The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT(2A) receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABA(A) receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT(2A) binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes.

Progesterone has a ubiquitous role in reproduction and fitness and may influence cognitive performance. We examined the effects of administration of progesterone (a regimen that facilitates sexual behaviour) on consolidation of complex information in Long-Evans rats, Rattus norvegicus, that may be relevant for social engagement. We also examined the effects of subcutaneous progesterone administration (4 mg/kg versus oil vehicle placebo) on memory of ovariectomized rats during various cognitive tasks. Ovariectomized rats that received progesterone, versus the vehicle, immediately post-training were better able to find a hidden platform in the water maze. In a recognition task, rats that received progesterone spent more time in the novel arm of the Y-maze task than rats that received the vehicle. Ovariectomized rats that received progesterone immediately after training spent significantly more time exploring a novel object (compared to a familiar object) than did vehicle-administered rats. When socially relevant stimuli (i.e. objects with the scent of familiar or novel conspecifics) were used in the social cognition task, ovariectomized rats that received progesterone spent more time exploring the object with the novel conspecifics' scent than did vehicle-administered rats. Pairing of progesterone, but not the vehicle, conditioned a place preference to the originally nonpreferred side of the conditioning chamber. We found no significant differences in motor activity measures in these tasks due to progesterone treatment. These results suggest that progesterone's effects to improve cognitive processes with nonsocial and socially relevant stimuli, as well as have reinforcing effects, may underlie some of its salient effects on reproduction-related behaviours.

Spatial memory is a well-characterized psychological function in both humans and rodents. The combined computations of a network of systems including place cells in the hippocampus, grid cells in the medial entorhinal cortex and head direction cells found in numerous structures in the brain have been suggested to form the neural instantiation of the cognitive map as first described by Tolman in 1948. However, while our understanding of the neural mechanisms underlying spatial representations in adults is relatively sophisticated, we know substantially less about how this network develops in young animals. In this article we briefly review studies examining the developmental timescale that these systems follow. Electrophysiological recordings from very young rats show that directional information is at adult levels at the outset of navigational experience. The systems supporting allocentric memory, however, take longer to mature. This is consistent with behavioral studies of young rats which show that spatial memory based on head direction develops very early but that allocentric spatial memory takes longer to mature. We go on to report new data demonstrating that memory for associations between objects and their spatial locations is slower to develop than memory for objects alone. This is again consistent with previous reports suggesting that adult like spatial representations have a protracted development in rats and also suggests that the systems involved in processing non-spatial stimuli come online earlier.

BACKGROUND We aimed to further understand the relationship between cAMP concentration and mnesic performance. METHODS AND FINDINGS Rats were injected with milrinone (PDE3 inhibitor, 0.3 mg/kg, i.p.), rolipram (PDE4 inhibitor, 0.3 mg/kg, i.p.) and/or the selective 5-HT4R agonist RS 67333 (1 mg/kg, i.p.) before testing in the object recognition paradigm. Cyclic AMP concentrations were measured in brain structures linked to episodic-like memory (i.e. hippocampus, prefrontal and perirhinal cortices) before or after either the sample or the testing phase. Except in the hippocampus of rolipram treated-rats, all treatment increased cAMP levels in each brain sub-region studied before the sample phase. After the sample phase, cAMP levels were significantly increased in hippocampus (1.8 fold), prefrontal (1.3 fold) and perirhinal (1.3 fold) cortices from controls rat while decreased in prefrontal cortex (∼0.83 to 0.62 fold) from drug-treated rats (except for milrinone+RS 67333 treatment). After the testing phase, cAMP concentrations were still increased in both the hippocampus (2.76 fold) and the perirhinal cortex (2.1 fold) from controls animals. Minor increase were reported in hippocampus and perirhinal cortex from both rolipram (respectively, 1.44 fold and 1.70 fold) and milrinone (respectively 1.46 fold and 1.56 fold)-treated rat. Following the paradigm, cAMP levels were significantly lower in the hippocampus, prefrontal and perirhinal cortices from drug-treated rat when compared to controls animals, however, only drug-treated rats spent longer time exploring the novel object during the testing phase (inter-phase interval of 4 h). CONCLUSIONS Our results strongly suggest that a "pre-sample" early increase in cAMP levels followed by a specific lowering of cAMP concentrations in each brain sub-region linked to the object recognition paradigm support learning efficacy after a middle-term delay.

