The medial prefrontal cortex—lateral entorhinal cortex circuit is essential for episodic‐like memory and associative object‐recognition

The prefrontal cortex directly projects to the lateral entorhinal cortex (LEC), an important substrate for engaging item‐associated information and relaying the information to the hippocampus. Here we ask to what extent the communication between the prefrontal cortex and LEC is critically involved in the processing of episodic‐like memory. We applied a disconnection procedure to test whether the interaction between the medial prefrontal cortex (mPFC) and LEC is essential for the expression of recognition memory. It was found that male rats that received unilateral NMDA lesions of the mPFC and LEC in the same hemisphere, exhibited intact episodic‐like (what‐where‐when) and object‐recognition memories. When these lesions were placed in the opposite hemispheres (disconnection), episodic‐like and associative memories for object identity, location and context were impaired. However, the disconnection did not impair the components of episodic memory, namely memory for novel object (what), object place (where) and temporal order (when), per se. Thus, the present findings suggest that the mPFC and LEC are a critical part of a neural circuit that underlies episodic‐like and associative object‐recognition memory. © 2015 Wiley Periodicals, Inc.     

Lateral entorhinal neurons are not spatially selective in cue‐rich environments

The hippocampus is a brain region that is critical for spatial learning, context‐dependent memory, and episodic memory. It receives major inputs from the medial entorhinal cortex (MEC) and the lateral EC (LEC). MEC neurons show much greater spatial firing than LEC neurons in a recording chamber with a single, salient landmark. The MEC cells are thought to derive their spatial tuning through path integration, which permits spatially selective firing in such a cue‐deprived environment. In accordance with theories that postulate two spatial mapping systems that provide input to the hippocampus—an internal, path‐integration system and an external, landmark‐based system—it was possible that LEC neurons can also convey a spatial signal, but that the signal requires multiple landmarks to define locations, rather than movement integration. To test this hypothesis, neurons from the MEC and LEC were recorded as rats foraged for food in cue‐rich environments. In both environments, LEC neurons showed little spatial specificity, whereas many MEC neurons showed a robust spatial signal. These data strongly support the notion that the MEC and LEC convey fundamentally different types of information to the hippocampus, in terms of their spatial firing characteristics, under various environmental and behavioral conditions. © 2010 Wiley Periodicals, Inc.     

Lateral entorhinal cortex is necessary for associative but not nonassociative recognition memory

The lateral entorhinal cortex (LEC) provides one of the two major input pathways to the hippocampus and has been suggested to process the nonspatial contextual details of episodic memory. Combined with spatial information from the medial entorhinal cortex it is hypothesised that this contextual information is used to form an integrated spatially selective, context‐specific response in the hippocampus that underlies episodic memory. Recently, we reported that the LEC is required for recognition of objects that have been experienced in a specific context (Wilson et al. (2013) Hippocampus 23:352‐366). Here, we sought to extend this work to assess the role of the LEC in recognition of all associative combinations of objects, places and contexts within an episode. Unlike controls, rats with excitotoxic lesions of the LEC showed no evidence of recognizing familiar combinations of object in place, place in context, or object in place and context. However, LEC lesioned rats showed normal recognition of objects and places independently from each other (nonassociative recognition). Together with our previous findings, these data suggest that the LEC is critical for associative recognition memory and may bind together information relating to objects, places, and contexts needed for episodic memory formation. © 2013 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Functional division of hippocampal area CA1 via modulatory gating of entorhinal cortical inputs

The hippocampus receives two streams of information, spatial and nonspatial, via major afferent inputs from the medial (MEC) and lateral entorhinal cortexes (LEC). The MEC and LEC projections in the temporoammonic pathway are topographically organized along the transverse-axis of area CA1. The potential for functional segregation of area CA1, however, remains relatively unexplored. Here, we demonstrated differential novelty-induced c-Fos expression along the transverse-axis of area CA1 corresponding to topographic projections of MEC and LEC inputs. We found that, while novel place exposure induced a uniform c-Fos expression along the transverse-axis of area CA1, novel object exposure primarily activated the distal half of CA1 neurons. In hippocampal slices, we observed distinct presynaptic properties between LEC and MEC terminals, and application of either DA or NE produced a largely selective influence on one set of inputs (LEC). Finally, we demonstrated that differential c-Fos expression along the transverse axis of area CA1 was largely abolished by an antagonist of neuromodulatory receptors, clozapine. Our results suggest that neuromodulators can control topographic TA projections allowing the hippocampus to differentially encode new information along the transverse axis of area CA1.     

