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Rodents are the animals most commonly employed to model human cognitive functions, but serious problems arise from the non-selective use of behavioral paradigms that measure different processes in rodents than those found in humans. To avoid problems stemming from the use of different paradigms on humans and mice, a new experimental paradigm for mice was developed to study the cognitive functions involved in delayed response tasks. The experiments were conducted in an olfactory tubing maze using three successive delayed response tasks: an alternation task, a non-alternation task, and a reversal task. Mice had to discover the rule by themselves by choosing one of two identical odor cues presented simultaneously at the left and right sides of a testing chamber. The success criterion was set at 10, 8, 6, or 4 consecutive correct responses, with a maximum of 80 trials per task, as used in primates. In the delayed alternation task with the criterion of 10 or 8 consecutive successful trials, the rule was discovered but required many more than 80 trials for most of the mice. With a criterion of 6 or 4, the mice were successful but twice as many trials were necessary to reach the criterion of 6 as opposed to 4. In the delayed non-alternation and reversal tasks, more than 80 trials were needed to figure out the new rule with the criterion of 10 or 8. All mice were successful with the criterion of 6 or 4. The results indicated that no matter what criterion was used, mice were able to discover the two rules on the three consecutive delayed response tasks, but they did so with more or less ease. This novel paradigm for mice should be useful in experiments on pharmacological treatments or for testing transgenic or gene-targeting mice to gain insight into the brain structures involved in this type of task.

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A new apparatus, the olfactory tubing maze for mice, was developed recently to study learning and memory processes in mice in regard to their ethological abilities. As in humans, BALB/c mice with selective bilateral lesions of the hippocampal formation showed selective impairment of subcategories of long-term memory when tested with the olfactory tubing maze. After three learning sessions, control mice reached a high percentage of correct responses. They consistently made the olfactory-reward associations, but antero-dorsal and postero-ventral hippocampal-lesioned mice did not. However, all lesioned mice learned the paradigm and the timing of the task as fast and as well as control mice. These data suggest that the olfactory tubing maze can be used to study subcategories of memory, such as declarative and non-declarative memory, which are similar in some respects to those observed in humans. Consequently, possible memory effects of classical approaches (i.e., pharmacological or lesion studies) or genetic modifications in transgenic or gene-targeting mice can be effectively analyzed using this new apparatus.

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Firstly, olfactory association learning was used to determine the modulating effect of 5-HT4 receptor involvement in learning and long-term memory. Secondly, the effects of systemic injections of a 5-HT4 partial agonist and an antagonist on long-term potentiation (LTP) and depotentiation in the dentate gyrus (DG) were tested in freely moving rats. The modulating role of the 5-HT4 receptors was studied by using a potent, 5-HT4 partial agonist RS 67333 [1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone] and a selective 5-HT4 receptor antagonist RS 67532 [1-(4-amino-5-chloro-2-(3,5-dimethoxybenzyloxyphenyl)-5-(1-piperidinyl)-1-propanone]. Agonist or antagonist systemic chronic injections prior to five training sessions yielded a facilitatory effect on procedural memory during the first session only with the antagonist. Systemic injection of the antagonist only before the first training session improved procedural memory during the first session and associative memory during the second session. Similar injection with the 5-HT4 partial agonist had an opposite effect. The systemic injection of the 5-HT4 partial agonist prior to the induction of LTP in the dentate gyrus by high-frequency stimulation was followed by a population spike increase, while the systemic injection of the antagonist accelerated the depotentiation 48 h later. The behavioural and physiological results pointed out the involvement of 5-HT4 receptors in processing related to the long-term hippocampal-dependent memory system, and suggest that specific 5-HT4 agonists could be used to treat amnesic patients with a dysfunction in this particular system.