BACKGROUND Curcumin has been demonstrated to have many neuroprotective properties, including improvement of cognition in humans and neurogenesis in animals, yet the mechanism of such effects remains unclear. METHODOLOGY We assessed behavioural performance and hippocampal cell proliferation in aged rats after 6- and 12-week curcumin-fortified diets. Curcumin enhanced non-spatial and spatial memory, as well as dentate gyrate cell proliferation as compared to control diet rats. We also investigated underlying mechanistic pathways that might link curcumin treatment to increased cognition and neurogenesis via exon array analysis of cortical and hippocampal mRNA transcription. The results revealed a transcriptional network interaction of genes involved in neurotransmission, neuronal development, signal transduction, and metabolism in response to the curcumin treatment. CONCLUSIONS The results suggest a neurogenesis- and cognition-enhancing potential of prolonged curcumin treatment in aged rats, which may be due to its diverse effects on genes related to growth and plasticity.

Emerging evidence suggests that the pathogenesis of depressive disorders (DDs) is associated with neuronal abnormalities in brain microtubule function, including changes in α-tubulin isoforms. Currently available antidepressant drugs may act by rescuing these alterations, but only after long-term treatment explaining their delayed therapeutic efficacy. The microtubule associated protein type-2 (MAP-2) modulates neuronal microtubule dynamics. Our hypothesis is that MAP-2 represents an innovative target for the treatment of DDs. The synthetic pregnenolone-derivative MAP4343 (3β-methoxy-pregnenolone) binds MAP-2 in vitro and increases its ability to stimulate tubulin assembly. Here, we show that MAP4343 has antidepressant efficacy in rats and advantages compared with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. A single injection of MAP4343 changes the expression of α-tubulin isoforms indicative of increased microtubule dynamics in the hippocampus of naïve Sprague-Dawley rats, whereas fluoxetine had no effects. MAP4343 has positive efficacy in the rat forced swimming test (FST), the most used assay to screen potential antidepressant drugs by decreasing immobility behavior. In the rat isolation-rearing model of depression, administration of MAP4343 showed more rapid and more persistent efficacy compared with fluoxetine in recovering "depressive-like" behaviors. These effects were accompanied by modifications of α-tubulin isoforms in the hippocampus, amygdala, and prefrontal cortex. Our findings suggest the potential therapeutic use of MAP4343 for the treatment of DDs, based on a unique mechanism of action.

Animal models of memory have been considered as the subject of many scientific publications at least since the beginning of the twentieth century. In humans, memory is often accessed through spoken or written language, while in animals, cognitive functions must be accessed through different kind of behaviors in many specific, experimental models of memory and learning. Among them, the novel object recognition test can be evaluated by the differences in the exploration time of novel and familiar objects. Its application is not limited to a field of research and enables that various issues can be studied, such as the memory and learning, the preference for novelty, the influence of different brain regions in the process of recognition, and even the study of different drugs and their effects. This paper describes the novel object recognition paradigms in animals, as a valuable measure of cognition. The purpose of this work was to review the neurobiology and methodological modifications of the test commonly used in behavioral pharmacology.

