition memory. The findings also strengthen the hypotheses that the familiarity discrimination component of recognition memory is dependent on reductions in perirhinal neuronal responses when stimuli are repeated and that these response reductions are due to a plastic mechanism also used in long-term depression.

In their review on the retrosplenial cortex Harker and Whishaw [Neurosci Biobehav Rev, 2004] claim that there is continued disagreement over the importance of this region for navigation. They argue that discrepancies in the published effects of retrosplenial lesions reflect two principal variables, choice of rat strain and choice of spatial task. In this reply, evidence is provided showing that Harker and Whishaw [Neurosci Biobehav Rev, 2004] have created a misleading impression and, in fact, there is a clear consensus that the rat retrosplenial cortex is necessary for navigation. Likewise, there is no dispute that the effects of retrosplenial lesions will differ for different tests of spatial learning. While Harker and Whishaw [Neurosci Biobehav Rev, 2004] also conclude that choice of rat strain has a critical impact on whether a lesion-induced deficit is found, a comprehensive review of the published data shows no systematic strain difference. There is, however, growing evidence that when interpreting the effects of retrosplenial lesions, account should be given of the lesion method and its interaction with lesion size.

Lesions involving the anterior thalamic nuclei stopped immediate early gene (IEG) activity in specific regions of the rat retrosplenial cortex, even though there were no apparent cytoarchitectonic changes. Discrete anterior thalamic lesions were made either by excitotoxin (Experiment 1) or radiofrequency (Experiment 2) and, following recovery, the rats foraged in a radial-arm maze in a novel room. Measurements made 6-12 weeks postsurgery showed that, in comparison with surgical controls, the thalamic lesions produced the same, selective patterns of Fos changes irrespective of method. Granular (caudal granular cortex and rostral granular cortex), but not dysgranular (dysgranular cortex), retrosplenial cortex showed a striking loss of Fos-positive cells. While a loss of between 79 and 89% of Fos-positive cells was found in the superficial laminae, the deeper layers appeared normal. In Experiments 3 and 4, rats 9-10 months postsurgery were placed in an activity box for 30 min. Anterior thalamic lesions (Experiment 3) led to a pronounced IEG decrease of both Fos and zif268 throughout the retrosplenial cortex that now included the dysgranular area. These IEG losses were found even though the same regions appeared normal using standard histological techniques. Lesions of the postrhinal cortex (Experiment 4) did not bring about a loss of retrosplenial IEG activity even though this region is also reciprocally connected with the retrosplenial cortex. This selective effect of anterior thalamic damage upon retrosplenial activity may both amplify the disruptive effects of anterior thalamic lesions and help to explain the posterior cingulate hypoactivity found in Alzheimer's disease.

Rats trained on a nonmatching-to-turn rule revealed that egocentric working memory is readily disrupted, hard to use, and transient. In Experiment 1, rats failed to acquire the rule in a plus-maze. Experiment 2 used 2 different plus-mazes to remove any intramaze cues. Task acquisition occurred only when rats could use direction cues (i.e., nonegocentric cues). In Experiments 3 and 4, a J maze was used to minimize the retention interval and eliminate handling rats within a trial. All rats acquired the nonmatching rule, although a 3-s retention delay severely impaired performance. Fornix lesions transiently disrupted performance of the J-maze task (Experiments 3 and 4), but neither fornix (Experiment 1) nor retrosplenial (Experiment 2) lesions impaired the plus-maze tasks.

This study examined the influence of selective mammillothalamic tract lesions in rats on the acquisition of two kinds of contextual conditional discrimination: one involving two contexts (A and B) that differed in their visuo-spatial properties and another involving two contexts (C and D) that differed in temperature. In contexts A (and C) presentations of a tone were paired with food whereas presentations of a clicker were not; and in contexts B (and D) presentations of the clicker were paired with food whereas those of the tone were not. Mammillothalamic tract lesions disrupted initial acquisition of the conditional discrimination involving visual contexts (A and B), but not the formally equivalent discrimination involving thermal contexts (C and D). These results provide support for the suggestion that mammillothalamic tract lesions disrupt visuo-spatial encoding.

Fos levels were measured in rats trained in one of two qualitatively different spatial memory tasks in a water maze. In one task, ( landmark condition) rats found a submerged platform that was always 25 cm south of a visible landmark, the absolute position of the platform and landmark changing after every trial. In the other task ( place condition), rats swam to a platform that remained in the same absolute position on every session, but changed session to session, with this task relying on the memory of allocentric cues. Despite matched swim times, the landmark condition resulted in higher levels of Fos in a wide range of cortical and subcortical sites, including the hippocampus and its connections. Structural equation modelling revealed two different patterns of hippocampal function. In the allocentric place task there was a significant association between Fos activity in the entorhinal cortices and the hippocampus proper, while in the non-allocentric landmark task this relationship was not present, but was replaced by a connection from the entorhinal cortices to the subiculum. Thus, the two different tasks engage two different modes of hippocampal activity as demonstrated by Fos expression.

