Wistar rats show episodic-like memory for unique experiences

Human episodic memory refers to the recollection of an unique past experience in terms of its details, its locale, and temporal occurrence. Episodic memory, even in principle, has been difficult to demonstrate in non-verbal mammals. Previously, we provided evidence that mice are able to form an integrated memory for "what," "where," and "when" aspects of single experiences by combining different versions of the novelty-preference paradigm, i.e., object recognition memory, the memory for locations in which objects were explored, and the temporal order memory for objects presented at distinct time points. In the present series of experiments we evaluated whether this paradigm, with minor modifications, also works with rats. We found that rats spent more time exploring an "old familiar" object relative to a "recent familiar" object, suggesting that they recognized objects previously explored during separate trials and remembered their order of presentation. Concurrently, the rats responded differentially to spatial object displacement dependent on whether an "old familiar" or "recent familiar" object was shifted to a location, where it was not encountered previously. These results provide strong evidence that the rats established an integrated memory for "what," "where," and "when." We also found that acute stress impaired the animal's performance in the episodic-like memory task, which, however, could be partially reversed by the N-Methyl-D-aspartate-receptors agonist D-cycloserine.     

Excitotoxic lesions restricted to the dorsal CA1 field of the hippocampus impair spatial memory and extinction learning in C57BL/6 mice

Recent studies in patients with hippocampal lesions have indicated that the degree of memory impairment is proportional to the extent of damage within the hippocampus. Particularly, patients with damage restricted to the CA1 field demonstrate moderate to severe anterograde amnesia with only slight retrograde amnesia. Comparable results are also seen in other species such as non-human primates and rats; however, the effect of selective damage to CA1 has not yet been characterized in mice. In the present study, we investigated the effects of excitotoxic (NMDA) lesions of dorsal CA1 on several aspects of learning and memory performance in mice. Our data indicate that dorsal CA1 lesioned mice are hyperactive upon exposure to a novel environment, have spatial working memory impairments in the Y-maze spontaneous alternation task, and display deficits in an 8-arm spatial discrimination learning task. Lesioned mice are able to acquire an operant lever-press task but demonstrate extinction learning deficits in this appetitive operant paradigm. Taken together, our results indicate that lesions to dorsal CA1 in mice induce selective learning and memory performance deficits similar to those observed in other species, and extend previous findings indicating that this region of the hippocampus is critically involved in the processing of spatial information and/or the processing of inhibitory responses.     

Reinstatement of episodic-like memory in rats by neurokinin-1 receptor antagonism

We previously showed that a systemic administration of the selective non-peptide neurokinin-1-receptor (NK-1-R) antagonist SR140333 increases hippocampal acetylcholine levels and facilitates long term memory. In the present study, we investigated whether systemic SR140333 has beneficial effects on episodic-like memory for unique experiences. Rats received either no injection, a vehicle injection or SR140333 at doses of 1, 3 and 9 mg/kg (i.p.) prior to the acquisition of an object memory for what, where and when. In line with previous results, untreated rats showed episodic-like memory, while vehicle-injected rats were impaired. A low dose of 1mg/kg SR140333 reinstated episodic-like memory. This result might be related to the effects of SR140333 on hippocampal cholinergic transmission and/or on the stress-response elicited by the injection procedure. Higher doses of SR140333 (3 and 9 mg/kg) induced psychomotor effects, including stereotypic behaviors and arched posture. Since NK-1-R antagonists have anxiolytic and promestic properties and induce hippocampal acetylcholine release at lower doses, they might be effective in the alleviation of the cognitive deficits and increased anxiety seen in early stages of Alzheimer's disease.     

Selective fimbria and thalamic lesions differentially impair forms of working memory in rats.

