The locus coeruleus involves in consolidation and memory retrieval, but not in acquisition of inhibitory avoidance learning task

The locus coeruleus (LC) located at the level of the pons, is involved in cognitive functions such as learning and memory. The bilateral lidocaine-induced reversible inactivation of this nucleus has been considered in order to study its role in the phases of memory processing (acquisition, consolidation and retention) without any interference with the function of the same structure either during earlier and/or later phases of the same process. In this study, inhibitory avoidance (IA) learning task used to find the LC function in acquisition, consolidation and retrieval. Saline or lidocaine 4% (0.5 microl/side) microinjected into the LC, for assessing the acquisition (5 min before training), consolidation (5, 90 and 360 min after training) and memory retrieval, 5 min before testing. The retention test was done 24h after learning. Our results indicated that: (1) The bilateral functional inactivation of LC before training did not affect acquisition, but affected subsequent memory retention 24h later in IA task. (2) The lidocaine-induced inactivation of LC only 5 min after training impaired consolidation but did not affect it after 90 or 360 min. (3) Inactivation of the LC, 5 min before pre-retrieval test, impaired memory retrieval in IA task. In conclusion, it seems that the nucleus locus coeruleus does not affect acquisition while it involves in the memory consolidation and retrieval of inhibitory avoidance learning task.     

The effect of reversible inactivation of the supramammillary nucleus on passive avoidance learning in rats

Previous studies have shown that the presence of hippocampal theta activity is important for learning and memory, and that the medial supramammillary nucleus (mSuM) is involved in the control of the frequency of theta rhythm. It has also been shown that the depression of mSuM activity by chlordiazepoxide causes modest impairment of spatial learning. On the other hand, the lateral supramammillary nucleus (lSum) increases long-term potentiation (LTP) of hippocampal population spikes. However, to our knowledge, no reports exist concerning the role of the supramammillary area (SuM) in passive avoidance (PA) learning. In the present study, rats were chronically implanted with a cannula aimed at SuM and were trained on a step-through PA task. They received intra-SuM injection of lidocaine or saline at the following intervals: 5 min before training, 5, 90, and 360 min after the acquisition trial, or 5 min before the retrieval test. When lidocaine was injected 5 min before training there was no effect on acquisition of PA but retrieval was significantly poorer than the control group injected with saline. Lidocaine injection 5 min after the acquisition trial impaired PA retention, but reversible inactivation of SuM at 90 and 360 min after training and 5 min before the retrieval test showed no significant effect on PA retention. It can be concluded that SuM contributes to PA consolidation at least 5 min after the acquisition trial and that this effect may be accomplished through SuM projections to the septal and/or hippocampal areas participating in the PA memorization processes.     

Different effects of scopolamine on the retrieval of spatial memory and fear memory

Retrieval of memory is fundamental for our life as individuals. The participation of cholinergic system in memory consolidation process has been extensively studied, but there are few data concerning the function of this system in memory retrieval process. In the current study, we inject non-selective muscarinic antagonist scopolamine peripherally 20 min before training or testing to see whether cholinergic modulation has effects on the acquisition or retrieval of spatial memory by water maze task and fear memory by inhibitory avoidance task. We find that the cholinergic system is essential for the acquisition of both spatial memory and fear memory. As for the memory retrieval, the cholinergic system has a positive role in the retrieval of spatial memory, because mice injected with scopolamine 20 min before the testing in the water maze show impaired spatial memory retrieval. Whereas injection of scopolamine 20 min before the testing in the inhibitory avoidance task does not cause memory retrieval deficits. That indicates the cholinergic system is not essential for the retrieval of fear memory.     

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.     