Ischemic stroke triggers a massive, although transient, glutamate efflux and excessive activation of NMDA receptors (NMDARs), possibly leading to neuronal death. However, multiple clinical trials with NMDA antagonists failed to improve, or even worsened, stroke outcome. Recent findings of a persistent post-stroke decline in NMDAR density, which plays a pivotal role in plasticity and memory formation, suggest that NMDAR stimulation, rather than inhibition, may prove beneficial in the subacute period after stroke. AIM: This study aims to examine the effect of the NMDAR partial agonist d-cycloserine (DCS) on long-term structural, functional and behavioral outcomes in rats subjected to transient middle cerebral artery occlusion, an animal model of ischemic stroke. MATERIALS #ENTITYSTARTX00026; METHODS: Rats (n = 36) that were subjected to 90 min of middle cerebral artery occlusion were given a single injection of DCS (10 mg/kg) or vehicle (phosphate-buffered saline) 24 h after occlusion and followed up for 30 days. MRI (structural and functional) was used to measure infarction, atrophy and cortical activation due to electrical forepaw stimulation. Memory function was assessed on days 7, 21 and 30 postocclusion using the novel object recognition test. A total of 20 nonischemic controls were included for comparison. RESULTS: DCS treatment resulted in significant improvement of somatosensory and cognitive function relative to vehicle treatment. By day 30, cognitive performance of the DCS-treated animals was indistinguishable from nonischemic controls, while vehicle-treated animals demonstrated a stable memory deficit. DCS had no significant effect on infarction or atrophy. CONCLUSION: These results support a beneficial role for NMDAR stimulation during the recovery period after stroke, most likely due to enhanced neuroplasticity rather than neuroprotection.

In a previous study the simple, naturally derived coumarin scopoletin (SCT) was identified as an inhibitor of acetylcholinesterase (AChE), using a pharmacophore-based virtual screening approach. In this study the potential of SCT as procholinergic and cognition-enhancing therapeutic was investigated in a more detailed way, using different experimental approaches like measuring newly synthesized acetylcholine (ACh) in synaptosomes, long-term potentiation (LTP) experiments in hippocampal slices, and behavior studies. SCT enhanced the K+-stimulated release of ACh from rat frontal cortex synaptosomes, showing a bell-shaped dose effect curve (E(max): 4 μM). This effect was blocked by the nicotinic ACh receptor (nAChR) antagonists mecamylamine (MEC) and dihydro-β-erythroidine (DHE). The nAChR agonist (and AChE inhibitor) galantamine induced a similar increase in ACh release (E(max): 1 μM). SCT potentiated LTP in hippocampal slices of rat brain. The high-frequency stimulation (HFS)-induced, N-methyl-D-aspartate (NMDA) receptor dependent LTP of field excitatory postsynaptic potentials at CA3-CA1 synapses was greatly enhanced by pre-HFS application of SCT (4 μM for 4 min). This effect was mimicked by nicotine (2 μM) and abolished by MEC, suggesting an effect on nAChRs. SCT did not restore the total inhibition of LTP by NMDA receptor antagonist D, L-2-amino-5-phosphonopentanoic acid (AP-5). SCT (2 μg, i.c.v.) increased T-maze alternation and ameliorated novel object recognition of mice with scopolamine-induced cholinergic deficit. It also reduced age-associated deficits in object memory of 15-18-month-old mice (2 mg/kg sc). Our findings suggest that SCT possesses memory-improving properties, which are based on its direct nAChR agonistic activity. Therefore, SCT might be able to rescue impaired cholinergic functions by enhancing nAChR-mediated release of neurotransmitters and promoting neural plasticity in hippocampus.

In rats, the effects of Piracetam (P), the prototype of nootropic drugs, were studied on a very widely used model of behavioral disturbance: the learned helplessness (LH) phenomenon. In this model, exposure to uncontrollable and unsignalled shocks impairs subsequent escape-avoidance learning. In a first experiment, this deficit was abolished by 200 mg/kg of P, and to a lesser extent, by a 100 mg/kg dose, administered before the training session. In non-stressed animals, no dose of P was able to have a facilitatory effect on escape-avoidance. In a second experiment, the administration of P, not before the training session as in Experiment I, but before the stress, had no effect on the LH phenomenon regardless of the dose.