We establish the importance of cholinergic neurotransmission to both recognition memory and plasticity within the perirhinal cortex of the temporal lobe. The muscarinic receptor antagonist scopolamine impaired the preferential exploration of novel over familiar objects, disrupted the normal reduced activation of perirhinal neurones to familiar compared to novel pictures, and blocked production of long-term depression (LTD) but not long-term potentiation (LTP) of synaptic transmission in perirhinal slices. The consistency of these effects across the behavioral, systems, and cellular levels of analysis provides strong evidence for the involvement of cholinergic mechanisms in synaptic plastic processes within perirhinal cortex that are necessary for recognition memory.

Rats rapidly learned to find a submerged platform in a water maze at a constant distance and angle from the start point, which changed on every trial. The rats performed accurately in the light and dark, but prior rotation disrupted the latter condition. The rats were then retested after receiving cytotoxic hippocampal or retrosplenial cortex lesions. Retrosplenial lesions had no apparent effect in either the light or dark. Hippocampal lesions impaired performance in both conditions but spared the ability to locate a platform placed in the center of the pool. A hippocampal deficit emerged when this pool-center task was run in the dark. The spatial effects of hippocampal damage extend beyond allocentric tasks to include aspects of idiothetic guidance.

Activity of the immediate early gene c-fos was compared across hemispheres in rats with unilateral anterior thalamic lesions. Fos protein was quantified after rats performed a spatial working memory test in the radial-arm maze, a task that is sensitive to bilateral lesions of the anterior thalamic nuclei. Unilateral anterior thalamic lesions produced evidence of a widespread hippocampal hypoactivity, as there were significant reductions in Fos counts in a range of regions within the ipsilateral hippocampal formation (rostral CA1, rostral dentate gyrus, ‘dorsal’ hippocampus, presubiculum and postsubiculum). A decrease in Fos levels was also found in the rostral and caudal retrosplenial cortex but not in the parahippocampal cortices or anterior cingulate cortices. The Fos changes seem most closely linked to sites that are also required for successful task performance, supporting the notion that the anterior thalamus, retrosplenial cortex and hippocampus form key components of an interdependent neuronal network involved in spatial mnemonic processing.

A combination of anterograde and retrograde tracing techniques was used to study the projections to the nucleus accumbens from the amygdala, the hippocampal formation (including the entorhinal cortex), and the perirhinal cortex in two species of macaque monkey. To help identify possible subregions within the nucleus accumbens, the distribution of calbindin was examined in two additional monkeys. Although this revealed evidence of "core"- and "shell"-like regions within the accumbens, these different regions could not consistently be related to cytoarchitectonic features. The rostral amygdala sent nearly equivalent projections to both the medial and the lateral portions of nucleus accumbens, whereas projections arising from the middle and caudal amygdala terminated preferentially in the medial division of nucleus accumbens. The basal nucleus was the major source of these amygdala efferents, and there was a crude topography as parts of the basal and accessory basal nuclei terminated in different parts of nucleus accumbens. The subiculum was the major source of hippocampal projections to the nucleus accumbens, but some hippocampal efferents also originated in the parasubiculum, the prosubiculum, the adjacent portion of CA1, and the uncal portion of CA3. These hippocampal projections, which coursed through the fornix, showed a rostrocaudal gradient as more arose in the rostral hippocampus. Hippocampal efferents terminated most densely in the medial and ventral portions of nucleus accumbens, along with light label in the adjacent olfactory tubercle. The entorhinal projections were more evenly distributed between the medial nucleus accumbens and the olfactory tubercle, whereas the perirhinal projections were primarily to the olfactory tubercle. These cortical inputs were less reliant on the fornix. Amygdala and subicular (hippocampal) projections overlapped most completely in the medial division of nucleus accumbens.