The effect of antagonization of orexin 1 receptors in CA1 and dentate gyrus regions on memory processing in passive avoidance task

The hippocampal formation plays an essential role in associative learning like passive avoidance (PA) learning. It has been shown; orexin-containing terminals and orexin receptors densely are distributed in the hippocampal formation. We have previously demonstrated that antagonization of orexin 1 receptor (OX1R) in CA1 region of hippocampus and dentate gyrus (DG) impaired spatial memory processing. Although, there are few studies concerning function of orexinergic system on memory processing in PA task, but there is no study about physiological function of OX1R on this process. To address this, the OX1R antagonist, SB-334867-A, was injected into DG or CA1 regions of hippocampus and evaluated the influence of OX1R antagonization on acquisition, consolidation and retrieval in PA task. Our results show that, SB-334867-A administration into CA1 region impaired memory retrieval but not PA acquisition and consolidation. However, SB-334867-A administration into DG region impaired acquisition and consolidation but not PA memory retrieval. Therefore, it seems that endogenous orexins play an important role in learning and memory in the rat through OX1Rs.     

Effects of acute restraint stress on different components of memory as assessed by object-recognition and object-location tasks in mice

Studies on how acute stress and the stress-related hormones affect learning and memory have yielded inconsistent findings, which might be due to some variables such as the properties of stressors, the nature of memory, the protocols for behavioral tasks and the characteristics of the subjects. However, the impacts of acute stress on different memory components have not been clearly demonstrated within one single experiment. The aim of present study was to evaluate the effects of 1-h restraint stress and the stress-induced plasma corticosterone elevation on memory acquisition, consolidation, and retrieval in mice, using object-recognition task (ORT) and object-location task (OLT) with a 4-h or 24-h intertrial interval (ITI). The results showed that, regardless of ITI, the recognition memory retrieval was significantly disrupted by acute restraint stress exposure, which started 75 min before the test session of both ORT and OLT. Acute restraint stress performed immediately after memory acquisition interrupted the consolidation of short-term recognition memories (4-h ITI) into long-term ones (24-h ITI). Moreover, the disrupted memory retrieval or consolidation was strongly related to the stress-induced plasma corticosterone elevation in a negative manner. These preliminary results clarified that acute restraint stress differently impacts three memory components, and the enhanced plasma corticosterone level under stressful situation plays critical roles in the information processing of memory under the stressful situation.     

Lidocaine reversible inactivation of the median raphe nucleus has no effect on reference memory but enhances working memory versions of the Morris water maze task

Numerous studies in the past have dealt with the role of serotonergic system lesions in tasks aimed at measurement of cognitive behavior, but the literature concerning the role of serotonin in cognition remains controversial. Rats with electrolytic lesions of the median raphe nucleus (MRN) were found to display a profound impairment in both the acquisition and retention of spatial memory task. In this study, the lidocaine inactivation was employed to evaluate the involvement of the rat's median raphe nucleus in reference and working memory versions of the Morris water maze (MWM) task. Lidocaine (0.5 microl, 2%) was injected through a single cannula aimed at the MRN; control groups were treated in the same way with a 0.5 microl injection of saline. In Experiment 1, rats were trained in a reference memory version of the MWM with two blocks of four trials per day for three consecutive days, with intra-cerebral injection made 5 min before training. No significant difference was found. In Experiment 2, intra-cerebral injection was applied immediately after two blocks of four trials, and in Experiment 3, the drug was injected 5 min before retention test in rats that had received eight trials per day on three consecutive days. Again, no significant difference between control and treatment groups was found. These results indicate that MRN has no role in acquisition, consolidation and retrieval of spatial reference memory. In subsequent experiments, rats were trained in a working memory version of the MWM task to find a new target position in trial 1, and retrieval was tested 75 min later. MRN inactivation 5 min before (Experiment 4) and immediately after the acquisition trial (Experiment 5) enhanced spatial working memory. It is concluded that normal activity of the MRN has no role in formation and retrieval of reference memory, but it has an inhibitory role in working memory. Our results are confirmed with other studies suggesting that the serotonergic system has a different role in long-term and short-term memory. Interaction with other neurotransmitter systems like acetylcholine may be involved in this case.     

