Review
The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents

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Abstract

Rats and mice are attracted by novel objects. They readily approach novel objects and explore them with their vibrissae, nose and forepaws. It is assumed that such a single explorative episode leaves a lasting and complex memory trace, which includes information about the features of the object explored, as well as where and even when the object was encountered. Indeed, it has been shown that rodents are able to discriminate a novel from a familiar object (one-trial object recognition), can detect a mismatch between the past and present location of a familiar object (one-trial object–place recognition), and can discriminate different objects in terms of their relative recency (temporal order memory), i.e., which one of two objects has been encountered earlier. Since the novelty-preference paradigm is very versatile and has some advantages compared to several other memory tasks, such as the water maze, it has become a powerful tool in current neurophamacological, neuroanatomical and neurogenetical memory research using both rats and mice. This review is intended to provide a comprehensive summary on key findings delineating the brain structures, neurotransmitters, molecular mechanisms and genes involved in encoding, consolidation, storage and retrieval of different forms of one-trial object memory in rats and mice.

Introduction

Rodents naturally tend to approach and explore novel objects, which are assumed to have no natural significance to the animal and which have never been paired with a reinforcing stimulus. They also show an innate preference for novel over familiar objects. Rodents readily approach objects and investigate them physically by touching and sniffing the objects, rearing upon and trying to manipulate them with their forepaws (Aggleton, 1985). This behavior can be easily quantified and utilized to study simple recognition memory as well as more complex spatial-, temporal- and episodic-like memory in rodents. The standard one-trial object recognition task measures spontaneous behavior. A large advantage over food-rewarded maze learning tasks and classical delayed matching- or non-matching to sample tasks is that it does not require spatial learning, food or water deprivation, the application of reinforcing stimuli (food or electric shock delivery), the learning, retention and application of rules, or the learning of response–reward associations. It, therefore, requires little training and is also, by far, less stressful and arousing than tasks based on negative reinforcement of behavior, such as the hidden platform version of the water maze, the inhibitory and active avoidance, or fear conditioning tasks, which have been widely used to study the neurobiology of learning and memory in rodents. The object recognition paradigm is especially suited to test the effects of pharmacological and genetic interventions on learning and memory. Whenever experimental manipulations such as the administration of a drug or the knockout of a gene, are known to or presumed to affect either weight regulation, food palatability and intake, or processes of reward and reinforcement, then food-rewarded paradigms might not be the best choice of task. In such the novelty-preference paradigm, would probably yield results, that can more safely be related to changes in learning and memory. Similarly, known or suspected effects of drugs or gene interventions on pain perception, stress susceptibility, anxiety and thermoregulation, preclude the use of shock-motivated or water-maze navigation tasks. Since the novelty-preference paradigm, in comparison to other animal models of learning and memory, does not require lengthy training and does not induce high levels of arousal and stress, it is more closely related to conditions under which human recognition memory is measured (Ennaceur and Delacour, 1988).

Furthermore, variations of the novelty-preference paradigm can be used to measure different forms of object memory, such as recognition of a familiar object (Ennaceur and Delacour, 1988), one-trial object–place recognition (Mumby et al., 2002a), temporal order memory (Hannesson et al., 2004; Mitchell and Laiacona, 1998) and recently, episodic-like memory in rats and mice (Dere et al., 2005a, Dere et al., 2005b; Kart-Teke et al., 2006, Kart-Teke et al., 2007). Since the learning and test situations in these different versions of the novelty-preference paradigm are very similar; i.e., the animal is placed into a familiar arena containing objects, it is possible to investigate the effects of experimental manipulations, such as a knockout of a gene, on these different forms of recognition memory, avoiding confounding influences of paradigm-specific demands on the animal's performance. For example, if a genetic manipulation disrupts motor or sensory systems required to explore and encode objects, the animals should be equally impaired in the one-trial object recognition, one-trial object–place recognition, temporal order memory and episodic-like memory versions, while impairments in one, but not the other versions, i.e., experimental dissociations, would suggest a specific involvement of the gene in a specific type of object memory.

