Retention Session Research Articles

Neprilysin-sensitive Synapse-associated Amyloid-β Peptide Oligomers Impair Neuronal Plasticity and Cognitive Function

Neprilysin-sensitive Synapse-associated Amyloid-β Peptide Oligomers Impair Neuronal Plasticity and Cognitive Function

DIFFERENTIAL EFFECTS OF TWO BLOCKERS OF SMALL CONDUCTANCECa2+-ACTIVATEDK+CHANNELS, APAMIN AND LEI-DAB7, ON LEARNING AND MEMORY IN RATS

SK channels are responsible for long-lasting hyperpolarization following action potential and contribute to the neuronal integration signal. This study evaluates the involvement of SK channels on learning and memory in rats, by comparing the effects of two SK channel blockers, i.e., apamin which recognizes SK2 and SK3 channels, and lei-Dab7 which binds SK2 channels only. lei-Dab7 totally competes and contests apamin binding on whole brain sections (IC(50): 11.4 nM). Using an olfactory associative task, intracerebroventricular blocker injections were tested on reference memory. Once the task was mastered with one odor pair, it was then tested with a new odor pair. Apamin (0.3 ng), injected before or after the acquisition session, improved new odor pair learning in a retention session 24 hours later, whereas lei-Dab7 (3 ng) did not significantly affect the mnesic processes. These results indicated that the blockage of SK channels by apamin facilitates consolidation on new odor associations; lei-Dab7, containing only SK2 subunits, remains without effect suggesting an involvement of SK3 channels in the modulation of the mnesic processes.

A study of learning and retention with a Web-based IR interface

This article reports on an empirical study on novices’ learning and retention with the Web-based interface to the Web of Science. The aim was to evaluate the performance of novice searchers in initially learning to use the search interface and in later use. Their performance in both sessions was measured in terms of time taken to perform tasks, search terms used, success of the tasks performed and error rates. At the end of each session, novices’ subjective satisfaction with the interface was also measured. The results showed that novices’ performance was better in the learning session. Their performance in the retention session declined significantly in terms of success score as they forgot the interface functionalities from one search session to another. Novices’ subjective satisfaction with the interface was also higher in their learning session. Their satisfaction rating with the interface declined sharply in the retention session. The Web of Science interface suffers from usability problems which made its functionalities difficult to learn and remember for naïve searchers.

Bidirectional effects of benzodiazepine binding site ligands on active avoidance acquisition and retention: differential antagonism by flumazenil and β-CCt

The pharmacological approach, using subtype selective ligands, complements genetic studies on the specific contribution of individual receptor subtypes to the various effects of benzodiazepines. The aim of this study was to examine the relative significance of alpha1-containing GABA(A) receptors in the effects of modulators at the benzodiazepine site on anxiety and memory processes. We tested the effects of the nonselective antagonist flumazenil, the preferential alpha1-subunit selective antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt), the nonselective agonist midazolam, the preferential alpha1-subunit selective agonist zolpidem, and the nonselective inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in a two-way active avoidance task in rats. The influence of flumazenil (10.0 mg/kg) and beta-CCt (30.0 mg/kg) on the effects of the two agonists were also examined. In the schedule 2 x 30 trials, drugs were administered i.p. 20 min before the training session. Avoidance responses in the training session are an anxiety-mediated behavior, whereas performance in the retention session relates to the effects on memory. Flumazenil and beta-CCt did not affect behavior. Midazolam (2.0 mg/kg) facilitated acquisition performance, while DMCM (1.0 and 2.0 mg/kg) induced the opposite effect. Flumazenil antagonized both effects. Beta-CCt potentiated the effect of midazolam, and partly antagonized the effect of DMCM. Midazolam (0.5 and 1.0 mg/kg) and zolpidem (1.0-3.0 mg/kg) impaired, while DMCM (0.1 mg/kg) facilitated the subjects' performance in the retention test. The amnesic effects were attenuated but not fully reversed, while the effect of DMCM was counteracted by both antagonists. The results indicate the alpha1-subunit interferes with the anxiolytic effect of a benzodiazepine site agonist and may contribute to the DMCM-induced anxiogenic effect. It is also substantially involved in the bidirectional memory processing in the active avoidance paradigm.