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This article begins with a review of recent experiments investigating the synaptic efficacy changes occurring in rat dentate gyrus and piriform cortex during an associative olfactory task. In all these experiments, animals were trained to discriminate among an artificial cue, a patterned electrical stimulation distributed to the lateral olfactory tract associated with a water reward, and a natural odor associated with a flash of light. Monosynaptic field potential responses evoked by single electrical stimuli to the lateral olfactory tract were recorded in the ipsilateral piriform cortex before and just after each training session. Monosynaptic field and polysynaptic field potentials evoked by single electrical stimuli applied respectively to the lateral perforant pathway and lateral olfactory tract were also recorded in ipsilateral dentate gyrus. The results showed an increase in synaptic efficacy subsequent to the first training session in the dentate gyrus network when compared with piriform cortex at the later stage of the learning. The early increase of monosynaptic response in the dentate gyrus was observed immediately after the first learning session but disappeared 24 h later. Inversely, a synaptic depression developed across sessions, becoming significant at the onset of the last (fifth) session. The polysynaptic potential recorded in this structure increased substantially when rats began to discriminate the leaming cues, usually after the second or third learning session. Then, from the third to the fifth session, an LTP like-phenomenon appeared in piriform cortex when rats perfectly mastered the associations. Experiments using high-frequency stimulation to prevent changes in gyrus dentatus indicated that the onset of the observed depression was necessary for the learning of the olfactory associations. The fact that hippocampal and cortical neuronal networks exhibited different timing in synaptic efficacy changes could physiologically explain learning and memory processes.

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In order to have an ethologically relevant behavioral task, we developed the olfactory tubing maze to study learning and memory processes in mice. Mice have to make two olfactory-reward associations across three training sessions. The maze is made up of four identical testing chambers connected to each other by semicircular cylinders. After having chosen one of two odors presented on each side of a testing chamber, the mice have to run to the next testing chamber. From one testing chamber to the next, the side for presentating each odor is randomly assigned. The mouse must run through the entire circular maze to make a response at the four testing chambers. A complete session consists of 20 trials made by running five times clockwise through the maze with 4 trials per run. The training and data recording are fully automated by a custom-made software program. Three different experiments were performed. The results indicated that mice can easily make the olfactory discriminative associations in this new apparatus. Analysis of the data suggests that it would be possible using this olfactory tubing maze to study sub-categories of memory similar in some respects to those observed in humans. Consequently, possible effects on learning and memory of classical treatments (i.e. pharmacological or lesions) or genetic modifications in transgenic or gene-targeting mice could be tested.

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Modifications of synaptic efficacy in the dentate gyrus were investigated during an olfactory associative task. A group of rats was trained to discriminate between a patterned electrical stimulation of the lateral olfactory tract, used as an artificial cue, associated with a water reward, and a natural odor associated with a flash of light. Monosynaptic field potential responses evoked by single electrical stimuli to the lateral perforant path were recorded in the granular layer of the ipsilateral dentate gyrus prior to and just after each training session. An early increase in this response was observed just after the first learning session but disappeared 24 hours later. Inversely, a synaptic depression developed across sessions, becoming significant at the onset of a last (fifth) session. When a group of naive animals was pseudo-conditioned, no increase was observed and the synaptic depression was noted since the onset of the second session. In a group of rats similarly trained for only one session, and in which EPSPs were recorded throughout the 24 hours that followed, it was demonstrated that the increase lasted at least two hours, while the significant synaptic depression started after the fourth hour. These results are consistent with the early involvement of the dentate gyrus in learning the association between the cues and their respective rewards. These early integrative processes physiologically observed in dentate gyrus suggest early hippocampal processing before dentate gyrus reactivation via entorhinal cortex which will allow long-term memory storage in cortical areas once the meaning of the olfactory cues is learned.

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Apamin blocks SK channels responsible for long-lasting hyperpolarization following the action potential. Using an olfactory associative task, the effect of an intracerebroventricular 0.3 ng apamin injection was tested on learning and memory. Apamin did not modify the learning of the procedure side of the task or the learning of the odor-reward association. To test reference memory specifically, the rats were trained on a new odor-association problem using the same procedure (acquisition session), and they were tested for retention 24 h later. Apamin injected before or after the acquisition session improved retention of the valence of a new odor pair. Apamin injected before the retention session did not affect the retrieval of the new valence. Thus, the results indicate that the blockage of apamin-sensitive SK channels facilitate consolidation on new-odor-reward association.