Pretraining hippocampal stimulation of melatonin type 2 receptors can improve memory acquisition in rats

Background: Learning and memory are among the most important cognitive functions of the brain. Melatonin receptor type 2 (MT2R) is located in the hippocampus and participates in learning and memory processes. In the present study, we examined the role of hippocampal MT2R activation in the acquisition, consolidation, and retrieval of learning and memory in novel object recognition (NOR) and passive avoidance (PA) tasks.

Methods: IIK7 (0.03, 0.3, and 3 μg/μl/side), as a selective MT2R agonist, or vehicle was injected bilaterally into the dentate gyrus (DG) region of the hippocampus in rats five minutes before training, immediately after training, and five minutes before the retrieval-behavioral tasks, respectively. The discrimination index (DI) was measured in the NOR task, while step-through latency in acquisition (STLa), number of trials to acquisition (NOT), step-through latency in the retention trial (STLr), and time spent in the dark compartment (TDC) were determined in the PA task.

Results: The pretraining intrahippocampal injection of IIK7 at all doses significantly improved acquisition in the PA task. On the other hand, the posttraining intrahippocampal administration of IIK7 had no significant effects on consolidation. The preretrieval intrahippocampal injection of IIK7 at different doses attenuated the retrieval of memory. However, the NOR data showed that the intrahippocampal injection of IIK7 at different doses had no significant effects on the acquisition, consolidation, or retrieval in this task.

Discussion: Based on the findings, stimulation of MT2R could improve acquisition, whereas it had no effects on consolidation. It could impair retrieval in the PA task, while it had no effects on object recognition in rats.     

(±)-α-Methyl-4-carboxyphenylglycine, a metabotropic glutamate receptor blocker, impairs retention of an inhibitory avoidance task in rats when infused into the basolateral nucleus of the amygdala

The amygdala is important for memory processes of emotionally motivated learning and the amygdala glutamatergic system may play a key role in this process. In this study we assessed the effect of the infusion of (±)-α-methyl-4-carboxyphenylglycine (MCPG), a metabotropic glutamate receptor (mGluR) antagonist, into the basolateral complex of the amygdala (BLA) on the learning and retention of an emotionally motivated task. Rats received either vehicle or three different doses of MCPG (0.2, or 1.0, or 5.0 μg/0.2μl/side, respectively) bilaterally into the BLA, 5 min before they were trained in a continuous multiple-trial inhibitory avoidance (CMIA) task. Response latencies during the training were recorded. Retention was assessed 8 days later. MCPG in the doses given did not significantly affect the acquisition of the CMIA task. However, MCPG at a dose of 5.0 μg/0.2 μl/side impaired the long-term retention test performance. Additionally, a nociception test indicated that dose of MCPG infused into the BLA did not affect the footshock sensitivity. Our results indicate that MCPG, when infused into the BLA of rats prior to the training, impaired long-term memory of aversive training without affecting acquisition.     

(+/-)-Alpha-methyl-4-carboxyphenylglycine, a metabotropic glutamate receptor blocker, impairs retention of an inhibitory avoidance task in rats when infused into the basolateral nucleus of the amygdala

The amygdala is important for memory processes of emotionally motivated learning and the amygdala glutamatergic system may play a key role in this process. In this study we assessed the effect of the infusion of (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG), a metabotropic glutamate receptor (mGluR) antagonist, into the basolateral complex of the amygdala (BLA) on the learning and retention of an emotionally motivated task. Rats received either vehicle or three different doses of MCPG (0.2, or 1.0, or 5.0 microg/0.2 microl/side, respectively) bilaterally into the BLA, 5 min before they were trained in a continuous multiple-trial inhibitory avoidance (CMIA) task. Response latencies during the training were recorded. Retention was assessed 8 days later. MCPG in the doses given did not significantly affect the acquisition of the CMIA task. However, MCPG at a dose of 5.0 microg/0.2 microl/side impaired the long-term retention test performance. Additionally, a nociception test indicated that dose of MCPG infused into the BLA did not affect the footshock sensitivity. Our results indicate that MCPG, when infused into the BLA of rats prior to the training, impaired long-term memory of aversive training without affecting acquisition.     