Activity of the immediate early gene c-fos was compared in rats with neurotoxic lesions of the anterior thalamic nuclei and in surgical controls. Fos levels were measured after rats had been placed in a novel room and allowed to run up and down preselected arms of a radial maze. An additional control group showed that in normal rats, this exposure to a novel room leads to a Fos increase in a number of structures, including the anterior thalamic nuclei and hippocampus. In contrast, rats with anterior thalamic lesions were found to have significantly less Fos-positive cells in an array of sites, including the hippocampus (dorsal and ventral), retrosplenial cortex, anterior cingulate cortex, and prelimbic cortex. These results show that anterior thalamic lesions disrupt multiple limbic brain regions, producing hypoactivity in sites associated in rats with spatial memory. Because many of the same sites are implicated in memory processes in humans (e.g., the hippocampus and retrosplenial cortex), this hypoactivity might contribute to diencephalic amnesia.

Rats with neurotoxic lesions of the perirhinal cortex (n = 9) were compared with sham controls (n = 14) on a working memory task in the radial arm maze. Rats were trained under varying levels of proactive interference and with different retention intervals. Finally, performance was assessed when the maze was switched to a novel room. None of these manipulations differentially impaired rats with perirhinal lesions. Rats were next trained on delayed matching-to-place in the water maze. Even with retention delays of 30 min, there was no evidence of a deficit. Although interactions between the perirhinal cortex and hippocampus may be important for integrating object-place information, the perirhinal cortex is often not necessary for tasks that selectively tax allocentric spatial memory.

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.

global efficiency and microstructure of cingulum portions predict aspects of cognitive control. Results: When global efficiency was used as a sole predictor, significant relationships were found with Category Fluency (t 1⁄43.25, p 1⁄4.004), Digit Symbol Substitution (t 1⁄42.43, p 1⁄4.025), and Stroop suppression score (t 1⁄42.26, p 1⁄4.035). Category Fluency correlated most strongly with mean diffusivity (MD) of the left posterior cingulum in MCI, while MD of the left parahippocampal and right middle cingulum were the main correlates of Digit Symbol and Stroop suppression scores, respectively. When the relevant microstructural measure from a portion of the cingulum was added to any of the individual regression models for the relevant task, the relationship with global efficiency was no longer significant. In contrast, independent relationship between left posterior cingulum and Category Fluency (t 1⁄4-2.25, p 1⁄4.037) and left parahippocampal cingulum and Digit Symbol Substitution (t 1⁄4-3.30, p 1⁄4.004) remained. Conclusions:Global efficiency of white matter network structure correlates with cognitive control inMCI. Multivariate analyses suggest that alterations in global efficiency potentially mediate the effect of microstructural variation in specific components of the cingulum. However, for some tasks there was also an association between performance and microstructure of cingulum segments that was independent of global network efficiency. Both global and local network properties are likely to play a role in the status of cognitive control in MCI.

Discrete populations of brain cells signal heading direction, rather like a compass. These ‘head direction’ cells are largely confined to a closely-connected network of sites. We describe, for the first time, a population of head direction cells in nucleus reuniens of the thalamus in the freely-moving rat. This novel subcortical head direction signal potentially modulates the hippocampal CA fields directly and, thus, informs spatial processing and memory. DOI: http://dx.doi.org/10.7554/eLife.03075.001, eLife digest Whether it is foraging for food or finding its way back to its nest, an animal often needs to know which direction it is heading in. Some neurons in a mammal’s brain have been shown to act like a compass, and send out nerve impulses whenever the animal points its head in a certain direction. For example, some of these neurons will fire when the animal faces northeast, but not when it faces northwest, and vice versa. Importantly these neurons, called ‘head direction’ cells, do not actually measure the Earth's magnetic field. Rather, they respond to information about landmarks in the environment and the animal's movements of its head or body to work out which way the animal is facing. Head direction cells are largely found in a closely-connected network of a few sites in the brain. However, Jankowski et al. have now discovered more of these cells in another region found deep within the centre of the brain. Measuring the nerve impulses from these neurons in rats that were moving freely around a test arena revealed that the neurons fired in exactly the same way as some other head direction cells in other regions of the brain. For example, they fired whenever the rat faced one direction, but stopped firing when it turned its head to face another. Jankowski et al. showed that the head direction cells in this region of the brain continued to work when the lights were turned off in the test arena, or when the shape of the arena was changed from a circle to a square. These neurons began sending information about head direction as soon as the rat entered the test arena, and many continued to fire when the rat faced the same direction even when they were retested on several different days. The head direction cells discovered by Jankowski et al. are connected to another region of the brain that is involved in remembering different locations in the environment and navigating between them. This suggests that these neurons might provide some of the information required to carry out these tasks. It also means that areas of the brain close to those that receive input from the outside world may perform more complex cognitive functions than previously thought. DOI: http://dx.doi.org/10.7554/eLife.03075.002