Different groups of rats received combined or separate administration of different doses of piracetam (P1:100, P2:200, and P4:400 mg/kg) and choline (C1:100 and C2:200 mg/kg). Compared to control treatment, C1 significantly improved performance in a delayed alternation (DA) task, while P1, P2, P4 or P1C1 had no effect. Moreover, rats receiving P2C1 and P4C1 were significantly inferior in acquiring DA to rats receiving the vehicle or separate administration of P1, P2 or C1. The different treatments with combined or separate administration of P and C had no effect on spontaneous locomotor activity and two-way avoidance conditioning. In a recognition-task only groups C1 and P4 were able to discriminate between familiar and new objects. The combined or separate administration of P1 and C1 on NA, DA, DOPAC, 5-HT, 5-HIAA levels, CAT activity and choline uptake were measured in frontal cortex and hippocampus: the only significant effect was a 5-HT increase in the hippocampus of rats treated with C1.

Rats were submitted to unsignalled and uncontrolled electrical shocks. When re-exposed to the same situation but not shocked, 24 h later, their locomotor activity was significantly reduced compared to that of controls. This conditioned suppression was associated with a significant decrease in p-octopamine (OA) in brain stem and hypothalamus. Shocks delivered just before brain fixation produced an even larger decrease in cerebral OA. Heart levels of OA were not affected. Cerebral and peripheral levels of dopamine and noradrenaline were not significantly or reliably affected. These results, as those of previous experiments, suggest that octopamine is involved in emotional, neurovegetative responses to stress.

The effects of the nootropic drugs Piracetam (Pir) and Pramiracetam (Pram) were evaluated on recognition-memory of rats in a new one-trial test. This test is based on spontaneous exploratory activity and does not involve rule learning or reinforcement. Recognition is measured by the time spent by rats in exploring two different objects, one familiar (the sample), the other new. When the retention interval is 1 min, normal rats spend more time exploring the new object which demonstrates that they recognize the familiar one, but they do not discriminate between the two objects after a 24-h interval. Three doses of Pram (15, 30 and 60 mg/kg) and Pir (100, 200 and 400 mg/kg) were administered i.p. 30 min before the acquisition trial. The doses of 30 mg/kg of Pram and of 400 mg/kg of Pir produced a significant improvement in retention when the intertrial interval was 24 h. This effect was not associated with a change in overall exploratory behavior. This study shows that the new object-recognition test may be a useful tool for pharmacological studies of memory in rats.

C57BL/6J mice were introduced to a nine arm radial maze without prior habituation and trained in the acquisition of a working memory task in 16 sessions, one session per day. In this maze mice need to climb onto an upward inclined bridge in order to reach and cross onto an arm. They received in each session an i.p. injection of MK-801 (0.1 mg/kg) 30 min before training or immediately after training. MK-801 pre-treated mice made significantly more entries onto the bridges, fewer entries onto the arms and took significantly longer time to make a first arm visit compared to saline and MK-801 post-treated mice during the first 3 session blocks (4 sessions per block). These results indicate that MK-801 induced anxiety which was extended throughout the first 3 session blocks. MK-801 pre-treated mice made also significantly more errors and required more sessions to reach the criterion compared to saline and MK-801 post-treated mice. Administration of MK-801 after training did not affect the acquisition of the task. The present results indicate that MK-801 pre-treatment impaired the acquisition of a spatial task and this can be accounted for by its effect on the baseline level of anxiety which was elevated. The introduction of mice to the acquisition of the task without prior habituation demonstrates that a drug treatment can affect learning and memory by increasing and/or prolonging anxiety. Such effect may be confounded with learning and memory performance and not detected with pre-habituation training procedures, particularly when the number of sessions is determined a-priori.