The one-trial object recognition task typically consists of a sample trial (of usually 2–10 min duration), during which rats or mice explore two equal objects in a familiar arena, followed by a delayed test trial, in which a novel object is presented together with one familiar object already explored during the sample trial (Fig. 1 I). In this situation, depending on (a) the inter-trial interval imposed between sample and test trials, (b) the duration of the sample trial, as well as on (c) the observation interval (usually the first 1–3 min of the test trial for rats and 3–10 for mice), untreated control animals spend more time exploring the novel object, suggesting that the familiar object was recognized (Dix and Aggleton, 1999; Ennaceur and Delacour, 1988). It is important to note that this task taxes the memory for unique episodes or events (one-trial learning), which makes it more sensitive to amnestic experimental interventions, compared to other tasks, in which incremental learning across multiple trials is induced, such as in the water-maze or radial-maze tasks.

One major challenge in memory research is the question of whether an “impairment” is due to “unspecific” effects on sensory, motor, pain and/or motivational systems, etc., or actually reflects an effect on the neurobiological substrate of the memory system under question. “Unspecific” effects of experimental manipulations, such as, the application of drugs, brain lesions, genetic manipulations, etc. on one-trial object recognition can be potentially detected by a detailed analysis of the animal's behavior during the sample trial in terms of (a) the frequency of contacts with the objects, (b) the time spent exploring the objects, (c) the distance traveled, (d) number of rearings, (e) abnormal postures, (f) defecation, etc.

In one-trial object recognition tasks, retention intervals ranging from minutes to several hours (and sometimes up to days) are used. The performance of the animals deteriorates as the delay between the sample and the test trial increases, e.g., from 3 to 24 h (Bertaina-Anglade et al., 2006; Obinu et al., 2002; Schiapparelli et al., 2006). However, the exact x, y-coordinates and the slope of the delay-dependent forgetting curve depend on various factors, including sample trial duration and the strain of mouse or rat used. One can also distinguish the effects of experimental manipulations on memory from other effects affecting primarily non-memory variables, given that other factors, such as state-dependent learning, are controlled, when an experimental intervention disrupts recognition memory, e.g., after a 3-h delay, but not after a 5-min delay (Baker and Kim, 2002; Winters and Bussey, 2005b). Intact performance at the short 5-min delay suggests that the experimental animals can perform the task just as well as the controls. In contrast, if one finds that one-trial object recognition is impaired after both short (<2 h) and long retention intervals (24 h), one cannot rule out the possibility that the experimental intervention has affected non-memory variables (De Lima et al., 2005; Ennaceur and Meliani, 1992a). Thus, one advantage of the one-trial object recognition paradigm is that the effects of lesions or drugs on attention, sensory–motor functions or the motivation to explore novel objects can be potentially distinguished from effects on memory, since the latter can also be inferred from delay-dependent differences in the time spent exploring a novel and familiar object. If a lesion or drug impairs, e.g., the motor performance required to explore objects, such an impairment should have the same effect on the exploration of the novel and familiar object, independent of the delay interposed between the sample and test trials. Conversely, a specific effect on recognition memory is assumed if the experimental intervention impairs or improves recognition memory after long, but not short delays.

One important aspect that has to be considerd in the one-trial object recognition task is that of innate preferences for particular objects or materials. Therefore, one has to make sure that objects used can be easily discriminated by the animals but should not be differentially preferred. It is recommended to use different objects made of the same material (e.g., glass, plastic, porcelain, ceramic, metal) but which are different in terms of height, color, shape and surface texture. Objects which are made of the same material cannot be discriminated by olfactory cues.

A modification of the paradigm allows measurement of the memory for spatial locations within a familiar arena, where objects have been initially explored. This is done by presenting two equal and familiar objects during the test trial, with one of the objects shifted to a novel location (Fig. 1 II). Here, the animals spend more time exploring the object encountered in the novel location (Dix and Aggleton, 1999; Ennaceur et al., 1997), suggesting that rodents not only encode and maintain the features of an object but also the spatial location in which it was encountered.