Several series of experiments were designed to compare the effects of selective lesions of the fimbria or of thalamic nuclei on three different tasks involving working memory in rats: object recognition, place recognition, and the radial arm maze test. The main effects of fimbria lesions were as follows: they produced deficits in the radial maze; object recognition was spared or even facilitated, whereas place recognition was impaired. Electrolytic lesions of either centromedian-parafascicularis (CM-Pf) or dorsomedialis (DM) nuclei produced highly significant deficits in the radial maze test but spared object and place recognition. Ibotenate lesions of the CM-Pf had no effect on any test, which means that the critical structure in the effects of the electrolytic lesions of the CM-Pf was the fasciculus retroflexus (FR). These data may contribute two main points to animal models of hippocampal and thalamic amnesia: (1) different forms of working memory in rats might have different neural bases and (2) the FR may be involved in learning and memory processes.     

Distinct roles for dorsal CA3 and CA1 in memory for sequential nonspatial events

Previous studies have suggested that dorsal hippocampal areas CA3 and CA1 are both involved in representing sequences of events that compose unique episodes. However, it is uncertain whether the contribution of CA3 is restricted to spatial information, and it is unclear whether CA1 encodes order per se or contributes by an active maintenance of memories of sequential events. Here, we developed a new behavioral task that examines memory for the order of sequential nonspatial events presented as trial-unique odor pairings. When the interval between odors within a studied pair was brief (3 sec), bilateral dorsal CA3 lesions severely disrupted memory for their order, whereas dorsal CA1 lesions did not affect performance. However, when the inter-item interval was extended to 10 sec, CA1 lesions, as well as CA3 lesions, severely disrupted performance. These findings suggest that the role of CA3 in sequence memory is not limited to spatial information, but rather appears to be a fundamental property of CA3 function. In contrast, CA1 becomes involved when memories for events must be held or sequenced over long intervals. Thus, CA3 and CA1 are both involved in memory for sequential nonspatial events that compose unique experiences, and these areas play different roles that are distinguished by the duration of time that must be bridged between key events.Episodic memory involves the ability to encode and retrieve the order of events in individual experiences (Tulving 1983). Recent evidence in both animals and humans indicates that the hippocampus plays a critical role in this capacity. In animals, damage to the hippocampus impairs memory for the order of associated elements that compose an episode (Fortin et al. 2002; Kesner et al. 2002), and hippocampal neuronal activity reflects processing of the order of events in both spatial (Dragoi and Buzsáki 2006; Foster and Wilson 2007) and nonspatial episodes (Manns et al. 2007). In humans, hippocampal activation has also been related to memory for the order of elements (Kumaran and Maguire 2006; Lehn et al. 2009; Ross et al. 2009).Within the hippocampal circuitry, contributions of the CA3 and CA1 fields are probably most extensively studied, but this work has not yet clarified the distinct roles of these areas in sequence memory. Computational models suggest that the recurrent connections of CA3 cells operate as an attractor network that computes associations between elements (Norman and O''Reilly 2003; Rolls 2007) and is suitable for representing sequences of events in episodic memories (Jensen and Lisman 1996; Levy 1996; Lisman 1999). Studies on the effects of selective damage within the hippocampus have shown that CA3 is critical for remembering sequences of spatial locations (Hunsaker et al. 2008a), but not sequences of nonspatial events (Hoge and Kesner 2007). It is, therefore, uncertain whether CA3 is critical for sequence memory per se, rather than other aspects of spatial processing. Other observations suggest that CA1 may be involved in memory for the order of both spatial (Hunsaker et al. 2008a) and nonspatial stimuli (Hoge and Kesner 2007; Manns et al. 2007). However, it is not clear whether the contribution of CA1 involves integrating sequential elements of a memory or instead participates by active maintenance of event memories that underlies bridging sequential events in an episode (Kesner et al. 2005).To shed light on these issues, we compared the effects of selective damage to CA3 and CA1 on memory for the order of nonspatial events that occurred in unique episodes. We designed a task, based on the delayed-nonmatching-to-sample test, wherein subjects were required to remember the order of two sequentially presented stimuli in trial–unique-paired associations (Fig. 1).Open in a separate windowFigure 1.Test of memory for the order of stimuli in trial-unique odor pairs. At study, animals were presented with 10 odor-paired associates and odors in a pair were presented one at a time. At test, animals were presented with the same 10 odor pairs and were required to distinguish pairs where the odors within a pair were presented in the same order as during study (“old”) from pairs where the odors were presented in the reverse order (“new”). Old and new order test pairs were presented in a pseudorandom order. The first odor in each test pair acted as a cue to the ordering of the odors within a test pair; the animal was required to place its nose over the cup, but no digging response was required or rewarded. When the second cup was presented, the animal could dig to retrieve a reward if the order was new. If the order was old, the animal was required to approach an empty cup in the back of the home cage to obtain reward.     