Effects of endogenous morphine deprivation on memory retention of passive avoidance learning in mice.

Memory and the processes of learning in mammals are well known to be affected by opioid agonists such as morphine, which has been proven to interfere and cause amnesia. The presence of endogenous morphine has been demonstrated in various tissues from mammals to invertebrates. In this study, we have investigated the effects caused by in-vivo immunodepletion of endogenous morphine on working memory under different experimental conditions. When mice were submitted to fasting, a stress condition, acquisition and consolidation of memory were significantly impaired compared to controls. This was demonstrated by a decrease in entry latency into the dark room in the retention session of the passive avoidance test. This effect was significantly reversed to baseline values when endogenous morphine was depleted from the extracellular brain space. These findings support a role for endogenous morphine in weakening memory processes under stress conditions.

Effects of electrical stimulation of the nucleus basalis on two-way active avoidance acquisition, retention, and retrieval

This study assessed the role of the nucleus basalis magnocellularis (NBM) in specific memory phases of two-way active avoidance conditioning. We evaluated the effects of NBM electrical stimulation applied during different phases of the avoidance task. Rats were trained in a 30-trial acquisition session, and were tested again 24 and 48 h later. NBM stimulation was applied at different stages of memory formation of the conditioning: (1) immediately before the first training session to determine the effects on acquisition of the two-way avoidance task; (2) immediately after the first training session to evaluate effects on memory consolidation; and (3) immediately before the 24-h retention session to analyze the effects on the retrieval process. NBM stimulation before training significantly improved the acquisition of the task, without affecting subsequent retention at either 24 or 48 h. Stimulation of the NBM immediately after the first training session slightly impaired performance in the 24-h retention session. Stimulation of the NBM immediately before the 24-h retention session did not affect performance in either the 24 or 48-h retention sessions. Therefore, the NBM may play a more important role in acquisition of memory in aversively motivated conditioning tasks than in consolidation or retrieval of such memories. These results are discussed in the context of attention enhancement and cortical and amygdala activation.

Intraseptal infusion of the cholinergic agonist carbachol impairs delayed-non-match-to-sample radial arm maze performance in the rat.

The medial septal nucleus regulates the physiology and emergent functions (e.g., memory formation) of the hippocampal formation. This nucleus is particularly rich in cholinergic receptors and is a putative target for the development of cholinomimetic cognitive enhancing drugs. A large number of studies have demonstrated that direct intraseptal drug infusions can produce amnestic or promnestic effects. While a few studies have examined the effects of direct intraseptal infusion of cholinomimetics on spatial memory performance (with drug "on-board" at the time of testing), the effects of post-acquisition infusions have not been assessed. We hypothesized that post-acquisition intraseptal infusion of cholinomimetics, by promoting hippocampal theta and suppressing the occurrence of hippocampal sharp waves, may disrupt the long-term retention and consolidation of memory. The present study examined the effects of intraseptal infusion of the cholinergic agonist carbachol in a delayed-non-match-to-sample radial maze task. Treatments were administered immediately following (within 1 min) the sample session with a retention session 2 h later. Carbachol infusions (12.5-125 ng in 0.5 microl) produced a linear dose-dependent decrease in correct entries and increase in retroactive errors, without any change in proactive errors or latency-per-choice. These findings suggest that post-acquisition intraseptal cholinergic treatments can produce amnesia. These findings are discussed with regard to multi-stage models of hippocampal-dependent memory formation and the further development of therapeutic strategies in the treatment of mild cognitive impairment as well as age-related cognitive decline and Alzheimer's dementia.