Training animals in spatial mazes have always been preceded by prior habituation to the test apparatus and testing conditions with the main goal to reduce fear and anxiety from exposure to the unfamiliar maze environment. This approach makes assumptions about the baseline level of emotionality in animals without actual objective measurements. It also ignores that genetic factors and experimental manipulations can reduce or prolong fear and anxiety from novelty, hence affecting the acquisition of a memory task. In the present study, C57, CD-1 and Balb/c mice were introduced to a working memory task in a radial-arm maze without habituation. Fear-induced anxiety from exposure to the novelty in this maze is demonstrated by a very low number of arm entries. Animals have to climb onto a bridge in order to reach an arm of the maze. In the first session block, Bab/c mice made very few arm entries and made more arm repeats than CD-1 and C57 mice, and CD-1 made few arm entries and made more arm repeats than C57/BL6J mice. In the second session block, all three strains of mice did make 8 arm entries. Balb/c mice seem to perform better than C57 and CD-1 mice as shown by a low number of arm repeats in the second session block, a high number of correct choices before first errors in the third session block, and low number of errors and sessions to criterion. In the present case, a high baseline level of emotionality did not prevent Balb/c mice to perform better than C57 and CD-1 mice.

Balb/c mice were exposed to an elevated platform that is extended on two opposite sides with lowered steep slopes. They were tested for 12min per session in 6 successive days. They received i.p. administration of either saline or one dose of diazepam (DZP 0.5, 1, 3mg/kg) in sessions 1-3, and saline in sessions 4 and 5. All groups of mice received a single dose of DZP (1mg/kg) in session 6. DZP produced inverted U-shaped dose-responses on the number of entries into different areas of the apparatus, with a peak in mean response at 1mg/kg whereas its effect on the duration of entries was mostly comparable between the 3 doses. It increased the number of crossings on the surface of the platform and facilitated entries onto the slopes. DZP-treated mice crossed frequently onto and spent longer time on the slopes in sessions 1-3 whereas saline-treated mice remained on the platform in sessions 1-6. Withdrawal of DZP in sessions 4-5 increased the latency of first entry and decreased the number and duration of entries onto the slopes which was reversed with the administration of 1mg/kg of DZP in the next session. This ON-OFF the drug may be due to the half-life of DZP which is very short in mice and rats ( approximately 0.88h). It also indicates that DZP-treated mice did not benefit from previous experience of entries onto the slopes which suggests a possible "state-dependent" effect. Administration of DZP after repeated exposures to the test did not facilitate entries onto the slopes but instead increased significantly the number of crossings on the surface of the platform; this increase was much higher than that observed in mice initially treated with DZP and exposed to the test. There is no evidence of habituation in saline-treated mice: the number of crossings on the platform was comparable between the first 5 sessions of the test. These results demonstrate that repeated exposures to the same anxiogenic environment resulted in avoidance responses developing tolerance and approach responses developing sensitization. They suggest that tolerance and sensitization are two opposite sides of the habituation process to the same stimulus and may account for the maintained state of anxiety.

The one-trial object recognition task involves memory of a familiar object in parallel with the detection and encoding of a novel object. It provides the basis for the study of a wide range of cognitive and neuropsychological functions and processes in rats and mice. However, unlike in humans, primate and pigeon studies, object recognition in rats and mice has been mostly limited to memory while little is known about object perception, affordances and acquisition of a representation of an object. In the present paper, we addressed some of these issues. We also described novelty preference models and hypotheses that account for one-trial object recognition and question the validity of the novelty preference concept. In addition, we discussed whether one-trial object recognition involves working memory and how it involves memory of an episode.