Spatial and stimulus‐type tuning in the LEC,MEC, POR,PrC, CA1, and CA3 during spontaneous item recognition memory

According to the “two streams” hypothesis, the lateral entorhinal (LEC) and the perirhinal (PrC) cortices process information related to items (a “what” stream), the postrhinal (POR) and the medial entorhinal cortices (MEC) process spatial information (a “where” stream), and both types of information are integrated in the hippocampus (HIP). However, within the framework of memory function, only the HIP is reliably shown to preferentially process spatial information, and the PrC items' features. In contrast, the role of the LEC and MEC in memory is virtually unexplored, and conflicting results emerge for the POR. Moreover, the specific contribution of the hippocampal subfields CA1 and CA3 to spatial and non‐spatial memory is not thoroughly understood. To investigate which of these areas is specifically tuned to spatial demands or stimulus identity (odor or object), we assessed the pattern of activation of these areas during recognition memory by detecting the immediate‐early gene Arc, commonly used as a marker of neuronal activation. We report that all MTL areas were recruited during the spatial and the non‐spatial tasks. However, the LEC, MEC, POR, and CA1 were activated to a comparable level in spatial and non‐spatial tasks, while the PrC was tuned to stimulus‐type, not spatial demands, and CA3 to spatial demands but not stimulus‐type. Results are discussed within the frame of a recent model suggesting that the MTL could be segregated in terms of memory processes, such as recollection and familiarity, rather than information content. © 2013 Wiley Periodicals, Inc.     

Lateral entorhinal cortex is critical for novel object‐context recognition

Episodic memory incorporates information about specific events or occasions including spatial locations and the contextual features of the environment in which the event took place. It has been modeled in rats using spontaneous exploration of novel configurations of objects, their locations, and the contexts in which they are presented. While we have a detailed understanding of how spatial location is processed in the brain relatively little is known about where the nonspatial contextual components of episodic memory are processed. Initial experiments measured c‐fos expression during an object‐context recognition (OCR) task to examine which networks within the brain process contextual features of an event. Increased c‐fos expression was found in the lateral entorhinal cortex (LEC; a major hippocampal afferent) during OCR relative to control conditions. In a subsequent experiment it was demonstrated that rats with lesions of LEC were unable to recognize object‐context associations yet showed normal object recognition and normal context recognition. These data suggest that contextual features of the environment are integrated with object identity in LEC and demonstrate that recognition of such object‐context associations requires the LEC. This is consistent with the suggestion that contextual features of an event are processed in LEC and that this information is combined with spatial information from medial entorhinal cortex to form episodic memory in the hippocampus. © 2013 Wiley Periodicals, Inc.     

Distal CA1 Maintains a More Coherent Spatial Representation than Proximal CA1 When Local and Global Cues Conflict

Entorhinal cortical projections show segregation along the transverse axis of CA1, with the medial entorhinal cortex (MEC) sending denser projections to proximal CA1 (pCA1) and the lateral entorhinal cortex (LEC) sending denser projections to distal CA1 (dCA1). Previous studies have reported functional segregation along the transverse axis of CA1 correlated with the functional differences in MEC and LEC. pCA1 shows higher spatial selectivity than dCA1 in these studies. We employ a double rotation protocol, which creates an explicit conflict between the local and the global cues, to understand the differential contributions of these reference frames to the spatial code in pCA1 and dCA1 in male Long–Evans rats. We show that pCA1 and dCA1 respond differently to this local-global cue conflict. pCA1 representation splits as predicted from the strong conflicting inputs it receives from MEC and dCA3. In contrast, dCA1 rotates more in concert with the global cues. In addition, pCA1 and dCA1 display comparable levels of spatial selectivity in this study. This finding differs from the previous studies, perhaps because of richer sensory information available in our behavior arena. Together, these observations indicate that the functional segregation along proximodistal axis of CA1 is not of the amount of spatial selectivity but that of the nature of the different inputs used to create and anchor spatial representations.SIGNIFICANCE STATEMENT Subregions of the hippocampus are thought to play different roles in spatial navigation and episodic memory. It was previously thought that the distal part of area CA1 of the hippocampus carries lesser information about space than proximal CA1 (pCA1). We report that distal CA1 (dCA1) spatial representation moves more in concert with the global cues than pCA1 when the local and the global cues conflict. We also show that spatial selectivity is comparable along the proximodistal axis in this experimental protocol. Thus, different parts of the brain receiving differential outputs from pCA1 and dCA1 receive spatial information in different spatial reference frames encoded using different sets of inputs, rather than different amounts of spatial information as thought earlier.     

