Expression of polysialyltransferases (STX and PST) in adult rat olfactory bulb after an olfactory associative discrimination task.

Neuronal plasticity and neurogenesis occur in the adult hippocampus and in other brain structures such as the olfactory bulb and often involve the neural cell adhesion molecule NCAM. During an olfactory associative discrimination learning task, NCAM polysialylation triggers neuronal plasticity in the adult hippocampus. The PST enzyme likely modulates this polysialylation, but not STX, a second sialyltransferase. How the two polysialyltransferases are involved in the adult olfactory bulb remains unknown. We addressed this question by investigating the effect of olfactory associative learning on plasticity and neurogenesis. After a hippocampo-dependent olfactory associative task learning, we measured the expression of both PST and STX polysialyltransferases in the olfactory bulbs of adult rats using quantitative PCR. In parallel, immunohistochemistry was used to evaluate both NCAM polysialylation level and newly-born cells, with or without learning. After learning, no changes were observed neither in the expression level of PST and NCAM polysialylation, nor in STX gene expression level and newly-born cells number in the olfactory bulb.

Evaluation of a joint distractor to facilitate arthroscopy of the tibio-tarsal joint in dogs.

OBJECTIVE: To evaluate the technical feasibility, efficacy and potential soft tissue damage of a joint distraction technique to facilitate arthroscopy of the tibio-tarsal joint and to test the effect of joint venting on the maximum distraction achieved. METHODS: Twenty hocks were preliminarily evaluated radiographically by standard and stressed projections. Joint distraction was applied with loads from 40 N up to 200 N, in 40 N increments, and radiographic images were obtained at each load. The effect of joint venting by an intra-articular needle was evaluated at the maximum load. Standard and stressed radiographs were repeated to evaluate potential laxity changes. RESULTS: Joint distraction caused a significant increase in the joint space at each load of distraction except for the 40 to 80 N load increase. Joint venting produced a significant increase in the joint space. No increase of joint laxity could be inferred from the postdistraction radiographic evaluation. CLINICAL SIGNIFICANCE: Hock distraction can be useful to facilitate arthroscopic procedures, increasing the joint space available for intra-articular manoeuvres. Further clinical studies are required to evaluate potential neurovascular complications.

Dorsolateral striatum and dorsal hippocampus: a serial contribution to acquisition of cue-reward associations in rats.

In laboratory rodents, procedural and declarative-like memory processes are often considered operating in dual, sometimes even competing with each other. There is evidence that the initial approach of a repetitive task first engages a hippocampus-dependent declarative-like memory system acquiring knowledge. Over repetition, there is a gradual shift towards a striatum-dependent response memory system. In the current experiment, Long-Evans male rats with bilateral, fiber-sparing ibotenic acid-induced lesions of the dorsolateral striatum or the dorsal hippocampus were trained in an olfactory associative task requiring the acquisition of both a procedural and a declarative-like memory. Rats with dorsolateral striatum lesions, and thus an intact hippocampus, were impaired on both sub-categories of memory performance. Rats with dorsal hippocampal lesions exhibited a substantial deficit in learning the declarative-like cue-reward associations, while the acquisition of the procedural memory component of the task was not affected. These data suggest that the dorsolateral striatum is required to acquire the task rule while the dorsal hippocampus is required to acquire the association between a given stimulus and its associated outcome. The finding is that the dorsolateral striatum and the dorsal hippocampus most probably contribute to successful learning of cue-reward associations in a sequential (from procedural to declarative-like memory) order using this olfactory associative learning task.

Increase in polysialyltransferase gene expression following LTP in adult rat dentate gyrus.

Neural cell adhesion molecule (NCAM) is frequently associated with polysialic acid (PSA), and its function is highly dependent on this polysialylation. PSA-NCAM plays an important role in synaptic plasticity in the hippocampus. STX and PST are the enzymes responsible for NCAM polysialylation. We investigated whether unilateral long-term potentiation (LTP) induction in vivo, in adult rat dentate gyrus (DG), triggered NCAM polysialylation by STX and PST produced in the hippocampus. We found that levels of STX and PST mRNA increased strongly since the early stage of hippocampal LTP and remained high during the maintenance of DG-LTP for 4 h. This rapid increase in polysialyltransferase gene expression occurred in both the hippocampi, probably resulting from bilateral LTP induction by strong unilateral HFS. Thus, LTP triggers interhemispheric molecular changes in the hippocampal network. This study is the first to describe the effects of LTP induction and maintenance on polysialyl-transferases in vivo. Our findings suggest that hippocampal synaptic remodeling requires NCAM polysialylation.

Extracellular recordings of rodents in vivo: their contribution to integrative neuroscience.

The prevalent theory in learning and memory processes is that they are underlain by short and long-term changes in synaptic weight, which continuously modulates neural networks during acquisition and recall. This synaptic plasticity has been revealed by recording extracellular field potentials. The enhancement of synaptic transmission was primarily noted in the hippocampus and was named long-term potentiation (LTP). The opposite mechanism, long-term depression (LTD), a reduction of synaptic transmission, was first discovered in the cerebellum. Since then, the LTP-model has been studied mainly using in vitro and acute anesthetized in vivo preparations. This approach has led to remarkable progress in the comprehension of intracellular molecular processes during LTP and LTD. In this review, we focus mainly on what we can learn about molecular events using extracellular field potential recordings with a more ecological model, i.e., studies using the freely behaving animal, with animals that are genetically modified or not, in several behavioral paradigms aimed at gaining insight into some of the conflicting results obtained with in vitro and in vivo preparations.