Cytotoxic lesions of the hippocampus do not impair social recognition memory in socially housed rats

Socially housed mice with cytotoxic lesions of the hippocampus do not exhibit social recognition memory 30 min following exposure to a juvenile mouse, however the social recognition memory of singly housed rats is unimpaired. The present study tests the hypothesis that social housing of rats could render social recognition memory hippocampally dependent as seen for mice. Rats were housed with juveniles or with adults. Two social recognition one-animal tests paralleling those used with mice were carried out. Seven social discrimination two-animal tests were also given. Sham operated and hippocampally lesioned rats had normal social memory at 30 min whether socially housed for 24, 48 h, 7 or 8 days prior to testing. These findings support other results indicating the hippocampus proper is not required for normal social memory in rats. In a final experiment, rats socially housed in groups of three since weaning, were tested for 30 min and 24 h social memory. Unlike mice, rats socially housed throughout life exhibited social memory only at 30 min, but not at 24 h. Manipulations that extend social memory in rats may be required to render social memory hippocampally dependent or rats and mice may differ in the neural mediation of social memory.     

NK(3) receptor agonism promotes episodic-like memory in mice

The mammalian tachykinins are a family of closely related peptides including substance P, neurokinin A, neurokinin B and, recently, also hemokinin-1. They are present in the peripheral and central nervous systems, and bind to three known neurokinin (NK) receptors, the NK(1)-, NK(2)- and NK(3) receptors. In both rodents and humans, NK(3) receptors are expressed in brain structures which have been associated with learning and memory. Evidence for a role of NK(3) receptors in learning and memory has been found in NK(3) receptor knockout mice. Here, we investigated the influence of the NK(3) receptor agonist, senktide (0.1, 0.2 and 0.4 mg/kg), on the performance of C57BL/6 mice in a recently developed episodic-like memory task. Since a promnestic effect of senktide was expected, we employed an experimental protocol that provided sub-optimal learning conditions for episodic-like memory. The results indicate that senktide promotes episodic-like memory in mice in a dose-dependent manner, providing, for the first time, evidence for an involvement of NK(3) receptors in episodic-like memory.     

Inferior colliculus lesions impair eyeblink conditioning in rats

The neural plasticity necessary for acquisition and retention of eyeblink conditioning has been localized to the cerebellum. However, the sources of sensory input to the cerebellum that are necessary for establishing learning-related plasticity have not been identified completely. The inferior colliculus may be a source of sensory input to the cerebellum through its projection to the medial auditory thalamus. The medial auditory thalamus is necessary for eyeblink conditioning in rats and projects to the lateral pontine nuclei, which then project to the cerebellar nuclei and cortex. The current experiment examined the role of the inferior colliculus in auditory eyeblink conditioning. Rats were given bilateral or unilateral (contralateral to the conditioned eye) lesions of the inferior colliculus prior to 10 d of delay eyeblink conditioning with a tone CS. Rats with bilateral or unilateral lesions showed equivalently impaired acquisition. The extent of damage to the contralateral inferior colliculus correlated with several measures of conditioning. The findings indicate that the contralateral inferior colliculus provides auditory input to the cerebellum that is necessary for eyeblink conditioning.     