The retrosplenial cortex supports navigation, with one role thought to be the integration of different spatial cue types. This hypothesis was extended by examining the integration of nonspatial cues. Rats with lesions in either the dysgranular subregion of retrosplenial cortex (area 30) or lesions in both the granular and dysgranular subregions (areas 29 and 30) were tested on cross-modal object recognition (Experiment 1). In these tests, rats used different sensory modalities when exploring and subsequently recognizing the same test objects. The objects were first presented either in the dark, i.e., giving tactile and olfactory cues, or in the light behind a clear Perspex barrier, i.e., giving visual cues. Animals were then tested with either constant combinations of sample and test conditions (light to light, dark to dark), or changed “cross-modal” combinations (light to dark, dark to light). In Experiment 2, visual object recognition was tested without Perspex barriers, but using objects that could not be distinguished in the dark. The dysgranular retrosplenial cortex lesions selectively impaired cross-modal recognition when cue conditions switched from dark to light between initial sampling and subsequent object recognition, but no impairment was seen when the cue conditions remained constant, whether dark or light. The combined (areas 29 and 30) lesioned rats also failed the dark to light cross-modal problem but this impairment was less selective. The present findings suggest a role for the dysgranular retrosplenial cortex in mediating the integration of information across multiple cue types, a role that potentially applies to both spatial and nonspatial domains.

By virtue of its frontal and hippocampal connections, the retrosplenial cortex is uniquely placed to support cognition. Here, we tested whether the retrosplenial cortex is required for frontal tasks analogous to the Stroop Test, i.e., for the ability to select between conflicting responses and inhibit responding to task-irrelevant cues. Rats first acquired two instrumental conditional discriminations, one auditory and one visual, set in two distinct contexts. As a result, rats were rewarded for pressing either the right or left lever when a particular auditory or visual signal was present. In extinction, rats received compound stimuli that either comprised the auditory and visual elements that signaled the same lever response (congruent) or signaled different lever responses (incongruent) during training. On conflict (incongruent) trials, lever selection by sham-operated animals followed the stimulus element that had previously been trained in that same test context, whereas animals with retrosplenial cortex lesions failed to disambiguate the conflicting response cues. Subsequent experiments demonstrated that this abnormality on conflict trials was not due to a failure in distinguishing the contexts. Rather, these data reveal the selective involvement of the rat retrosplenial cortex in response conflict, and so extend the frontal system underlying cognitive control.

Although anterograde amnesia can occur after damage in various brain sites, hippocampal dysfunction is usually seen as the ultimate cause of the failure to learn new episodic information. This assumption is supported by anatomical evidence showing direct hippocampal connections with all other sites implicated in causing anterograde amnesia. Likewise, behavioural and clinical evidence would seem to strengthen the established notion of an episodic memory system emanating from the hippocampus. There is, however, growing evidence that key, interconnected sites may also regulate the hippocampus, reflecting a more balanced, integrated network that enables learning. Recent behavioural evidence strongly suggests that medial diencephalic structures have some mnemonic functions independent of the hippocampus, which can then act upon the hippocampus. Anatomical findings now reveal that nucleus reuniens and the retrosplenial cortex provide parallel, disynaptic routes for prefrontal control of hippocampal activity. There is also growing clinical evidence that retrosplenial cortex dysfunctions contribute to both anterograde amnesia and the earliest stages of Alzheimer's disease, revealing the potential significance of this area for clinical studies. This array of findings underlines the importance of redressing the balance and the value of looking beyond the hippocampus when seeking to explain failures in learning new episodic information.

Two strategies used to uncover neural systems for episodic–like memory in animals are discussed: (i) an attribute of episodic memory (what?when?where?) is examined in order to reveal the neuronal interactions supporting that component of memory; and (ii) the connections of a structure thought to be central to episodic memory in humans are studied at a level of detail not feasible in humans. By focusing on spatial memory (where?) and the hippocampus, it has proved possible to bring the strategies together. A review of lesion, disconnection and immediate early–gene studies in animals reveals the importance of interactions between the hippocampus and specific nuclei in the diencephalon (most notably the anterior thalamic nuclei) for spatial memory. Other parts of this extended hippocampal system include the mammillary bodies and the posterior cingulate (retrosplenial) cortex. Furthermore, by combining lesion and immediate early–gene studies it is possible to show how the loss of one component structure or tract can influence the remaining regions in this group of structures. The validity of this convergent approach is supported by new findings showing that the same set of regions is implicated in anterograde amnesia in humans.