Unlike the one-trial object recognition and object–place versions, this task is a three-trial procedure, composed of two sample trials and one test trial. During the sample trials, two copies of a novel object are presented. Sample trial 1 takes place in context 1, sample trial 2 takes place in context 2, that is, in a distinct environment. During the test trial, which is given in either context 1 or context 2, one copy of the object presented in sample trials 1 and 2 is presented simultaneously (Fig. 1 III). Rodents not only associate particular spatial positions with objects within a particular arena, but can also detect whether they have previously encountered an object in a different spatial context (e.g., an open-field having a different floor texture). If the animal encounters an object in such an incongruent context, in which it was not encountered during the sample trial, even if it is placed in a familiar spatial position within the arena and relative to extrafield visual cues (Fig. 1 III), the animal tends to spend more time exploring the object in the incongruent, but otherwise familiar, context compared to an object which was initially encountered in this context during the sample trial (Dere et al., 2003; Mumby et al., 2002a; Norman and Eacott, 2005).

Another variant of the novelty-preference paradigm measures the memory for the temporal order in which two different objects were presented in the past. This task is also a three-trial procedure, composed of two sample trials, usually with an inter-trial interval of about 1 h, during which two copies of a novel object are presented (Fig. 1 IV). During the test trial 1 “old familiar” object known from sample trial 1, and another “recent familiar” object from sample trial 2 are presented together. Here, one finds that the animals spend more time exploring the “old familiar” object relative to the “recent familiar” object, indicating that the previously explored objects are recognized and discriminated in terms of their relative recency (Mitchell and Laiacona, 1998) and not in respect of their relative familiarity (Hannesson et al., 2004).

Episodic memory can be inferred from behavioral manifestations of the knowledge regarding the content (what happened), place (where did it happened) and temporal context (in terms of the sequence of events attended) of personally experienced events (Dere et al., 2006, but see Tulving, 2001 for discussion of philosophical implications and phenomenological aspects of episodic memory). A recent attempt to model what, where and when memory for unique experiences in mice made use of a three-trial object exploration task. The mice were placed into an open field containing four copies of a novel object. After a delay of 50 min, the mice received a second trial identical to the first, except that four novel objects were presented. After an additional delay of 50 min, the mice received a test trial, identical to the sample trials, except that two copies of the object from sample trial 1 (“old familiar” objects) and two copies of the object known from sample trial 2 (“recent familiar” objects) were present. Furthermore, one “old familiar” object was shifted to a novel location, whereas the “recent familiar” objects were presented at familiar locations (Fig. 1 V). In this situation, the mice are simultaneously “asked” two questions, first, when have you encountered these different objects, and, second where have you encountered them. Here, the mice spent more time exploring two “old familiar” objects relative to two “recent familiar” objects, reflecting memory for what and when, and concomitantly directed more exploration at a spatially displaced “old familiar” object relative to a stationary “old familiar” object, reflecting memory for what and where (Dere et al., 2005a, Dere et al., 2005b). Thus, the object recognition paradigm can also be used to measure what, where and when memory for unique events. Subsequent studies confirmed that rats are able to integrate and remember the what, where and when of unique experiences, and that this task can be used for pharmacological studies (Kart-Teke et al., 2006, Kart-Teke et al., 2007).