Lateral and anterior thalamic lesions impair independent memory systems

Damage to the medial region of the thalamus, both in clinical cases (e.g., patients with infarcts or the Korsakoff's syndrome) and animal lesion models, is associated with variable amnesic deficits. Some studies suggest that many of these memory deficits rely on the presence of lateral thalamic lesions (LT) that include the intralaminar nuclei, presumably by altering normal function between the striatum and frontal cortex. Other studies suggest that the anterior thalamic nuclei (AT) may be more critical, as a result of disruption to an extended hippocampal system. Here, highly selective LT and AT lesions were made to test the prediction that these two regions contribute to two different memory systems. Only LT lesions produced deficits on a preoperatively acquired response-related (egocentric) working memory task, tested in a cross-maze. Conversely, only AT lesions impaired postoperative acquisition of spatial working memory, tested in a radial maze. These findings provide the first direct evidence of a double dissociation between the LT and AT neural aggregates. As the lateral and the anterior medial thalamus influence parallel independent memory processing systems, they may each contribute to memory deficits, depending on lesion extent in clinical and experimental cases of thalamic amnesia.     

Recollection in an episodic-like memory task in the rat

Episodic memory in humans is the conscious recollection of a past event. Animal models of episodic-like memory assess the memory for "what"happened, "where" it happened, and either "when" it happened, or in "which" context it happened, although recollection on such tasks is often difficult to measure. Here we present the first evidence of successful recollection of a past event in a rat in a task which is easily performed, requires little training, and is easily adaptable for other commonly used laboratory species.     

Discrimination of what,when, and where: Implications for episodic-like memory in rats

We investigated the discrimination of what, when, and where in rats (n = 5) using an eight-arm radial maze. Rats received daily training consisting of forced-choice visits to four baited arms, one of which was randomly chosen each day to contain chocolate (Phase 1). In Phase 2, all eight arms were available. After a short (30 min) retention interval (RI), the four arms that were not available in Phase 1 provided food. After a long (4 h) RI, the four remaining arms plus the arm containing chocolate provided food (i.e., the chocolate arm replenished). The rats visited the chocolate location after the long RI more than after the short RI. Next, chocolate was paired with lithium chloride, and subsequent testing used the long RI. The rats visited the chocolate location less after the taste-aversion manipulation than in previous training, demonstrating knowledge of what, when, and where. Implications for episodic-like memory are discussed.     

Neurotoxic dorsal CA1 lesions versus 4 VO ischaemic lesions: behavioural comparisons

Anterograde amnesia, a common consequence of transient cerebral ischaemia, has been attributed to cell loss in the hippocampal CA1 subfield. However, variable, widespread damage outside hippocampal CA1 can also occur following ischaemia. We compared the functional consequences of ischaemia and ibotenate acid CA1 lesions on 2 spatial memory tasks (water maze 'place' and 'matching-to-position') to address the possibility that extra-CA1 loss contributes to ischaemia-induced memory deficits in the rat. During place task acquisition, ischaemic rats showed deficits on more measures than ibotenic rats, and during a 1 min probe trial, only ischaemic rats were impaired. On the matching-to-position task, ibotenic rats showed greater impairment than ischaemic rats in terms of one-trial learning, whereas ischaemic rats were more impaired after Trial 2. Ischaemia and ibotenic acid lesions resulted in equivalent CA1 loss, but silver impregnation revealed additional extra-CA1 cell loss in ischaemic rats. Together with the greater behavioural deficits of ischaemic rats, these data indicate a role for extra-CA1 cell loss in ischaemia-induced memory impairments in both animals and humans.     

Medial dorsal thalamic lesions and working memory in the rat

Pigmented rats of the DA strain with either radiofrequency or ibotenic acid lesions of the thalamic nucleus medialis dorsalis were postoperatively given nonspatial and spatial tests of working memory. In the nonspatial task, delayed nonmatching-to-sample, rats with both types of thalamic lesions showed acquisition impairments. The subgroup of rats with nucleus medialis dorsalis lesions that were able to reach the acquisition criterion did, however, perform normally when the retention interval was extended to 60 s. In the spatial task, delayed forced-alternation, rats were tested with differing retention intervals and with both spaced and massed trials. Damage to nucleus medialis dorsalis had no effect on acquisition or on spaced trials, but a slight deficit was found in the animals with radiofrequency lesions under the massed trial condition. Much clearer deficits were, however, present in those animals in which the lesion extended appreciably into the anterior thalamic nuclei. The findings indicate that while cellular damage to nucleus medialis dorsalis may disrupt learning, some impairments in tests of spatial working memory attributed to this nucleus may reflect damage to the adjacent anterior thalamic nuclei.     