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.     

Lesions of the medial or lateral perforant path have different effects on hippocampal contributions to place learning and on fear conditioning to context.

The axons of the neurons in the medial and lateral components of the entorhinal cortex (MEC and LEC) form the medial and lateral perforant paths (MPP and LPP) which represent the major source of cortical input to the hippocampus. Anatomical, physiological, and pharmacological studies have shown that MPP and LPP are distinct. Unfortunately, assessment of the functional significance of damage to either of these pathways has not used tasks known to be sensitive to hippocampal function in the rodent. In this study, we performed dissociated lesions of MPP and LPP using a combined physiological and anatomical method. Rats with lesions of either the MPP or the LPP were tested on place learning in the water task and on a discriminative fear conditioning to context task. The results indicated that the MPP, but not LPP, lesions resulted in impaired place learning. The context discrimination data revealed an amygdala-like, reduced fear effect of MPP lesions and an enhanced discriminative fear conditioning to context effect of LPP lesions. Consistent with a two-stage model of spatial learning proposed by Buzsaki (Buzsaki G. Two-stage model of memory trace formation: a role for 'noisy' brain states. Neuroscience 1989;31(3):551-570), the impairment in the water task can be interpreted as reflecting the higher efficiency of the MPP synapses in activating hippocampal neurons. The context discrimination results can be explained by either a dissociation of sensory information that reaches the MEC and LEC, or alternatively, by a dissociation between the limbic nature of the MEC and the sensory nature of the LEC.     

Medial Entorhinal Cortex Excitatory Neurons Are Necessary for Accurate Timing

The hippocampal region has long been considered critical for memory of time, and recent evidence shows that network operations and single-unit activity in the hippocampus and medial entorhinal cortex (MEC) correlate with elapsed time. However, whether MEC activity is necessary for timing remains largely unknown. Here we expressed DREADDs (designer receptors exclusively activated by designer drugs) under the CaMKIIa promoter to preferentially target MEC excitatory neurons for chemogenetic silencing, while freely moving male rats reproduced a memorized time interval by waiting inside a region of interest. We found that such silencing impaired the reproduction of the memorized interval and led to an overestimation of elapsed time. Trial history analyses under this condition revealed a reduced influence of previous trials on current waiting times, suggesting an impairment in maintaining temporal memories across trials. Moreover, using GLM (logistic regression), we show that decoding behavioral performance from preceding waiting times was significantly compromised when MEC was silenced. In addition to revealing an important role of MEC excitatory neurons for timing behavior, our results raise the possibility that these neurons contribute to such behavior by holding temporal information across trials.SIGNIFICANCE STATEMENT Medial temporal lobe (MTL) structures are implicated in processing temporal information. However, little is known about the role MTL structures, such as the hippocampus and the entorhinal cortex, play in perceiving or reproducing temporal intervals. By chemogenetically silencing medial entorhinal cortex (MEC) excitatory activity during a timing task, we show that this structure is necessary for the accurate reproduction of temporal intervals. Furthermore, trial history analyses suggest that silencing MEC disrupts memory mechanisms during timing. Together, these results suggest that MEC is necessary for timing behavior, possibly by representing the target interval in memory.     