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Olfactory associative learning was used to investigate the involvement of Kv channels containing Kv1.1 and Kv1.3 alpha-subunits in learning and memory. Kaliotoxin (KTX), a specific inhibitor of these Kv channels, was injected intracerebroventricularly in the rat brain, at a dose of 10 ng that did not disturb the rats' locomotor activity or drinking behaviour. In the first paradigm (odour-reward training), KTX improved learning but not information consolidation. Moreover, KTX increased the long-term retrieval of an odour-reward association tested by a reversal test 1 month after the odour-reward training. The second paradigm (successive odour-pair training) tested reference memory. The first session was an acquisition session where the rats learned a new odour-discrimination problem with the same procedure. The second was a retention session held 24 h later to test retrieval of the learned information. KTX injected before the acquisition or retention session improved performance, but no effect was found when KTX was injected immediately after acquisition. We showed that these effects were not due to the action of KTX on attention processes. Thus, these results suggest that the blockage of Kv1.1 or Kv1.3 channels by KTX facilitates cognitive processes as learning, in particular in a reference representation.

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Learning and memory are related both to cognitive processes and to neurobiological mechanisms. The human pathology focused on the role of the hippocampus and animal experiments have analyzed its implications. The most usually admitted hypothesis is that memories are underlied by distributed specific neural networks defined through the strengthening of certain synapses, under the action of the flow of information during learning. The best candidate for this strengthening of the synapses is a change in synaptic plasticity similar to the artificial phenomenon of long-term potentiation. During memory processes, the hippocampus would play a particular role in information processing (analyzing novelty and significance of the information) and would allow the specification of the neural network, mainly in the cortical territories. We report data in olfactory learning in rats comforting these hypotheses. Considering neurochemistry of memory processes, specific synaptic changes and neuromodulatory processes must be distinguished. We report data about vasopressin illustrating both kinds of mechanisms in the hippocampus.

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The involvement of [Arg(8)]vasopressin in memory processes was analyzed in the hippocampal structure, since we have reported that this is one of the main central target structures of the vasopressin-enhancing effect on memory. This structure is functionally differentiated along its dorsoventral axis, and the expression of the vasopressinergic system is dependent upon whether the dorsal or ventral part of the hippocampus is involved. For this reason, the effect of vasopressin injected into hippocampus was evaluated on the basis of the site of injection. We have shown, using a Go-No Go visual discrimination task with mice that both parts of the hippocampus are involved in the effect of endogenous or exogenous vasopressin, but with higher sensitivity for the ventral part. Based on the expression of Fos protein following intracerebroventricular injection of vasopressin in unconditioned or conditioned mice, we confirmed the greater involvement of the ventral hippocampus in the enhancing effect of vasopressin on memory processes. The effect of the peptide seems specific, since only a few of the hippocampal cells that expressed Fos protein in the unconditioned mice did so in the conditioned mice (cells in the dentate gyrus and the CA3 hippocampal field). Moreover, we have shown that in the ventral hippocampus, vasopressin generates different behavioral effects whether treatment is performed at the beginning or in the middle of the learning process, suggesting that the mnemonic context is an important factor for understanding the effect of vasopressin on memory in the ventral hippocampus.

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Recent data suggest that activation of 5-HT(4) receptors may modulate cognitive processes such as learning and memory. In the present study, the effects of two potent and selective 5-HT(4) agonists, RS 17017 [1-(4-amino-5-chloro-2-methoxyphenyl)-5- (piperidin-1-yl)-1-pentanone hydrochloride] and RS 67333 [1(4-amino-5-chloro-2-methoxyphenyl)-3- (1-n-butyl-4-piperidinyl)-1-propanone], were studied in an olfactory associative discrimination task. The implication of 5-HT(4) receptors in the associative discriminative task was suggested by the following observation. Injection of a selective 5-HT(4) receptor antagonist RS 67532 [1-(4-amino-5-chloro-2-(3, 5-dimethoxybenzyloxyphenyl)-5-(1-piperidinyl)-1-pentanone; 1 mg/kg: i.p.] before the third training session induced a consistent deficit in associative memory during the following training sessions. This deficit was absent when the antagonist was injected together with either a specific hydrophilic 5-HT(4) (RS 17017, 1 mg/kg) or a specific hydrophobic (RS 67333, 1 mg/kg) 5-HT(4) receptor agonist. RS 67333 was more potent than RS 17017. This difference in potency certainly reflects a difference in their capacity to enter into the brain. This is also likely to be the reason why, injected alone, the hydrophobic 5-HT(4) agonist (RS 67333) but not the hydrophilic 5-HT(4) agonist (RS 17017) improved learning and memory performance.