In the present report we describe the behavior of two albinos (BALB/c and CD-1) and one pigmented (c57/BL6) strains of mice exposed to a novel open space anxiety test in a single 12 min session. The test is based on exposure of mice to an unfamiliar elevated platform which is extended on two opposite sides with steep slopes presented downward or upward. In the first experiment, the behavior of mice was examined on the elevated platform at two different heights (75 and 100 cm) with downward slopes. In the second experiment, we examined the behavior of mice on the platform at the lowest height (75 cm) but with upward slopes which lead to a stand. In the third experiment, we examined the behavior of Balb/c mice on the platform at the lowest height (75 cm) with downward slopes, and a hub enclosure providing a protected space located in the centre of the platform. The least anxious strain of mice was expected to take risks and cross onto the slopes (experiments 1 and 3) and onto the stands (experiment 2). The results of experiment 1 show that Balb/c mice did not cross onto the slope, and CD-1 mice made more crossings into and spent more time on the slopes than c57 mice. The increase in the heights of the platform reduced the number of crossings on the platform in all three strains of mice, and decreased the time spent on the platform before first entry onto a slope in c57 and in CD-1 mice. It also decreased the number of entries and duration of entries onto the slopes in CD-1 mice. In experiment 2, Balb/c mice did cross onto the upward slopes but significantly less than c57 and CD-1 mice but they did not cross onto the stands attached to the end of the slopes. CD-1 mice made more entries onto and spent more time on the stands than c57 mice. In the third experiment, Balb/c and c57 mice spent most of their time inside a protective space (cylinder) placed in the centre of the platform demonstrating strong avoidance responses of the outer area of the platform, and only three c57 mice crossed onto the slopes for a very brief duration in one or two entries. In all three experiments, mice entered more frequently and spent more time in the outer areas than in the inner areas of the platform, particularly in the areas adjacent to slopes than in the areas adjacent to a void space. CD-1 mice appears the least anxious taking more risks by venturing onto the slopes and onto the stands while Balb/c appears the most anxious spending a large amount of time in the areas adjacent to the slopes. The different configurations of the test apparatus (experiments 1 and 2) seem to provide different incentives for the drive to explore and escape which may account for differences in anxiety responses whereas the presence of a protective space (experiment 3) appears to encourage avoidance responses.

This report describes the emotional responses of mice exposed to an unfamiliar elevated platform that is extended on two opposite sides by downward lowered steep slopes. Balb/c mice were exposed to the test for 12 min per session in 3 successive days. They received i.p. administration of diazepam (0, 0.5, 1 and 3 mg/kg) or amphetamine (0, 1, 2.5, 5 and 10 mg/kg) 30 min prior to test sessions. Separate groups of Balb/c mice were used for each dose of the drugs. Both drugs increased the number of crossings on the platform, indicating increased motor activity, and the effects were dose-dependent. Diazepam also significantly increased the number and duration of entries onto the slopes indicating an anxiolytic effect, whereas none of the saline or amphetamine-treated mice adventured onto the slopes. Amphetamine and diazepam produced an inverted U-shaped dose-response effect on different parameters of the test and demonstrate that the drug concentration which elicited a peak in mean number of entries is different from the drug concentration which elicited a peak in mean duration of entries. This study demonstrates the sensitivity and discriminatory power of an open space anxiety test for future pharmacological studies.

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.

The role of the posterior parahippocampal area of the brain in spatial types of memory in conditions of one-trial visual perception of the positions of objects was studied by training eight cats to remember the spatial positions of either two different objects covering two of three feeders placed on a test tray (tests for the "object-place" association) or the positions of two of three feeders (tests for place). Each trial used new objects and new positions for the two of three feeders. After training, four cats were subjected to electrolytic lesioning of the posterior parahippocampal area, primarily the parahippocampal cortex, parasubiculum, and presubiculum; the remaining four cats underwent all the surgical procedures except electrocoagulation of nervous tissue; this was the sham-operated control group. Cats of this group showed no impairment to the performance of tests of both types, while the experimental group showed similar levels of impairment to the performance of both tests. Thus, memory for one-trial perception of "object-place" associations and, more simply, two different object places in cats were critically dependent on the posterior parahippocampal area.

Memory for visual recognition in primates is at least partially mediated by the peripheral and entorhinal (i.e., rhinal) areas of the cerebral cortex. The roles of these structures in visual recognition in cats was studied by producing electrolytic combined lesions of the rhinal (perirhinal + entorhinal) areas in a group of cats trained in a modified Wisconsin test apparatus to delayed selection of an object on the basis of its image on presentation of a new object in every trial in the test. Control groups consisted of intact and sham-operated cats. Animals with rhinal lesions were no different from sham-operated and intact animals in the initial training to the rules for correct responding to the objects presented; they also showed no difference at the minimum delay period of 5 sec used in these experiments. However, a statistically significant difference was seen on testing with a delay of 10 sec, demonstrating impairment of intrinsic visual recognition memory.