Apamin improves reference memory but not procedural memory in rats by blocking small conductance Ca(2+)-activated K(+) channels in an olfactory discrimination task

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.     

Atypical acquisition and atypical expression of memory consolidation gains in a motor skill in young female adults with ADHD

Individuals with ADHD often show performance deficits in motor tasks. It is not clear, however, whether this reflects less effective acquisition of skill (procedural knowledge), or deficient consolidation into long-term memory, in ADHD. The aim of the study was to compare the acquisition of skilled motor performance, the expression of delayed - consolidation phase - gains and retention, in persons with and without ADHD. Thirty-two participants, 16 with ADHD, were trained on a sequence of finger movements using a well-established training protocol, and tested before training and immediately, 24 h and 2 weeks after training. Both groups showed similar within-session gains in speed; additional, delayed gains were expressed at 24 h, but less robustly in ADHD, and at 2 weeks post-training. However, while controls showed significant delayed gains in accuracy at 24 h and 2 weeks post-training, accuracy deteriorated in ADHD from pre-training to 24 h post-training and was only at pre-training levels by 2-weeks post-training. Our results demonstrate a latent memory consolidation phase in motor sequence learning, expressed as delayed gains in speed and a much delayed recovery of pre-training accuracy, in individuals with ADHD. However, both the acquisition and memory consolidation of motor skills are atypical in ADHD.     

Reversible lesion of the rat's orbitofrontal cortex interferes with hippocampus-dependent spatial memory

In this study, tetrodotoxin (TTX) inactivation was employed to evaluate the involvement of the rat's orbitofrontal cortex (OFC) in hippocampus-dependent spatial memory using Morris water maze (MWM) and place avoidance learning (PAL) tasks. In Experiment 1, rats trained in MWM task with two blocks of four trials per day for 3 consecutive days received bilateral injections of either TTX or saline into the OFC 60 min before each daily training session. The acquisition of spatial memory was evaluated 24h after the last training day and it was shown an impairment by the TTX. In Experiment 2, bilateral intra-OFC injections of TTX or saline were made immediately after two blocks of four trials. Testing 24h later, it was revealed that TTX also impairs spatial memory consolidation. In Experiments 3 and 4, rats were trained in a single 30-min session to avoid a 60 degrees segment of the stable circular (80-cm diameter) arena, entering which was punished by a mild shock (PAL task) and retention was tested 24h later in a 30-min extinction session. Bilateral injections of TTX or saline were made into the OFC 60 min before training or immediately after training. Again, TTX impaired the place avoidance retention when it was injected into the OFC either before (acquisition phase) or after (consolidation phase) training. These findings indicate that functional integrity of the OFC is necessary for both the acquisition and the consolidation of hippocampus-dependent spatial memory in rats.     

Empirical tests of the functional significance of amygdala-based modulation of hippocampal representations: evidence for multiple memory consolidation pathways