Topographic organization of orbitofrontal projections to the parahippocampal region in rats

The parahippocampal region, which comprises the perirhinal, postrhinal, and entorhinal cortices, as well as the pre‐ and parasubiculum, receives inputs from several association cortices and provides the major cortical input to the hippocampus. This study examined the topographic organization of projections from the orbitofrontal cortex (OFC) to the parahippocampal region in rats by injecting anterograde tracers, biotinylated dextran amine (BDA) and Phaseolus vulgaris‐leucoagglutinin (PHA‐L), into four subdivisions of OFC. The rostral portion of the perirhinal cortex receives strong projections from the medial (MO), ventral (VO), and ventrolateral (VLO) orbitofrontal areas and the caudal portion of lateral orbitofrontal area (LO). These projections terminate in the dorsal bank and fundus of the rhinal sulcus. In contrast, the postrhinal cortex receives a strong projection specifically from VO. All four subdivisions of OFC give rise to projections to the dorsolateral parts of the lateral entorhinal cortex (LEC), preferentially distributing to more caudal levels of LEC. The medial entorhinal cortex (MEC) receives moderate input from VO and weak projections from MO, VLO, and LO. The presubiculum receives strong projections from caudal VO but only weak projections from other OFC regions. As for the laminar distribution of projections, axons originating from OFC terminate more densely in upper layers (layers I–III) than in deep layers in the parahippocampal region. These results thus show a striking topographic organization of OFC‐to‐parahippocampal connectivity. Whereas LO, VLO, VO, and MO interact with perirhinal–LEC circuits, the interactions with postrhinal cortex, presubiculum, and MEC are mediated predominantly through the projections of VO. J. Comp. Neurol. 522:772–793, 2014. © 2013 Wiley Periodicals, Inc.     

Memory in the aging brain: doubly dissociating the contribution of the hippocampus and entorhinal cortex

Since the time of Aristotle it has been thought that memories can be divided into two basic types; conscious recollections and familiarity-based judgments. Neuropsychological studies have provided indirect support for this distinction by suggesting that different regions within the human medial temporal lobe (MTL) are involved in these two forms of memory, but none of these studies have demonstrated that these brain regions can be fully dissociated. In a group of nondemented elderly subjects, we found that performance on recall and recognition tests was predicted preferentially by hippocampal and entorhinal volumes, respectively. Structural equation modeling revealed a double dissociation, whereby age-related reductions in hippocampal volume resulted in decreases in recollection, but not familiarity, whereas entorhinal volume was preferentially related to familiarity. The results demonstrate that the forms of episodic memory supported by the human hippocampus and entorhinal cortex can be fully dissociated, and indicate that recollection and familiarity reflect neuroanatomically distinct memory processes.     

Unstable CA1 place cell representation in rats with entorhinal cortex lesions

Recent studies emphasize the importance of the entorhinal cortex in spatial representation and navigation. Furthermore, evidence is accumulating to show that spatial processing depends on interactions between the entorhinal cortex and the hippocampus. To investigate these interactions, we examined the effects of entorhinal cortex lesions on the activity of hippocampal CA1 place cells. Rats received bilateral radiofrequency lesions of the entorhinal cortex or sham lesions before place cell recording. Place cells were recorded as the rats performed a pellet-chasing task in a cylinder containing three cue-objects. Entorhinal cortex lesions did not abolish place cell spatial firing but reduced noticeably discharge rate and field size. Most importantly, the lesions affected firing field stability when cells were recorded both in constant conditions and following cue manipulations (object rotation, object removal). These findings indicate that the entorhinal cortex is necessary for the stability of hippocampal representations across exposures to a familiar environment. Consistent with the recent discovery of grid cells in the medial entorhinal cortex, our results suggest that the entorhinal cortex contributes to providing a spatial framework that would enable the hippocampus to maintain stable environment-specific representations.     

Late post-learning effect of entorhinal cortex electrical stimulation persists despite destruction of the perforant path

In an appetitive learning task in mice, stimulation of the lateral entorhinal cortex (LEC) 30 min after training produced an improvement in retention 24 h later, as well as faster extinction of conditioning. This effect persisted in animals with bilateral lesions of the perforant path. In addition, the threshold for hippocampal after-discharges produced by LEC stimulation was raised significantly in perforant-path lesioned animals. The results indicate a functional dissociation between hippocampal and cortical mechanisms involved in memory consolidation.     