Usually the one-trial object recognition task and its derivates are performed in a recognition-type format, that is, the animal has the choice between a visible novel and a familiar object in an open-field arena. Since the objects are visible to the animals right at the beginning of the test trial, some authors suggest that the preference for the novel object might be explained by relative object-familiarity judgments, which do not require the recollection of the sample trial event. Recently, Eacott et al. (2005) designed a task, which was intended to require rats to recollect (rather than just visually recognize) the object information attended during a sample trial in order to decide where in an E-maze a relatively novel or non-habituated object can be found. The experimental design used was rather complex, including four stages of pre-training performed prior to the test for recollection-like object memory (Fig. 2 I–IV). Two different E-mazes provided two distinct contexts (context 1 and context 2). They differed in terms of color and floor texture and provided two distinct contexts. First, the rats were habituated to the two contexts in the absence of objects (Fig. 2 I). Thereafter, the rats received two consecutive trials per context, with an inter-trial interval of 5 min. Two different objects present at either end of the backbone of the E-maze (e.g., objects A and B in context 1 and objects C and D in context 2). The objects were visible to the rat when emerging from the start arm (Fig. 2 II). Next, the rats received three consecutive trials. On the first trial they were placed in one context (e.g., context 1) containing two different objects (e.g., E and F) placed at either end of the backbone of the E-maze (e.g., E placed on the left and F on the right side relative to the start arm). After a delay of 3 min, which the animals spent in their home cage, the rats were placed into the other context (context 2) and with the same objects placed in opposite locations (e.g., F on the left and E on the right side). After a further delay of 3 min, the rats were returned to either the first or the second context (e.g., context 2 with object F present on the left and object E on the right side; Fig. 2 III). At this stage of pre-training, the rats had presumably learned that the objects and their locations remain stable within a context. The final stage of pre-training was similar to the last one, with the exception that one of the objects explored in the maze was again presented during the inter-trial interval in the home cage. Thus, the animals were already habituated to this object when they were replaced into a given context during the third trial. As expected, the rats spent more time exploring the object which was not presented during the inter-trial interval (Fig. 2 IV). Thereafter, the recollection-like object memory test was performed with the same procedure just described, but with the difference that the objects were placed in the outside arms of the maze, thus being out of sight of the animal emerging from the start arm (Fig. 2 V). When the objects are visible on emerging from the start box (as in the last stage of pre-training described above), a preference for the non-habituated object can also be due to familiarity. However, although the objects were not visible, on trial 3 they still turned towards the direction of the object not recently seen in their home cages. The authors conclude that the rats were able to recollect the sample trial information and first turned towards the location where they expected to encounter the object, which was not recently presented to them in their home cages (Eacott et al., 2005).

Section snippets

Applications

Compared to incremental learning tasks using multiple learning trials, the one-trial object recognition task allows the investigation of drug effects on different stages of memory formation and recollection. To assess the effects of a drug on the encoding of object characteristics and/or early stages of memory consolidation, the drug can be administered prior to the sample trial. It can also be administered immediately after the sample trial to study drug effects on the consolidation of object

Remarks

In this review, we will summarize studies dealing with the neuroanatomy, pharmacology and neurogenetics of different forms of one-trial object recognition in rats and mice. As in any field of behavioral neuroscience, the reader of this chapter will inevitably encounter inconsistent and sometimes contradictory results. In this regard, one should keep in mind that such discrepancies might be due to (a) differences in animal housing conditions, (b) the rodent strains used, (c) the age and sex of

The hippocampus and glutamate receptors

It was proposed that the medial temporal lobe system, including the hippocampal formation (enthorinal cortex, dentate gyrus, areas CA1–CA4 and subiculum), amygdala and parahippocampal cortices, such as the peri- and postrhinal cortex, serves as a declarative memory system (Buffalo et al., 1999; Squire et al., 2004). Lesions to the medial temporal lobe system causes retrograde and anterograde amnesia in humans and primates for trial unique stimuli and events (Corkin, 2002). The severity of

The perirhinal cortex and glutamate receptors

The perirhinal cortex is part of the parahippocampal region and is located dorsally to the hippocampal formation. The perirhinal cortex has both direct and indirect connections with the hippocampus via the entorhinal cortex (Witter et al., 1986). Both structures are part of the medial temporal lobe system (Buffalo et al., 2000). Lesions of the perirhinal cortex, dependent on the delay between sample and test trials, impair one-trial object recognition in rats. In rats with permanent perirhinal

The medial prefrontal cortex and temporal order memory

It is known that lesions to the medial prefrontal cortex impair relative recency discriminations in humans, non-human primates and rodents across a range of stimulus modalities (Fuster, 2001; Kesner and Holbrook, 1987), while simple recognition of novel and familiar stimuli is preserved (Kesner et al., 1994; McAndrews and Milner, 1991). Stimulus order-selective unit activity has been recorded from neurons in the medial prefrontal cortex of monkeys (Ninokura et al., 2004). Excitotoxic lesions of

The cholinergic basal forebrain and acetylcholine receptors

The cholinergic basal forebrain includes the medial septum, vertical and horizontal limb of the diagonal band of Broca, the substantia innominata, the ventral pallidum and globus pallidus, and projects to both cortical and limbic areas involved in learning and memory processes. A great deal of evidence suggests that the depletion of neocortical and hippocampus acetylcholine contributes to the memory deficits observed in Alzheimer's disease (for review, see Bartus, 2000; Wrenn and Wiley, 1998).