Parafascicular electrical stimulation attenuates nucleus basalis magnocellularis lesion-induced active avoidance retention deficit

Previous experiments from our laboratory showed that retention of two-way active avoidance learning is improved by post-training intracranial electrical stimulation (ICS) of the parafascicular nucleus (PF) and impaired by pre-training electrolytic lesions of the nucleus basalis magnocellularis (NBM). The question investigated here was whether post-training PF ICS is able to attenuate the active avoidance retention deficit observed in rats lesioned pre-training in the NBM. To this goal, the following experimental design was used: rats bilaterally lesioned in the NBM and stimulated in the PF, rats lesioned in the NBM, rats stimulated in the PF, control rats implanted in the PF, and sham-operated rats were first trained in a shuttle-box for a single 30-trial session and tested again following two successive retention intervals (24 h and 11 days). The results showed that: (1) NBM lesions impaired the 11-day performance without affecting either the acquisition or the 24-h retention of the avoidance learning; (2) PF ICS treatment in unlesioned rats improved performance in both retention sessions only when the stimulation was applied in the posterior region of the nucleus; and (3) stimulation of the posterior PF compensated the 11-day retention impairment induced by NBM lesions. These results are discussed in relation to the interaction of arousal systems in the modulation of cognitive processes.

Waking EEG power spectra in the rat: correlations with training performance

Adult rats chronically implanted with supradural electrodes were telemetrically EEG recorded during a baseline session, a training session for a two-way active avoidance task, and a retention session. Rats were assigned to a fast learning (FL), slow learning (SL) and non learning (NL) group if they achieved criterion during the training session, the retention session, or in neither session. High-resolution EEG analyses indicated that intergroup differences were present in the low frequency range of waking baseline power spectra. Moreover, baseline δ emissions directly correlated with freezings, and inversely correlated with avoidances, while emissions at 7–10 Hz directly correlated with avoidances and inversely correlated with freezings. Interestingly, during the first training period, waking δ emission selectively increased in FL rats in concomitance with a marked performance improvement; instead, SL and NL rats displayed increments at 7–9 Hz. In addition, freezings scored during the first two training periods directly correlated with post-training waking emission at 2 Hz, and inversely correlated with emission at 7–10 Hz. Conversely, escapes and avoidances directly correlated with waking emission at 7–10 Hz. The data indicate that (i) waking baseline power spectra differ among behavioral groups, and correlate with behavioral performance the following day; (ii) selective modifications of waking power spectra occur in each behavioral group during training; and (iii) behavioral responses during training correlate with post-training waking power spectra. Notably, the δ increment selectively occurring in training FL rats is assumed to reflect online memory processing leading to better performance. The latter observation supports the primary involvement of δ waves in learning.

Differential involvement of dopamine in the anterior and posterior parts of the dorsal striatum in latent inhibition

The involvement of mesostriatal dopaminergic neurons in cognitive operations is not well understood, and needs to be further clarified. The use of latent inhibition paradigms is a means of investigating cognitive processes. In this study, we investigated the involvement in latent inhibition of dopaminergic inputs in the anterior part and posterior part of the dorsal striatum. The latent inhibition phenomenon was observed in a conditioned olfactory aversion paradigm. Changes in extracellular dopamine levels induced by the conditioned olfactory stimulus (banana odor) were monitored in the two parts of the dorsal striatum in the left hemisphere after pre-exposure to the olfactory stimulus using in vivo voltammetry in freely moving rats. During the conditioning session animals received either an i.p. injection of NaCl (0.9%) (control groups) or an i.p. injection of LiCl (0.15 M) (conditioned groups). Dopamine variations and place preference or aversion toward the stimulus were analyzed simultaneously in pre-exposed and non-pre-exposed animals. Data collected during the retention (test) session were as follows. Where the anterior part of the striatum was concerned, similar enhancements in dopamine levels (+100%) were obtained in pre-exposed and non-pre-exposed control animals, as well as in the pre-exposed experimental animals. In contrast, dopamine levels in the non-pre-exposed experimental group (conditioned animals) remained fairly consistently close to the baseline after the presentation of the olfactory stimulus. Where the posterior part of the striatum was concerned, increases in extracellular dopamine levels were similar (+50%) for the different groups. The present results suggested that dopaminergic neurons reaching the anterior part of the dorsal striatum are implicated in the latent inhibition phenomenon and affective perception, whereas dopaminergic terminals in the posterior part of the dorsal striatum appeared to be involved neither in latent inhibition nor in affective perception of the stimulus, seeming only to be affected by the intrinsic properties of the stimulus. Cognitive as well as affective deficits have been reported in patients with schizophrenia. Thus the present data may be considered in the context of the pathophysiology of schizophrenic psychoses.