How do spatial learning and memory occur in the brain? Coordinated learning of entorhinal grid cells and hippocampal place cells

Spatial learning and memory are important for navigation and formation of episodic memories. The hippocampus and medial entorhinal cortex (MEC) are key brain areas for spatial learning and memory. Place cells in hippocampus fire whenever an animal is located in a specific region in the environment. Grid cells in the superficial layers of MEC provide inputs to place cells and exhibit remarkable regular hexagonal spatial firing patterns. They also exhibit a gradient of spatial scales along the dorsoventral axis of the MEC, with neighboring cells at a given dorsoventral location having different spatial phases. A neural model shows how a hierarchy of self-organizing maps, each obeying the same laws, responds to realistic rat trajectories by learning grid cells with hexagonal grid firing fields of multiple spatial scales and place cells with unimodal firing fields that fit neurophysiological data about their development in juvenile rats. The hippocampal place fields represent much larger spaces than the grid cells to support navigational behaviors. Both the entorhinal and hippocampal self-organizing maps amplify and learn to categorize the most energetic and frequent co-occurrences of their inputs. Top-down attentional mechanisms from hippocampus to MEC help to dynamically stabilize these spatial memories in both the model and neurophysiological data. Spatial learning through MEC to hippocampus occurs in parallel with temporal learning through lateral entorhinal cortex to hippocampus. These homologous spatial and temporal representations illustrate a kind of "neural relativity" that may provide a substrate for episodic learning and memory.     

Neuropsychological correlates of hippocampal and rhinal cortex volumes in patients with mesial temporal sclerosis

Considerable progress has been made toward understanding the function of the primate rhinal cortex, comprising the entorhinal (ErC) and perirhinal (PrC) cortices. However, translating animal models to human memory has been limited by the technological problems associated with characterizing neural structures in vivo. Functional correlates of hippocampal and rhinal cortex volume changes were examined in a sample of 61 temporal lobe epilepsy patients with mesial temporal sclerosis (MTS; 33 left, 28 right). Patients were administered the Wechsler Adult Intelligence Scale (revised or third edition), the Wechsler Memory Scale (revised or third edition), and a spatial maze task. Neuropsychological data, together with rhinal cortex and hippocampal volumes, collected in our earlier study (O'Brien CE, Bowden SC, Whelan G, Cook MJ, unpublished observations), were analyzed using multiple regression. The only significant predictor of verbal memory function was the difference score between the volume of left hippocampus and the left PrC. Spatial maze scores were predicted by the bilateral sum of ErC volume. The difference score between the left hippocampus and left PrC volumes was the most powerful predictor of verbal episodic memory. Right hippocampal volume was not a significant predictor of nonverbal episodic memory. Verbal and nonverbal semantic memory were not significantly predicted by any combination of rhinal cortex structures. This quantitative study suggests a lateralized or material-specific memory function for the left hippocampus and left PrC, in contrast to the bilateral role of the ErC. The left hippocampus and left PrC appear to act on verbal memory function through an opposing relationship. Finally, differentiation between hippocampal and subhippocampal components in terms of episodic and semantic memory, respectively, could not be supported by the current data.     

Preserved hippocampal novelty responses following anterior temporal‐lobe resection that impairs familiarity but spares recollection

Although it is well established that the integrity of the medial temporal lobe (MTL) is critical for declarative memory, the functional organization of the MTL remains a matter of intense debate. One issue that has received little consideration so far is whether the hippocampus can function normally in the presence of a lesion to perirhinal cortex that produces noticeable memory impairments. This question is intriguing as the MTL forms a hierarchical system, in which perirhinal cortex represents one of the critical nodes in the reciprocal projections between neocortical association areas and the hippocampus. Here, we used functional magnetic resonance imaging to examine whether NB, an individual who underwent surgical resection of the left anterior temporal lobe that included large aspects of perirhinal and entorhinal cortex but spared the hippocampus, exhibits intact hippocampal novelty responses to auditory sentences. Our results revealed such evidence in NB's left and right hippocampus. They complement previous behavioral work in NB, indicating that recollective processes considered to rely on hippocampal integrity are also preserved. Further analyses revealed intact novelty responses in structures that provide neuroanatomical input to the hippocampus, including remaining perirhinal cortex and surgically spared parahippocampal cortex. These findings point to viable neuroanatomical mechanisms as to how functional integrity in the hippocampus may be maintained in the face of widespread, but incomplete removal of its input structures. © 2010 Wiley‐Liss, Inc.     