Electrolytic lesions of the dorsal hippocampus disrupt renewal of conditional fear after extinction

There is a growing body of evidence that the hippocampus is critical for context-dependent memory retrieval. In the present study, we used Pavlovian fear conditioning in rats to examine the role of the dorsal hippocampus (DH) in the context-specific expression of fear memory after extinction (i.e., renewal). Pre-training electrolytic lesions of the DH blunted the expression of conditional freezing to an auditory conditional stimulus (CS), but did not affect the acquisition of extinction to that CS. In contrast, DH lesions impaired the context-specific expression of extinction, eliminating the renewal of fear normally observed to a CS presented outside of the extinction context. Post-extinction DH lesions also eliminated the context dependence of fear extinction. These results are consistent with those using pharmacological inactivation of the DH and suggest that the DH is required for using contextual stimuli to regulate the expression of fear to a Pavlovian CS after extinction.     

Encoding, consolidation, and retrieval of contextual memory: differential involvement of dorsal CA3 and CA1 hippocampal subregions

Studies on human and animals shed light on the unique hippocampus contributions to relational memory. However, the particular role of each hippocampal subregion in memory processing is still not clear. Hippocampal computational models and theories have emphasized a unique function in memory for each hippocampal subregion, with the CA3 area acting as an autoassociative memory network and the CA1 area as a critical output structure. In order to understand the respective roles of the CA3- and CA1-hippocampal areas in the formation of contextual memory, we studied the effects of the reversible inactivation by lidocaine of the CA3 or CA1 areas of the dorsal hippocampus on acquisition, consolidation, and retrieval of a contextual fear conditioning. Whereas infusions of lidocaine never impaired elementary tone conditioning, their effects on contextual conditioning provided interesting clues about the role of these two hippocampal regions. They demonstrated first that the CA3 area is necessary for the rapid elaboration of a unified representation of the context. Secondly, they suggested that the CA1 area is rather involved in the consolidation process of contextual memory. Third, they showed that CA1 or CA3 inactivation during retention test has no effect on contextual fear retrieval when a recognition memory procedure is used. In conclusion, our findings point as evidence that CA1 and CA3 subregions of the dorsal hippocampus play important and different roles in the acquisition and consolidation of contextual fear memory, whereas they are not required for context recognition.     

Inferior olive lesions impair concurrent taste aversion learning in rats.

Taste aversion learning can be established according to two different procedures, concurrent and sequential. For the concurrent task, two different taste stimuli are offered at the same time, one associated with simultaneous intragastric administration of an aversive stimulus and the other associated with physiological saline. This discrimination is learned by sham-lesioned control animals and by animals with lesions in the cerebellar cortex but not by rats lesioned in the inferior olive. At the same time, animals with lesions in the inferior olive and sham-lesioned animals achieve sequential learning when the gustatory stimuli are offered individually during each daily session. The results obtained show that electrolytic lesions in the inferior olive impair acquisition of concurrent learning and are analyzed in terms of an anatomical system consisting of the vagus nerve, inferior olive, and cerebellum, which differentiates between the two modalities of taste aversion learning, concurrent and sequential.     

Disruption of delayed memory for a sequence of spatial locations following CA1- or CA3-lesions of the dorsal hippocampus

Axon-sparing neurotoxic lesions of CA1 or CA3 were produced in the dorsal hippocampus to test dissociative lesion effects on spatial working memory for sequential items. Rats were required to remember four different sections sequentially presented on a newly devised maze (i.e., Tulum maze) during a study phase. Each section was cued by a unique object that was specifically associated with each location within the section during the study phase. Following a 15-s delay and during the test phase, rats were required to revisit the location within a section randomly chosen among the previously visited sections in the absence of the cued object. Both CA1 and CA3 lesions similarly disrupted accurate relocation of a previously visited place. However, differential effects of the CA1 and CA3 lesions were observed in serial position curves. CA3-lesions disrupted performance for the first three serial positions, but did not disrupt performance for the last serial position (recency). In contrast, CA1-lesions disrupted performance for all serial positions. The results suggest that temporal separation of spatial memory may depend on the conjoint function of CA1 and CA3 of the hippocampus with a disruption of a spatial pattern completion process following CA3 lesions and a disruption of a temporal pattern separation process following a CA1 lesion.     