Single Neurons in CA1 Hippocampus Encode Trace Interval Duration during Trace Heart Rate (Fear) Conditioning in Rabbit

This study sought to determine whether CA1 hippocampal neurons encode the duration of the trace interval during trace fear conditioning. Single neurons were recorded extracellularly in the CA1 of rabbits during and after a single trace fear classical conditioning session. Trace fear conditioning trials consisted of an auditory conditioned stimulus (CS; 3 sec) and a fear-producing shock unconditioned stimulus (US; 0.5 sec) separated by a silent trace interval. One group of rabbits was trained using a 10 sec trace interval (n = 5), and another group was trained using a 20 sec trace interval (n = 4). These groups were compared with pseudoconditioning control rabbits (n = 5 and n = 4, respectively) that received unpaired CSs and USs. One day after trace and pseudo fear conditioning rabbits received a CS-alone retention session in which no USs were presented. The trace conditioned groups showed larger bradycardiac-fear responses on CS-alone trials compared with the pseudoconditioning groups. A significant percentage of CA1 neurons from the 10 and 20 sec trace groups (24 and 28%, respectively) showed maximal firing on CS-alone retention trials timed to 10 sec (+/-1.5 sec) and 20 sec (+/-2.0 sec) after CS offset, respectively. These latencies were similar to the duration of the trace interval used on previous CS-trace-US trials. Timed CA1 firing was not seen in pseudoconditioning control animals, suggesting that a subset of CA1 neurons encoded the trace interval duration. The percentage of neurons encoding trace duration was largest when rabbits exhibited significant fear responses to the CS, suggesting that trace encoding was related to the strength of the CS and US association.

Fos imaging reveals ageing-related changes in hippocampal response to radial maze discrimination testing in mice.

A two-stage radial arm maze (RAM) task has been designed recently to demonstrate a specific age-related memory deficit in mice. It highlights the contrast between normal and deficient memory expression in a spatial discrimination problem depending on how to-be discriminated arms were presented to the animal. This specific deficit has been interpreted as a preferential loss in a relational/declarative form of memory, thereby implying an underlying hippocampal dysfunction. To test this hypothesis, neuronal activation measured by Fos immunostaining was compared in aged (21-23 months) and adult (4-6 months) mice trained in the aforementioned task and killed after a retention session consisting in age-insensitive probe trials, performed 6 days later (6-day RAM). Two comparison conditions were included: (i) repeated locomotor training on a treadmill (TM); (ii) the same RAM training, except for the use of a longer (30 days instead of six) retention interval (30-day RAM). Although all RAM groups displayed similar levels of performance at the end of the experiment, immediately before the mice were killed, significant between-group differences in brain activation were observed. In adult mice, 6-day RAM testing was associated with greater septal and hippocampal (CA1, CA3, DG) Fos expression than the TM condition. Lengthening the retention interval from 6 days to 30 days resulted in a significant decrease in RAM testing-induced Fos expression in most of the septo-hippocampal regions. With respect to adult mice, aged mice displayed reduced Fos expression (except for DG) and a lack of interrelationships between levels of Fos produced in each of the SH regions, in the 6-day RAM testing condition. Conversely, there was no effect of ageing on Fos expression associated with either TM training or 30-day RAM testing. These results are interpreted as reflecting age- (or time-) related alterations in recruiting of brain structures that underlie a relational/declarative form of memory expression.

Improvement of shuttle-box performance by anterodorsal medial septal lesions in rats

Septal lesions impair a variety of tasks, including inhibitory avoidance and one way active avoidance. In contrast, these lesions improve two-way active avoidance, probably by reducing anxiety. The present work aimed to study whether anterodorsal medial septal lesion (a) improves performance of two-way active avoidance task (Experiment I), as it has been observed with wider septal lesion, and (b) affect anxiety and/or locomotor activity (Experiment II).This precise region was chosen because some evidences suggest that its lesion do not lead to a reduction of anxiety. Lesioned rats tended to make a higher, but statistically non-significant ( P=0.074), number of avoidances regardless of the session, being this difference statistically significant on the retention session (RT). The same lesion did not appear to have an anxiolytic effect, and did not affected basal locomotor activity. Different possible explanations of our results are discussed.