Common pathway in the medial temporal lobe for storage and recovery of words as revealed by event-related functional MRI

Lesion studies have provided compelling evidence that episodic memory is dependent on the integrity of the medial temporal lobe (MTL). This role of the MTL in episodic memory has been supported by several neuroimaging studies during both episodic encoding and retrieval. After two meta-analyses of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies, we investigated a possible dissociation within the MTL memory system in relation to encoding and retrieval processes. Based on previous reports that specifically related the function of the MTL in episodic memory to successful encoding and actual recovery of information, we applied event-related fMRI to compare successful encoding of words (ES) directly with successful recognition of those same words (RS). Our results did not indicate a clear dissociation between encoding and retrieval activations in the MTL. Instead, a region in the left MTL, covering the parahippocampal cortex and hippocampal formation, which was activated during ES almost completely overlapped with the area that was activated during RS. An additional region in the left anterior MTL, including the entorhinal cortex, was found to be activated exclusively during ES. Research has indicated that a large percentage of cells in this region are particularly sensitive to the relative novelty of stimuli. Our results, therefore, suggest that the parahippocampal/hippocampal region is involved in the formation and subsequent reactivation of memory traces, whereas the activity observed in the entorhinal cortex may reflect elementary memory processes related to novelty detection.     

Dissociation of limbic structures by pharmacological effects of diazepam on electrical self-stimulation in the mouse

The effect of diazepam was tested on self-stimulation (SS) in 21 mice implanted with a bipolar electrode in the lateral hypothalamus (LH), the dorsolateral hippocampus (HPC) or the lateral entorhinal cortex (LEC). Diazepam, injected i.p. in doses of 0.5, 1 and 2 mg/kg, significantly increased SS rates with electrodes in LH while 4 and 8 mg/kg of diazepam had no significant effect. At low doses, similar increases were seen in mice with LEC electrodes but high doses produced a significant suppression. HPC animals showed an almost total suppression of SS beginning at 2 mg/kg of diazepam; lower doses had no significant effect. The results indicate that entorhinal and hippocampal SS are at least partly independent phenomena; in addition, the suppression of SS by moderate doses of diazepam remains specific to the HPC among the brain structures studied to date.     

Differential neuronal responsiveness in primate perirhinal cortex and hippocampal formation during performance of a conditional visual discrimination task

Neuronal responses in the hippocampal formation, including the entorhinal cortex, have been compared with those in the inferior temporal cortex, including the perirhinal cortex, during performance by monkeys of a visual conditional discrimination task. In the task, the arrangement of three geometric shapes determined the correctness of either a left or right behavioural response according to a conditional rule. Neurons that responded differently to different types of trial were common (50% of the visually responsive neurons) in the entorhinal cortex, perirhinal cortex and area TE of the inferior temporal cortex, but significantly less common in the hippocampus (13%). This differential incidence suggests a more important role for the rhinal cortices and area TE than for the hippocampus in this task. Based on the neuronal responses, arguments are advanced that the animals probably solved the task by a strategy that did not require spatial or hippocampal processing. Thus, of the differential responses, those that would allow the animals to solve the task by using a conditional rule and so avoid spatial processing were twice as common (37%) as those allowing solution to be by selection of a particular spatially directed response to each arrangement of shapes (19%). Moreover, the differential latencies of responses that allowed the task to be solved by a conditional rule were shorter (< approximately 165 ms), and hence processing was faster, than those that provided information about particular individual types of trial ( approximately 195 ms). Even so, hippocampal responsiveness in the conditional task was differentially enhanced when compared with that during a recognition memory task, and the neuronal responses potentially allow the animal to employ a second, alternative strategy that might be expected to depend on hippocampal processing.