To provide information about the possible regions involved in auditory recognition memory, this study employed an imaging technique that has proved valuable in the study of visual recognition memory. The technique was used to image populations of neurons that are differentially activated by novel and familiar auditory stimuli, thereby paralleling previous studies of visual familiarity discrimination. Differences evoked by novel and familiar sounds in the activation of neurons were measured in different parts of the rat auditory pathway by immunohistochemistry for the protein product (Fos) of the immediate early gene c-fos. Significantly higher counts of stained neuronal nuclei (266 ± 21/mm2) were evoked by novel than by familiar sounds (192 ± 17/mm2) in the auditory association cortex (area Te3; AudA). No such significant differences were found for the inferior colliculus, primary auditory cortex, postrhinal cortex, perirhinal cortex (PRH), entorhinal cortex, amygdala or hippocampus. These findings are discussed in relation to the results of lesion studies and what is known of areas involved in familiarity discrimination for visual stimuli. Differential activation is produced by novel and familiar individual stimuli in sensory association cortex for both auditory and visual stimuli, whereas the PRH is differentially activated by visual but not auditory stimuli. It is suggested that this latter difference is related to the nature of the particular auditory and visual stimuli used.

We analysed the effects of lesions of hippocampal-diencephalic projections -- fornix (FX) mamillary bodies (MB) and anterior thalamic nuclei (AT) -- and retrohippocampal (RH) lesions including entorhinal cortex and ventral subiculum, upon scene processing. All lesions except FX were neurotoxic. Rats learned to discriminate among computer-generated visual displays ("scenes") each comprising three different shapes ("objects"). The paradigm was constant-negative; one constant scene (unrewarded) appeared on every trial together with a trial-unique variable scene (rewarded). Four types of variable scene were intermingled: (1) unfamiliar objects in different positions from those of the constant (type O+P), (2) unfamiliar objects in same positions as in the constant (type O), (3) same objects as the constant in different positions (type P), (4) same objects and positions as the constant but recombined (type X). Group RH performed like controls while groups FX, AT and MB showed (surprisingly) enhanced performance on types X and O. One explanation is that normal rats attempt to process all objects in a scene concurrently, while hippocampal-projection lesions disrupt this tendency, producing a narrower attention, which paradoxically aids performance with some variable types. The results confirm that the entorhinal cortex has a different function from other components of the hippocampal system.

1 We have investigated the prediction of a relationship between the magnitude of activity-dependent increases in postsynaptic calcium and both the magnitude and direction of synaptic plastic change in the central nervous system. Activity-dependent increases in calcium were buffered to differing degrees using a range of concentrations of EGTA and the effects on synaptic plasticity were assessed. 2 Activity-dependent synaptic plasticity was induced during whole-cell recording in rat perirhinal cortex in vitro. In control conditions (0.5 mm EGTA) low frequency stimulation (LFS; 200 stimuli) delivered to neurones held at -40 or -70 mV induced long-term depression (LTD) or, at -10 mV, induced long-term potentiation (LTP). 3 The relationship between EGTA concentration (0.2 to 10 mm) and the magnitude of LTD was examined. This relationship described a U-shaped curve, as predicted by models of synaptic plasticity. This provides strong evidence that the magnitude of LTD is determined by the magnitude of the increase in intracellular calcium concentration. 4 LFS paired with depolarisation to -10 mV induced LTD, no change or LTP as activity-dependent postsynaptic calcium levels were allowed to increase progressively by the use of progressively lower concentrations of buffer (10 to 0.2 mm EGTA). 5 We investigated if the lack of plasticity that occurs at the transition between LTD and LTP is due to induction of both of these processes with zero net change, or is due to neither LTD nor LTP being induced. These experiments were possible as LTP but not LTD was blocked by the protein kinase inhibitor staurosporine while LTD but not LTP was blocked by the mGlu receptor antagonist MCPG. At the transition between LTD and LTP, blocking LTP mechanisms did not uncover LTD whilst blocking LTD mechanisms did not uncover LTP. This suggests that the transition between LTD and LTP is due to the lack of induction of both of these processes and also suggests that these two processes are induced independently of one another.

This study sought to characterize the effects of removing the nuclei of primary importance in relaying the thalamic head direction signal to the hippocampal formation (the anterior dorsal [AD] and lateral dorsal [LD] nuclei) on the performance of a variety of spatial and nonspatial tasks. The results indicate that combined excitotoxic lesions of the AD and LD nuclei produce marked deficits on a variety of spatial tasks. These tasks included T-maze alternation and the ability to locate a hidden platform set at a fixed distance and fixed direction from a beacon in a Morris water maze. Although object recognition appeared unaffected, marked impairments were found in the ability to detect when an object was placed in a novel position (object-in-place memory).