The nucelus accumbens, AMPA, NMDA and dopamine receptors

The nucleus accumbens is part of the basal ganglia and has been implicated in brain reward and reinforcement (Wise, 2000), as well as learning and memory processes, especially in terms of spatial learning and drug-induced place preference (Setlow, 1997; Wise, 1989). It has long been held that the nucleus accumbens is involved in the detection of stimuli which predict the availability of a reward and the subsequent initiation of approach or goal directed behaviors (Robinson and Berridge, 1993).

The serotoninergic system and one-trial object recognition

The modulatory function of serotoninergic pathways for learning and memory is well documented (Cassel and Jeltsch, 1995; Meneses, 1999). Lesions to the dorsal raphe by the neurotoxin 5,7-DHT, which is highly selective for 5-HT neurons, impair one-trial object recognition at a 1-h delay (Lieben et al., 2006), suggesting that 5-HT is involved in some aspects of one-trial object recognition. Pharmacological studies using diverse 5-HT-R agonists and antagonists also suggest an, albeit indirect,

Nitric oxide and one-trial object recognition

The free radical gas, nitric oxide, functions as an intercellular messenger and has been implicated in hippocampal synaptic plasticity, where it acts as a retrograde messenger for LTP-induced presynaptic changes in transmitter release (Son et al., 1996). Infusion of the nitric oxide synthase blocker L-NA (N(omega)-nitro l-arginine) in doses of 10, 30 μg into the hippocampus of rats immediately after, but not 45 min before, the sample trial impaired one-trial object recognition at a delay of 1 h,

The impact of sex hormones on one-trial object recognition

Steroid sex hormones (estrogens, gestagens and androgens) are secreted by the gonads (ovaries and testes) after stimulation by gonadotropic hormones released by the anterior pituitary gland. During perinatal ontogenesis, these sex hormones have organizational effects on tissue differentiation and development, inducing a masculine or feminine phenotype. Activational effects of sex hormones are found in the mature organism and serve reproductional purposes. While it was long held that steroid sex

Differences between rats and mice in the one-trial object recognition task

It is well known that rats and mice exhibit differences in performance in learning and memory paradigms, such as the Morris water maze (Whishaw and Tomie, 1996). It is, therefore, interesting to know whether, and in which respect, rats and mice differ in the one-trial object recognition task. Compared to rats, mice show generally lower levels of novel object exploration both in terms of the number of contacts, as well as the time spent exploring the objects. Therefore, in pharmacological

Differences between mouse strains

Although there is an increasing number of pharmacological and gene-targeting studies using the one-trial object recognition task to assess memory performance in mice, only few studies have directly compared the learning performance of different inbred mouse strains on this task. Brooks et al. (2005) tested six inbred strains (129S2/Sv, BALB/c, C3H/He, C57BL/6J, CBA/Ca and DBA/2), commonly used in the areas of behavioral pharmacology and transgenic models of neuropsychiatric diseases, in the

The neurogenetics of one-trial object recognition

The ability to inactivate targeted genes using homologous recombination in embryonic stem cells of mice has been a powerful tool in elucidating the molecular and cellular mechanisms of learning and memory. Molecular genetics and transgenic technology have been continuously refined to a level which permits the inactivation, knock-in, overexpression or replacement of targeted genes in a cell-type, region-specific and/or temporally restricted manner (Tsien, 1998; Winder and Schramm, 2001). In the

Episodic-like memory

In patients suffering from Alzheimer's disease, episodic memory deficits are among the first signs of cognitive decline (Small et al., 2003). In the past several years different transgenic mouse models for Alzheimer's disease have been generated (Bloom et al., 2005). However, due to a lack of a valid mouse model of episodic memory, it has not yet been possible to test the efficiency of possible therapies. Recent attempts to model human episodic memory in rodents are based on a definition of

Conclusions

The one-trial object recognition paradigm has proven to be a useful tool in neurobiological memory research in both rats and mice. Since its introduction in 1985 by John P. Aggleton, the potential of this paradigm to address critical questions about the neurobiology of learning and memory is increasingly and widely appreciated. Some of the key structures involved in mediating different types of object recognition have been delineated and neurotransmitter systems modulating these types of memory

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft (DFG) through Grants no. DE 1149/1-1 and DE 1149/1-2 to Ekrem Dere.

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