Visual recognition memory in primates is mediated at least in part by the perirhinal and entorhinal (i.e., rhinal) cortices. To examine the role of these structures in cats' visual recognition memory, we performed combined electrolytic rhinal (perirhinal and entorhinal) lesions in a group of cats trained in visual delayed matching-to-sample with trial-unique objects in the modified Wisconsin General Testing Apparatus. Sham-operated and intact cats were used as control groups. Cats with rhinal lesions did not differ from the control sham-operated and unoperated groups in initial learning of the rules of the task; difference between experimental and control groups under conditions of minimum 5-sec delay was nonsignificant as well. However, significant difference between experimental and control groups was revealed under conditions of testing with 10-sec delay. This finding suggests a disorder in the visual recognition memory.

Delayed disturbances of cognitive functions caused by intrahippocampal injection of subconvulsive dose of kainic acid were studied in rats. Animals were behaviorally tested for the presence of cognitive deterioration 1 week after bilateral injection of 0.25 microg kainic acid into the left and right hippocampi. Behavioral tests included the retrieval of a food-procuring task, its experimental extinction, and learning of a new similar task. Kainate-treated rats showed deterioration of performance of the task learned before the treatment: An impairment of the task performance occurred in the first trial of a daily session (each daily session consisted of 10 trials), and beginning from the second trial, the task was performed as rapidly as by control animals. This deterioration of retrieval in the first trial took place during several days, in spite of daily training during the retrieval test. Other disturbances of cognitive functions in kainate-treated rats were revealed in the test of experimental extinction of the response. At the initial step of this test, the rats showed active behavioral perseveration, performing habitual response with short latencies in spite of reinforcement removal. Besides, kainate-treated rats made significantly more responses before full extinction (inhibition of the previously learned response) than the control rats. In the learning test, kainate-treated rats did not exhibit any disturbances: repeated learning was the same as in the control group. Therefore, results showed that hippocampal dysfunctions induced by kainic acid resulted in the following cognitive disturbances: difficulties in memory retrieval and weakening of inhibitory control. These disturbances can be most adequately explained on the basis of the concept, according to which the hippocampus acts as a detector and comparator of new signals, thereby accomplishing selective attention.

Rats and mice have a tendency to interact more with a novel object than with a familiar object. This tendency has been used by behavioral pharmacologists and neuroscientists to study learning and memory. A popular protocol for such research is the object-recognition task. Animals are first placed in an apparatus and allowed to explore an object. After a prescribed interval, the animal is returned to the apparatus, which now contains the familiar object and a novel object. Object recognition is distinguished by more time spent interacting with the novel object. Although the exact processes that underlie this 'recognition memory' requires further elucidation, this method has been used to study mutant mice, aging deficits, early developmental influences, nootropic manipulations, teratological drug exposure and novelty seeking.

Episodic memory has been found to be impaired in several neuropsychiatric disorders. The object recognition task (ORT), introduced by Ennaceur and Delacour [Ennaceur A., Delacour J. A new one-trial test for neurobiological studies of memory in rats: 1. Behavioral data. Behav Brain Res 1988; 31: 47-59.], is a method to measure a specific form of episodic memory in rats and mice. It is based on the spontaneous behavior of rodents and can be considered as a retention test completely free of reference memory components. Therefore, the ORT has been increasingly used as an experimental tool in assessing drug effects on memory and investigating the neural mechanisms underlying learning and memory. In the present study, the main goal was to evaluate the effects of galantamine in Swiss mice in the ORT on scopolamine-induced deficits and with different retention intervals. Mice had a good object recognition memory at the 15 min retention intertrial interval (ITI). Object discrimination was absent at the longer intervals (1 h, 4 h and 24 h). Galantamine (10 mg/kg, administered s.c., 30 min prior to acquisition) partially reversed effects of scopolamine (0.63 mg/kg, administered s.c., 30 min prior to acquisition) and normalized performance to control levels. A lower dose of galantamine (0.63 mg/kg) was also investigated when two different retention intervals (15 min and 1 h) were used. Galantamine (0.63 mg/kg) had no adverse effects. Solvent-treated mice in the 1 h ITI condition did not discriminate between the novel and the familiar object (discrimination index was equal to zero), while galantamine (0.63 mg/kg)-treated mice attained a good object recognition memory performance. In conclusion, galantamine was shown to possess memory-enhancing effects in two conditions that reduced object discrimination: scopolamine-induced deficits and when a longer retention interval was used.