Complete recovery of olfactory associative learning by activation of 5-HT4 receptors after dentate granule cell damage in rats.

Bilateral intradentate injections of 3.0microg of colchicine induced a substantial loss of granule cells and damage to the overlying pyramidal cell layer in region CA1 in adult male Long-Evans rats. All rats with such lesions showed a significant associative learning deficit in an olfactory discrimination task, while being unimpaired in the procedural component of this task. Injection of a partial selective 5-HT(4) agonist (SL65.0155; 0.01mg/kg, i.p., vs. saline) before the third of six training sessions enabled complete recovery of associative learning performance in the lesioned rats. Activation of 5-HT(4) receptors by a selective agonist such as SL65.0155 might therefore provide an opportunity to reduce learning and memory deficits associated with temporal lobe damage, and could be useful for the symptomatic treatment of memory dysfunctions related to pathological aging such as Alzheimer's disease.

Involvement of tissue inhibition of metalloproteinases-1 in learning and memory in mice.

Tissue inhibitor of metalloproteinases (TIMP-1) is one of the four-member family (TIMPs-1-4) of multifunctional proteins that inhibit matrix metalloproteinases (MMPs). Its expression in the hippocampus is neuronal-activity-dependent and dramatically induced by stimuli leading to long-term potentiation (LTP), suggesting that TIMP-1 is a candidate plasticity protein potentially involved in learning and memory processes. We tested this hypothesis in a hippocampus-dependent task using the new olfactory tubing maze, with mice carrying a null mutation for TIMP-1 (TIMP-1 KO) and mice overexpressing TIMP-1 (TIMP-1 (tg)). The TIMP-1 KO mice were significantly impaired in making correct odor-reward associations when compared with their respective wild type (WT) littermates, while TIMP-1 overexpressing mice performed better than their WT controls. Both genetically modified mice learned the paradigm and the timing of the task, like their respective WTs, and no olfactory dysfunctioning was observed. These data suggest that TIMP-1 is involved in learning and memory processes related to the hippocampus, and support the hypothesis that the MMP/TIMP ratio, and hence MMP activity, modulates neuronal plasticity in normal learning and memory processes, while altered proteolytic activity could impair cognitive functions.

Strain differences in rewarded discrimination learning using the olfactory tubing maze.

We trained BALB/c Byllco (C), CD-1, SV 129/SvPasCr1 (129 SV), C57BL/6 (B6) and DBA/2J (D2) mice using the olfactory tubing maze with the hope of gaining insight into behavioral genetics related to learning and memory processes. All strains of mice acquired the odor-reward associations using this new task except the D2 strain. The C, CD-1, and 129 SV consistently remembered the associations from the sixth 20-trial training session, reaching 80% +/- 5 correct responses in session seven. The B6 mice required one more session to reach 76%, while the D2 mice never learned the correct odor-reward associations. All mice learned the paradigm and the timing of the task, although the 129 SV mice decreased slower the inter-trial intervals across sessions. With this new task, D2 mice, with a deficit totally devoted to an impairment on learning and memory, can be used as a model of hippocampal dysfunction, in some respects like that observed in human amnesic patients whose selective hippocampal-dependent memory is deeply impaired. The high-scoring strains (C, CD-1, and 129 SV) seem to be ideal in this task to study a gene-targeting mutation postulated to reduce behavioral performance, and inversely, for D2 mice. The moderate-scoring strain, B6, should be ideal for allowing gene-targeting to go either way. In addition, this new task, which enables automated training of odor associations, could be used for studying the phenomenon of transitivity in mice, as described in rats.

A novel experimental paradigm for studying cognitive functions related to delayed response tasks in mice.

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.

Selective impairment of subcategories of long-term memory in mice with hippocampal lesions accessed by the olfactory tubing maze.

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.

Modulation of memory processes and cellular excitability in the dentate gyrus of freely moving rats by a 5-HT4 receptors partial agonist, and an antagonist.

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.

Learning and memory of cue-reward association meaning by modifications of synaptic efficacy in dentate gyrus and piriform cortex.

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.

The olfactory tubing maze: a new apparatus for studying learning and memory processes in mice.

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.

Early integrative processes physiologically observed in dentate gyrus during an olfactory associative training in rat.

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.

Differential modulation of the 5-HT(4) receptor agonists and antagonist on rat learning and memory.

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.

Early polysynaptic potentiation recorded in the dentate gyrus during an associative learning task.

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.

Correlations between electrophysiological observations of synaptic plasticity modifications and behavioral performance in mammals.

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.

Involvement of 5-HT receptors in learning and memory.

Cumulative evidence indicates that the serotonin (5-HT) system plays a modulatory role in cognitive processes, particularly in learning and memory. The present review focuses on the effects of agonists and antagonists on different 5-HT receptors, administered during pre-learning, post-learning or pre-retention, in different behavioral tasks. The effects of these pharmacological compounds were either facilitative or disruptive, or allowed for recovery from impaired cognitive performance following the activation or blockade of 5-HT1, 5-HT2, 5-HT3 and 5-HT4 receptors. Since little or no data on learning and memory are currently available for the 5-ht5, 5-ht6 and 5-HT7 receptors, this article presents an overview of their brain locations and possible involvement in these highly cognitive processes.