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In this report, we investigated the electrophysiological dynamics of the neuronal circuit including the dentate gyrus during an associative task. A group of rats was trained to discriminate between a patterned electrical stimulation of the lateral olfactory tract, used as an artificial cue associated with a water reward, and a natural odor associated with a light flash. Polysynaptic field potential responses, evoked by a single electrical stimulation of the same lateral olfactory tract electrode, were recorded in the molecular layer of the ipsilateral dentate gyrus prior to and just after each training session. An increase in this response was observed when a significant discrimination of the two cues began. A positive correlation was found between the change in the polysynaptic potentiation and behavioral performances. The onset latency of the potentiated polysynaptic response was 35-45 ms. When a group of naive animals was pseudoconditioned, no change in field potential was observed. These results are consistent with the hypothesized dynamic activation of the dentate gyrus early in the making of association, allowing gradual storage of associative information in a defined set of synapses. Moreover, the onset latency of the potentiated response suggests the existence of reactivating hippocampal loops during the processing of associative information.

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Within the past century it has been well established that most mature neurons lose their ability to divide. Since then, it has been assumed that behavioral performance leads to synaptic changes in the brain. The existence of these potential changes has been demonstrated in numerous experiments, and different mechanisms contributing to synaptic plasticity have been discovered. Many structures involved in different types of learning have now been identified. This article reviews the different methods used with mammals to detect electrophysiological modifications in synaptic plasticity following behavior. Evidence of long-term potentiation and long-term depression has been found in the hippocampus and cerebellum, respectively, and empirical data has been used to correlate these mechanisms with specific learning performance. Similar observations were made recently in the septum and amygdala. These phenomena seem to be involved in maintaining the performance in the cortical areas of the brain. Ongoing attempts to find the relationship between behavioral performance and modifications in synaptic efficacy allow to speculate upon the dynamics of cellular mechanisms that contribute to the ability of mammals to modify wide neuronal networks in the brain during their life.

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Arginine8-vasopressin (AVP) has been shown to improve memory consolidation in various mnemonic tasks. Our previous studies have pointed out the involvement of the hippocampus in memory consolidation and retrieval processes during discriminative learning by mice. The present study attempts to determine what other brain areas besides the hippocampus might be involved in the enhancing effect of intracerebroventricularly (i.c.v.) injected AVP on memory consolidation in a visual discrimination task using a polyclonal antibody that acts against Fos and Fos-like proteins. For behavioral testing, AVP was i.c.v. injected at the behaviorally active dose of 2 ng after the last learning session and improvement in consolidation processes was assessed in a retention session. Changes in Fos and Fos-like protein expression were determined in non-conditioned and conditioned mice. In non-conditioned mice, AVP i. c.v. injected at a dose of 2 ng evoked a time-dependent increase in Fos and Fos-like protein expression in the dentate gyrus (DG), CA1 and CA3 hippocampal fields, lateral septum (LS), bed nucleus of the stria terminalis, and basolateral and central amygdaloid nuclei, with a peak 120 min after the injection in most of the these brain areas. In contrast, in conditioned mice, an increase in the level of Fos expression, assessed 120 min after the end of learning and the injection of AVP, was detected only in the DG, ventral CA3 hippocampal field, and LS. Thus, the pattern observed after post-training injection of AVP was not the same as that evoked by AVP alone, since among the limbic structures activated following AVP alone, only the DG, the CA3 hippocampal field, and the LS seem to be involved in the enhancing effect of AVP on memory consolidation in discriminative learning.

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[Arg8]vasopressin improved long-term retrieval processes and relearning in a go-no go visual discrimination task when bilaterally microinjected at a dose of 25 pg/animal into the ventral hippocampus of mice, 10 min prior to the retention session. We had shown that this enhancing effect is antagonized by pretreatment with equal or lower doses (25 pg or 1 ng) of the vasopressin V1 receptor antagonist, (d(CH2)5Tyr(Me)-vasopressin). The present study was an attempt to determine whether the vasopressin V2 receptor antagonist or oxytocin receptor antagonist is as effective as the vasopressin V1 receptor antagonist to block the behavioral effect of vasopressin in the ventral hippocampus. We tested the effect of 25 pg of [d(CH2)5-D-Ile2,Ile4,Arg8]vasopressin, a vasopressin V2 receptor antagonist, and [d(CH2)5,Tyr(Me)2,Thr4,Tyr-NH9(2)]ornithine vasotocin, an oxytocin receptor antagonist, under the same experimental conditions as those used to test the effect of the vasopressin V1 receptor antagonist. The results showed that the vasopressin V2 receptor antagonist microinjected into the ventral hippocampus did not alter the enhancing effect of vasopressin on retrieval and relearning. In contrast, the oxytocin receptor antagonist blocked the vasopressin-enhancing effect on retention processes. We can conclude from the data that both vasopressin V1 receptors and oxytocin receptors seem to be involved in the enhancing effect of vasopressin on memory retention. In contrast, the vasopressin V2 receptors do not seem to be involved in the effect of the peptide.