Based on computational models of the hippocampus, it has been suggested that a possible mechanism for memory retrieval is pattern completion, wherein an autoassociative network recalls previous patterns of activity given noisy or degraded cues. However, there are few behavioral data examining pattern completion per se in the hippocampus. Here, we present a study in which rats were tested on a spatial location retrieval paradigm, each trial of which consisted of a sample and choice phase. During the sample phase, rats were trained to displace an object in one of 15 possible locations to retrieve a food reward and return to the start-box on a cheeseboard maze. The object was then removed and the same location was re-baited for the choice phase. The rats' accuracy in returning to the correct location was recorded. On test trials, visual extramaze cues, vestibular cues, or both were manipulated to assess pattern completion in normal rats. Subjects were then randomly assigned to receive a cortical control, a sham, or a dorsal and ventral hippocampal lesion and were retested on the task. Control and unoperated rats were able to perform the task when visual extramaze or vestibular cues were reliable, but not when they were manipulated. Rats with hippocampal lesions were impaired in the baseline condition, as well as during all manipulations. These results support the hypothesis that the hippocampus supports the retrieval of a spatial location, possibly through a process of pattern completion.

Retrograde and anterograde object-recognition memory was assessed in rats with cytotoxic lesions of the hippocampal formation (HPC), using a paradigm based on the natural tendency of rats to spend more time exploring novel objects than familiar objects. The rats were allowed to explore a sample object for 5 min/day on 5 consecutive days, either 5 weeks or 1 week before surgery. After surgery, retrograde recognition was assessed by comparing the amount of time spent exploring the sample versus a novel object in a free-choice situation. Control rats spent more time exploring the novel object than the sample objects from both presurgery time periods, whereas rats with HPC lesions did not discriminate between the novel objects and sample objects from either presurgery time period. Despite their deficits on the retrograde recognition test, the rats with HPC lesions performed like control rats on anterograde recognition tests, displaying a strong exploratory preference for novel objects over sample objects, with retention delays of either 15 min or 24 h. The findings suggest that extrahippocampal circuitry is capable of supporting object recognition, but only if the HPC does not participate in encoding the original encounter with the object.

Estrogenic effects on visual (object recognition) and place (object placement) memory were investigated. Ovariectomized (OVX) rats received acute sc injections 30 min before a sample trial (viewing objects), and 4 h later a recognition/retention trial was performed. During recognition/retention trials, discrimination between sample (old) and new objects (visual memory) or between objects in sample (old) and new locations (place memory) was tested. Subjects given 17alpha- or 17beta-estradiol or diethylstilbestrol (DES) 30 min before sample trials discriminated between objects or locations during recognition/retention trials whereas vehicle-treated, OVX rats did not. Estrogens were given a postsample trial to investigate whether enhancements were due to effects on memory processes or psychological/performance parameters. Hormones were given immediately after or 2 h after sample trials (delayed injections), and recognition/retention were tested 4 h after the sample trial. Both object and place discriminations were enhanced when estrogens were given immediately after sample trials, but not when injections were delayed. These results provide evidence that estrogen rapidly enhances visual and place memory. Moreover, posttraining injections suggest effects on mnemonic processes, consolidation, or encoding, not on performance parameters. Place memory enhancements required higher estrogen doses, both pre- and postsample trial. The rapid time course, stereospecificity of responses (alpha- and beta-estradiol are effective), and efficacy of various estrogens suggest interactions at other than classic estrogen alpha- or beta-receptors in mediating the effects. Thus, these results provide the first demonstration of rapid memory enhancements by estrogen and implicate nongenomic mechanisms, possibly an extranuclear receptor(s), in mediating the response.