N-methyl-D-aspartate prevented memory deficits induced by MK-801 in mice.

An interaction between N-methyl-D-aspartate (NMDA) and MK-801 was examined in mice using a modified elevated plus-maze paradigm that allows assessment of the adaptive form of spatial memory. NMDA administered (s.c.) immediately after the acquisition session protected the animals against the amnesia induced by MK-801 given shortly before the retention session. Behavioral performance, expressed as the transfer latency, and therefore spatial memory potency of NMDA plus MK-801 treated animals was comparable with that of both NMDA-treated animals and the controls.

Effects of the antidepressant drug moclobemide on learning and memory in rats

Moclobemide is a well known drug with antidepressant action. The aim of this study was to investigate the effects of moclobemide on learning and memory processes in Sprague Dawley rats. Over a 5-day period, learning sessions with 30 trials per day and memory retention tests were performed. The conditioned responses (avoidances), the unconditioned responses (escapes) and the intertrial crossings were observed. An active avoidance test was carried out using a shuttle box. Two passive avoidance tests were used: step-through (using a light chamber) and step-down (using a platform). In the step-through passive avoidance test, the learning and retention sessions consisted of three trials each and the latency of reaction times (the rat remaining in the light chamber for more than 180 sec) was used as criterion. In the step-down passive avoidance test, learning and retention sessions consisted of two trials and the latency of reaction times (the rat remaining on the platform for 60 sec) was used as criterion. In the active avoidance tests, moclobemide dose-dependently increased the number of avoidances during learning sessions and maintained this number in memory retention tests. Moclobemide did not alter the number of escapes, but did increase motor activity. In the passive avoidance tests, moclobemide also increased the latency of reaction times in learning and short memory retrieval tests. These findings suggest that moclobemide improves learning and memory processes in active and passive avoidance tests and has a cognition-enhancing effect.

Predicting treatment-outcome in cocaine dependence from admission urine drug screen and peripheral serotonergic measures

We investigated whether urine drug screens (UDS) at admission and platelet paroxetine binding, a measure of serotonin transporter sites, were related to outcome measures for cocaine patients in treatment. Tritiated paroxetine binding sites on platelets were assayed and UDS were obtained for 105 African American cocaine-dependent outpatients. Outcome measures included number of negative urines, days in treatment, dropouts, and number of treatment sessions attended. A significant association was found between cocaine-positive UDS at admission and negative urines, treatment retention, dropouts, and treatment sessions; while Bmax values of paroxetine binding (density of serotonin transporter sites) were significantly associated with treatment retention and negative urines. Moreover, UDS and paroxetine binding combined to enhance prediction of retention and abstinence. Although both admission UDS and paroxetine binding seem to contribute individually in predicting outcome of cocaine patients, a combination of the two variables seems to have a stronger effect in terms of predicting treatment-outcome.

Role of peripheral afference during acquisition of a complex coordination task.

It has long been supposed that the interference observed in certain patterns of coordination is mediated, at least in part, by peripheral afference from the moving limbs. We manipulated the level of afferent input, arising from movement of the opposite limb, during the acquisition of a complex coordination task. Participants learned to generate flexion and extension movements of the right wrist, of 75 degrees amplitude, that were a quarter cycle out of phase with a 1-Hz sinusoidal visual reference signal. On separate trials, the left wrist either was at rest, or was moved passively by a torque motor through 50 degrees, 75 degrees or 100 degrees, in synchrony with the reference signal. Five acquisition sessions were conducted on successive days. A retention session was conducted 1 week later. Performance was initially superior when the opposite limb was moved passively than when it was static. The amplitude and frequency of active movement were lower in the static condition than in the driven conditions and the variation in the relative phase relation across trials was greater than in the driven conditions. In addition, the variability of amplitude, frequency and the relative phase relation during each trial was greater when the opposite limb was static than when driven. Similar effects were expressed in electromyograms. The most marked and consistent differences in the accuracy and consistency of performance (defined in terms of relative phase) were between the static condition and the condition in which the left wrist was moved through 50 degrees. These outcomes were exhibited most prominently during initial exposure to the task. Increases in task performance during the acquisition period, as assessed by a number of kinematic variables, were generally well described by power functions. In addition, the recruitment of extensor carpi radialis (ECR), and the degree of co-contraction of flexor carpi radialis and ECR, decreased during acquisition. Our results indicate that, in an appropriate task context, afferent feedback from the opposite limb, even when out of phase with the focal movement, may have a positive influence upon the stability of coordination.