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The involvement of arginine8-vasopressin (VP) in learning and memory in the hippocampus is examined in mice using a discriminative learning task. Bilateral dorsal hippocampal lesion blocks the enhancing effect of intracerebroventricular (i.c.v.) injection of VP on retrieval and relearning processes. An additional study showed that immunoneutralization of dorsal hippocampal endogenous VP inhibited the facilitating effect of i.c.v. injection of VP, suggesting that hippocampus is essential for the expression of VP's behavioral effects. Using in situ microinjection, a greater sensitivity of the ventral part of the hippocampus to the memory enhancing effects of VP has been reported. This effect is mediated by vasopressin V1 type receptors and oxytocin receptors. Then, we examined the effects on behavior of VP applied to the ventral hippocampus, in relation to the time of treatment during learning. When the animals have no previous information about the task to learn, a deleterious effect of VP appears (pre-first session treatment). Regarding memory consolidation, the effects of VP may depend upon the previous level of performance acquired by the animals since, when injected after the first learning session, the peptide slightly delayed performance, whereas when the injection took place after the second learning session, it enhanced learning. Concerning memory retrieval, the effects of VP depend on the quality of the previously stored information. The fact that VP did not generate the same behavioral effects when the treatment was performed at the beginning or in the middle of the learning processes, suggests that mnemonic context is an important factor in understanding the effect of VP on memory in the ventral hippocampus. Finally, the role of hippocampal adrenergic receptors in the enhancing VP effects on memory retrieval has been examined. The facilitatory effects of VP seem to depend upon the functional state of both alpha- and beta-adrenergic receptors, but further studies will be necessary to clarify the role played by each receptor type in retrieval processes, and to determine the relationships that might exist between them.

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A visual discrimination task was used to investigate the effect of the intra-hippocampal injection of arginine8-vasopressin (AVP) in male Balb/c mice at different stages of the learning processes. The peptide was bilaterally microinjected at a dose of 25 pg per animal, i.e. 833 pg/kg, into the ventral hippocampus, in a volume of 0.3 microliter 10 min before either the first or the second learning session, or immediately after the first or second learning session. Following pre-session administration of AVP, no effect of the peptide was observed on the session prior to which it was administered. On the other hand, 48 h after the pre-first session treatment, it seems that AVP animals had trouble learning the task. Following post-session injection of AVP, no effect was observed when the treatment was given after the first learning session and a tendency to improve performance was noted when the treatment was given after the second learning session. Thus, whatever time AVP was injected during learning, little or no effect was observed. These results and previous work on the same behavioral task showing a clear enhancing effect of the peptide on retrieval processes, suggest that prior experience or mnemonic context before AVP treatment is as important a factor in understanding the effects of AVP on memory processes as the administration route or the doses used.

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Adult neonatally gamma-irradiated rats were compared with control animals in a non-spatial olfactory associative task using two different procedures. Irradiation induced a clear reduction in the total mean area of the olfactory bulbs and hippocampus but not of the orbital prefrontal cortex, diagonal band and cell layers of the entorhinal and piriform cortex. The gamma-irradiation affected the granule cells of the olfactory bulbs and differentially altered the cell layers of the subfields of the ammonic fields and the dorsal and ventral blades of the dentate gyrus. In the CA1 ammonic field, dorsal and ventral blades of the dentate gyrus, the cellular loss was significant in comparison with control adult rats. The behavioural data indicated that irradiated rats were deeply disturbed in learning the odour-reward association, and substantially impaired in a reversal experiment, but not in the discrimination of the odours per se. The cellular loss in the olfactory bulbs, in the CA1 and in the ventral blade of the gyrus dentatus was positively correlated with the deficit in behavioural performance. The data support the findings that the hippocampal system participates in the odour-reward associations and facilitates the long-term storage of associations after learning is achieved in this olfactory associative task.

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