Bilateral entorhinal cortex lesions impair acquisition of delayed spatial alternation in rats

Entorhinal cortex lesions induce significant reorganization of several homotypic and heterotypic inputs to the hippocampus. This investigation determined whether surviving heterotypic inputs after bilateral entorhinal lesions would support the acquisition of a learned alternation task. Rats with entorhinal lesions or sham operations were trained to acquire a spatial alternation task. Although the sham-operated rats acquired the task within about 3 weeks postsurgery, rats with bilateral entorhinal lesions failed to learn the task after 12 consecutive weeks of training despite heterotypic sprouting of the cholinergic septodentate pathway and the expansion of the commissural/associational fiber plexus within the dentate gyrus. Thus, heterotypic sprouting failed to ameliorate significantly the effects of bilateral entorhinal lesions. Rather, entorhinal lesions produced a persistent impairment of spatial memory, characterized by a mixture of random error production and perseverative responding.     

Transient activation of the CA3 Kappa opioid system in the dorsal hippocampus modulates complex memory processing in mice

The hippocampus plays a central role in various forms of complex learning and memory. Opioid peptides and receptors are abundant in the hippocampus. These peptides are co-released with glutamate from mossy fiber- and lateral perforant path-synapses. In this study, we evaluated the functional relevance of the CA3 Kappa opioid receptors (KOR) by transient pharmacological activation or inactivation using single bilateral intrahippocampal microinjections of a selective agonist (U50,488H, 1 or 2.5 nmol), a selective antagonist (nor-binaltorphimine, norBNI 5 nmol) or a mixture of both. C57Bl/6J mice were tested in a fear conditioning paradigm (FC) or in a modified version of the water maze task thought to reveal how flexibly animals can learn and manipulate spatial information (WM). In FC, the agonist (2.5 nmol) decreased context-induced (but not tone-induced) freezing whereas norBNI had no effect. The impairment caused by the agonist U50,488H was blocked by the injection of norBNI, suggesting that overstimulation of CA3-KOR impairs the acquisition and consolidation of contextual fear-related memory. In the WM task, mice were trained repeatedly each day to find a hidden platform. After having reached this goal, the platform position was changed the next day for a new task. U50,488H injection before the last task abolished the previously acquired ability to find rapidly a new platform location, whereas adding norBNI reversed this impairment. Thus, in the mouse, even partial and topographically restricted activation of CA3-KOR entails impairments in two different hippocampus-dependent tasks, indicating functional relevance of the kappa opioid system.     

Extensive lesions of cholinergic basal forebrain neurons do not impair spatial working memory

A recent studysuggests that lesions to all major areas of the cholinergic basal forebrain in the rat (medial septum, horizontal limb of the diagonal band of Broca, and nucleus basalis magnocellularis) impair a spatial working memory task. However, this experiment used a surgical technique that mayhave damaged cerebellar Purkinje cells. The present studytested rats with highlyselective lesions of cholinergic neurons in all major areas of the basal forebrain on a spatial working memorytask in the radial arm maze. In postoperative testing, there were no significant differences between lesion and control groups in working memory, even with a delayperiod of 8 h, with the exception of a transient impairment during the first 2 d of postoperative testing at shorter delays (0 or 2 h). This finding corroborates other results that indicate that the cholinergic basal forebrain does not playa significant role in spatial working memory. Furthermore, it underscores the presence of intact memoryfunctions after cholinergic basal forebrain damage, despite attentional impairments that follow these lesions, demonstrated in other task paradigms.