Effects of nicotine on motor activity, passive avoidance and plus‐maze behavior in aged NMRI and C57BL mice

AbstractThe aim of the present study is to evaluate the effects of nicotine (0.35 and 0.175 mg/kg) on locomotor activity, passive avoidance and plus maze behavior in aged mice of two strains (C57BL and NMRI). In a first experiment, aged mice of these strains were injected with nicotine or saline and immediately afterwards were put on the actimeter. Results showed that nicotine significantly decreased locomotor activity in C57 mice. In a second experiment, nicotine was administered before training and retention sessions of a passive avoidance task. Results indicated that 0.175 mg/kg nicotine significantly increased entry latency in aged NMRI mice but had no effects on C57 mice. In the last experiment, mice were injected with nicotine and 15 min later evaluated in the plus‐maze for 5 min. It was observed that in NMRI mice no measure was significantly affected by nicotine but in C57 mice this drug significantly reduced the number of total entries, number of entries in open arms and in the central area of the maze. It is concluded that in aged mice nicotine effects depend on the baseline behaviors of the strains evaluated.

Oxiracetam prevented the scopolamine but not the diazepam induced memory deficits in mice

In mice, the elevated plus-maze paradigm was used to investigate the effect of scopolamine hydrobromide and diazepam and their interaction with oxiracetam on the retrieval of spatial memory trace. This paradigm measures (using the transfer latency) an animal's capacity to escape from the open arm to the enclosed one. The retention session followed 24 h after the acquisition one. Experiment 1: Scopolamine (0.25 and 0.5 mg/kg) and diazepam (0.5 and 1.0 mg/kg) given 30 min before the retention session significantly prolonged the transfer latency as compared with the saline treated mice and those given the lowest dose of scopolamine (0.125 mg/kg) and diazepam (0.25 mg/kg). Experiment 2: Oxiracetam administered at doses of 3, 10 and 30 mg/kg immediately after the acquisition session prevented the scopolamine induced prolongation of the transfer latency. Thus, oxiracetam forestalled the impairment of retrieval of memory trace: the animals were able to remember the spatial configuration of the plus-maze. On the contrary, oxiracetam was not effective in the diazepam treated mice. We suggest that beneficial effect of oxiracetam might be confounded or blocked by the anxiolytic effect of diazepam.

MK-801 induced amnesia for the elevated plus-maze in mice

MK-801, a non-competitive NMDA receptor antagonist, has been shown to have amnesic properties in animal models. The purpose of the present study was to examine potential amnesic effects of MK-801 in mice using the modified elevated plus-maze paradigm. An animal was placed on the distal end of an open arm, and the transfer latency, i.e. the time in which it moves to the enclosed arm, was measured. Four different experimental schedules (i.e. the combination of the treatment and the testing) were used: MK-801 (0.075, 0.15, 0.25 and 0.4 mg/kg or saline) were given (a) 30 min before the acquisition session, (b) immediately after the acquisition session, (c) 60 min after the acquisition session, and (d) 30 min before the retention session. The retention session always followed 24 h after the acquisition session. Analysis of data showed a significant shortening of the transfer latency in saline-treated animals during the retention session. Further, MK-801 (at the dose range of 0.15–0.4 mg/kg) administered before and immediately after the acquisition session as well as before the retention session prolonged the transfer latency during the retention session. In fact, transfer latencies in MK-801 treated mice did not differ from those measured during the acquisition session. Thus, prolongation of the transfer latency in MK-801-treated mice indicates deficits in ‘memorization’ processes. On the contrary, MK-801 given 60 min after the acquisition session failed to increase the transfer latency, which suggests that the memory trace was sufficiently consolidated at this time. Based on the present results, the glutamatergic NMDA receptor mechanisms play an important role in a spatial orientation of mice placed on the elevated plus-maze.