This series of experiments evaluated the effects of amygdala damage on the acquisition and long-term retention of variants of the water task, and tested the hypothesis that the amygdala is an essential neural system for consolidation of hippocampal memories. In Experiment 1, rats with large, neurotoxic lesions of the amygdala (AMYG) showed normal acquisition on the standard spatial version of the water task, as well as normal retention and decay rate profiles on the 24-h and 30-day retention probes. In Experiment 2, AMYG rats showed normal one-trial place learning abilities and could retain this one-trial information over a 24 h delay. Experiment 3 showed that the amygdala lesions used in this study were functionally significant because AMYG rats, from Experiment 2, showed impairments in a discriminative fear conditioning to context paradigm. Experiment 4 was a critical test of the idea that the amygdala is a decisive locus for consolidation of hippocampal memories. AMYG rats were trained to sub-asymptotic levels of performance on the standard version of the water task. Following each training session, the subjects were given a post-training peripheral injection of D-amphetamine. A probe test revealed that normal subjects and AMYG rats showed similar post-training memory improvement effects. Taken together, the results show that hippocampal memory consolidation processes do not require amygdala modulation. Arguments for an alternative view are presented suggesting that there are multiple memory consolidation pathways, one of which may depend on amygdala neural circuitry.     

Psychotropic effects of angiotensin II and III in rats: locomotor and exploratory vs cognitive behaviour

One nmol of angiotensin II (AII) or angiotensin III (AIII) given intracerebroventricularly (i.c.v.) increased locomotor and exploratory activity in an open field apparatus but not in the electromagnetic field motimeter. Both peptides significantly enhanced stereotyped behaviour produced by apomorphine (2 mg/kg) and amphetamine (6.5 mg/kg) given intraperitoneally. Also, AII and AIII improved consolidation but not retrieval of memory for an appetitively reinforced spatial discrimination task in a T-maze. AII as well as AIII, given prior to the learning session on day 1, increased rate of acquisition of conditioned avoidance responses in a shuttle-box over the next 7 days. Both angiotensins, injected i.c.v. 15 min before the retention testing, remarkably (5-fold) prolonged re-entry latencies in the passive avoidance situation, suggesting facilitation of the retrieval of memory for an aversively motivated behaviour.     

Intra hippocampal injection of testosterone impaired acquisition, consolidation and retrieval of inhibitory avoidance learning and memory in adult male rats

The hippocampus is essentially involved in learning and memory, and is known to be a target for androgen actions. Androgen receptors are densely expressed in CA1 of rat hippocampus, and mediate the effects of testosterone (T) on learning and memory. T depletion or administration can modulate neural function and cognitive performance. We conducted series of experiments to further investigate the effect of castration or intra hippocampal injection of T on acquisition, consolidation and retrieval of inhibitory avoidance learning and memory. Male adult rats were bilaterally cannulated into CA1 of hippocampus, and then received T (1, 10, 20, 40 and 80mug/0.5mul/side) or vehicle (DMSO), 30min before training, immediately after training and 30min before retrieval in inhibitory avoidance task. Castration was made by gonadectomy of male rats and behavioral tests performed 4 weeks later. Our results showed that gonadectomy of male rats did not influence performance on inhibitory avoidance task, as compared to sham-operated rats. We have also found that pre-training, post-training and pre-retrieval intra CA1 injections of T significantly decreased step-through latencies in inhibitory avoidance learning at doses 1 and 80, 20, and 20 and 40mug/0.5mul/side, respectively. The data suggest that intra CA1 administration of T could impair learning and memory acquisition, consolidation and retrieval, while systemic androgen's depletion have no effect on memory, in inhibitory avoidance task.     

The effects of rutin on a passive avoidance test in rats

Various synthetic derivatives of natural flavonoids are known to have neuroactive properties. The aim of the present study was to investigate the effects of rutin (3, 3′, 4′, 5, 7-pentahydroxyflavone-3-rhamnoglucoside), a flavonoid that is an important dietary constituent of foods and plant-based beverages, on memory retrieval in rats. To this end, we assessed the effect of rutin on memory retrieval using a step-through passive avoidance task. Rutin (5, 10, and 100 mg/kg) was administered intraperitoneally (i.p.) one week before the start of training. Three retention tests were performed to assess memory in rats. Rutin (10 mg/kg) significantly increased the step-through latency of the passive avoidance response compared to the control in the three retention tests of the passive avoidance paradigm. These results indicate that rutin has a potential role in enhancing memory retrieval. Several mechanisms may contribute to the potential role of rutin in memory enhancement. This result supports the potential beneficial effects of rutin as a dietary supplement on memory retrieval in a passive avoidance task.     

Critical role of insular cortex in taste but not odour aversion memory

Conditioned odour aversion (COA) and conditioned taste aversion (CTA) result from the association of a novel odour or a novel taste with delayed visceral illness. The insular cortex (IC) is crucial for CTA memory, and the present experiments sought to determine whether the IC is required for the formation and the retrieval of COA memory as it is for CTA. We first demonstrated that ingested odour is as effective as taste for single-trial aversion learning in rats conditioned in their home cage. COA, like CTA, tolerates long intervals between the ingested stimuli and the illness and is long-lasting. Transient inactivation of the IC during acquisition spared COA whereas it greatly impaired CTA. Similarly, blockade of protein synthesis in IC did not affect COA but prevented CTA consolidation. Moreover, IC inactivation before retrieval tests did not interfere with COA memory expression when performed either 2 days (recent memory) or 36 days after acquisition (remote memory). Similar IC inactivation impaired the retrieval of either recent or remote CTA memory. Altogether these findings indicate that the IC is not necessary for aversive odour memory whereas it is essential for acquisition, consolidation and retrieval of aversive taste memory. We propose that the chemosensory stimulations modulate IC recruitment during the formation and the retrieval of food aversive memory.     

Amnestic effect of cocaine after the termination of its stimulant action

The effects of cocaine on memory are controversial. Furthermore, the psychostimulant action of cocaine can be a critical issue in the interpretation of its effects on learning/memory models. The effects of a single administration of cocaine on memory were investigated during the presence of its motor stimulating effect or just after its termination. The plus-maze discriminative avoidance task (PM-DAT) was used because it provides simultaneous information about memory, anxiety and motor activity. In Experiment I, mice received saline, 7.5, 10, 15 or 30 mg/kg cocaine 5 min before the training session. In Experiment II, mice were trained 30 min after the injection of saline, 7.5, 10, 15 or 30 mg/kg cocaine. In Experiment III, mice received 30 mg/kg cocaine 30 min pre-training and pre-test. In Experiment IV, mice received 30 mg/kg cocaine immediately post-training. Tests were always conduced 24 h following the training session. Given 5 min before training, cocaine promoted a motor stimulant effect at the highest dose during the training session but did not impair memory. When cocaine was injected 30 min pre-training, the drug did not modify motor activity, but produced marked amnestic effects at all doses tested. This amnesia induced by cocaine given 30 min pre-training was not related to a state-dependent learning because it was not abolished by pre-test administration of the drug. Post-training cocaine administration did not induce memory deficits either. Our results suggest that the post-stimulant phase is the critical moment for cocaine-induced memory deficit in a discriminative task in mice.     

Effect of reversible inactivation of the supramammillary nucleus on spatial learning and memory in rats

Memory includes processes such as acquisition, consolidation and retrieval. Reference memory (RM) and working memory (WM) are two kinds of memory that can be assessed in rodents using spatial tasks, especially using the Morris water maze. The Morris water maze is particularly sensitive to hippocampal lesions. The supramammillary nucleus (SuM) has strong links with the hippocampus and septum. The role of the SuM on spatial learning is controversial. In the present study, involvement of SuM in the different steps of spatial RM and WM was investigated in the Morris water maze using reversible inactivation of SuM with lidocaine. Lidocaine (0.5 microl, 4%) was injected into the SuM through a guide cannula implanted above the SuM. The rats were trained on RM and WM versions of the Morris water maze. SuM was inactivated before training or immediately after training or before the probe trial of retrieval tests. Reversible inactivation of the SuM impaired consolidation of RM, and of consolidation and retrieval of WM. Therefore, it seems that activity of SuM neurons plays a role in spatial RM and WM learning and memory in the rat.