Inhibition of guanylate cyclase and protein kinase G impairs retention for the passive avoidance task in the day-old chick

Nitric oxide (NO) is a highly labile chemical messenger which has previously been implicated in memory processes in a variety of learning paradigms and species. However, there is only limited evidence to suggest which enzymes are acted upon by NO during the formation of memory. The present study investigates the role of guanylate cyclase (GC) and protein kinase G (PKG) in a form of passive avoidance learning known to be dependent on nitric oxide activity. It was determined that in vivo pharmacological inhibition of GC using either 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one or 6-anilino-5,8-quinolinedione resulted in two transitory memory retention deficits centred around 40 and 120 min posttraining, respectively. In contrast, inhibition of PKG with N-[2-(methylamino)ehtyl]-5-isoquinoline-sulfornamide hydrochloride (H-8) resulted in a single temporary retention loss centered at 120 min posttraining. These temporary retention losses appear to be specific to memory since they were dose-dependent and could not be explained by nonspecific performance effects. Further, these results suggest that these agents inhibit memory retrieval rather than formation, since memory is subsequently available. The current findings indicate that guanylyl cyclase mediates two memory retrieval processes, the latter of which appears to be PKG-dependent. In contrast, since inhibition of NO results in a permanent retention loss, it is suggested that NO is required for memory formation through GC-independent processes.     

A scavenger of peroxynitrite prevents long-term memory formation using a single trial passive avoidance task for the day-old chick

The important role of nitric oxide (NO) in memory processing has been recognised for some time. However, the mechanisms through which NO may act are only partially understood. One highly reactive radical brought about by the reaction of NO and superoxide ions is peroxynitrite. The current study investigated the effect of peroxynitrite scavenging on retention for a single trial passive avoidance task developed for the day-old chick. Administration of a range of concentrations of the peroxynitrite scavenger Trolox (0.1 microM-1.2 mM) yielded a bimodal retention curve. This dose-response curve had nadirs at 300 and 800 microM. A time of administration study was conducted for each optimal concentration of Trolox and in both studies, the effective range of administration times extended from at least 10 min before training to 20 min post-training. Finally, a retention function was conducted for each optimum concentration of Trolox and in both studies a persistent retention loss was observed from 40 min post-training until the conclusion of the experiment 24 h post-training. The findings suggest that physiological levels of peroxynitrite may be required for the consolidation of long-term memory in this model of memory formation. Interestingly, the effective times of administration and time of retention loss onset are consistent with previous studies which blocked NO synthesis. Therefore it may be suggested that NO acts to facilitate long-term memory formation through the production of peroxynitrite.     

Inhibition of monoADP-ribosylation prevents long-term memory consolidation of a single-trial passive avoidance task in the day-old chick

The cytosolic posttranslational protein-modifying mechanism of monoADP-ribosylation has been implicated in long-term potentiation, a synaptic model of memory formation. The current study investigated the effect of inhibiting mono(ADP-ribosyl) transferase on memory for the passive avoidance task in day-old chicks (white Leghorn-black Australorp). Various doses of novobiocin or menadione sodium bisulfite were administered intracranially at different times before or after training. Control chicks were administered saline at matched times. Novobiocin (650 microM) or menadione sodium bisulfite (250 microM) administered between 5.0 min pretraining and 2.5 min posttraining was found to cause a persistent loss of retention from 120 min posttraining. These data provide the first demonstration that monoADP-ribosylation is required for the maintenance of long-term memory. Furthermore, the temporal characteristics of the memory loss caused by monoADP-ribosylation inhibition appears to exclude this mechanism as a downstream effect of the well-established nitric oxide activity previously shown to occur within 40 min of passive avoidance training.     

Pharmaco-behavioural evidence indicating a complex role for ryanodine receptor calcium release channels in memory processing for a passive avoidance task

Calcium signalling is an important process underlying neuronal function and consequently behaviour. The release of calcium from intracellular stores via the ryanodine receptor calcium release (RyR) channel has been implicated in both synaptic plasticity and to a limited extent in memory processing. While past investigations have suggested a role for RyR channels in long-term memory, the present study suggests their action is more complex. Using a single trial passive avoidance task developed for the day-old chick, it is proposed that RyR channels are necessary both prior to the expression of long-term memory and also in retrieval processes. Specifically, 5 mM dantrolene (a specific RyR channel blocker) resulted in a persistent retention loss from 40 min post-training while 10 nM dantrolene produced a transient retention loss centred at 40 min post-training. We speculate that in the context of memory formation, RyR channels may be activated by nitric oxide and in the context of memory retrieval may lead to the activation of large conductance calcium-activated potassium BK(Ca) channels which, when blocked by 50 nM iberiotoxin, also demonstrated a transient retention loss centred at 40 min post-training.     

Effects of nitric oxide inhibition on avoidance learning in the chick are lateralized and localized

Bilateral administration of nitric oxide synthase inhibitors into the intermediate medial hyperstriatal (IMHV) region of the chick brain impairs memory formation for an avoidance task. The aim of the current study was to determine whether this effect was restricted to a particular location in the brain, and whether inhibition was equally effective in both hemispheres. White Leghorn x black Australorp chicks were administered 0.5 mM N(omega)-Nitro-L-arginine methyl ester bilaterally into the lobus parolfactorius (LPO), or unilaterally into the IMHV. Injections into the LPO between 5 min pre-training and 40 min post-training had no effect on retention. In contrast, unilateral injections into the IMHV impaired retention and memory loss occurred from 40 min post-training. The effective administration time was hemisphere-dependent, requiring left hemisphere administration around the time of training and right hemisphere administration between 15 and 25 min post-training. These data suggest that localized nitric oxide activity in each hemisphere of the chick brain is necessary for the consolidation of memory for this task.     

On the requirement of nitric oxide signaling in the amygdala for consolidation of inhibitory avoidance memory

Evidence suggests that the NO/sGC/PKG pathway plays a key role in memory processing but the actual participation of this signaling cascade in the amygdala during memory consolidation remains unknown. Here, we show that when infused in the amygdala immediately after inhibitory avoidance training, but not later, the NO synthase inhibitor L-NNA hindered long-term memory retention without affecting locomotion, exploratory behavior, anxiety state or retrieval of the avoidance response. The amnesic effect of L-NNA was not state-dependent and was mimicked by the soluble guanylyl cyclase inhibitor LY83583 and the PKG inhibitor KT-5823. On the contrary, post-training intra-amygdala infusion of the NOS substrate L-Arg, the NO-releasing compound SNAP or the non-hydrolysable analog of cGMP 8Br-cGMP increased memory retention in a dose-dependent manner. Co-infusion of 8Br-cGMP reversed the amnesic effect of L-NNA and LY83583 but not that of KT-5823. Our data indicate that the NO-induced activation of PKG in the amygdala is a necessary step for consolidation of inhibitory avoidance memory.     

Inhibition of the Endothelial Isoform of Nitric Oxide Synthase Impairs Long-Term Memory Formation in the Chick

Previous studies with general inhibitors of nitric oxide synthase have yielded variable and contradictory results with respect to their effects on memory. This may have been due to differential effects of blocking the various isoforms of this enzyme. We show that day-old chicks trained on a single-trial passive-avoidance task suffered significant memory loss from ~40 min post-training following post-training intracranial administration of a potent inhibitor of eNOS. Administration of a specific nNOS or iNOS inhibitor at the same time had no effect on retention, although a role for either of these isoforms when administered at a different time after learning has yet to be fully investigated. The onset of memory loss following eNOS inhibition is the same as observed following general NOS inhibition, which suggests that amnestic effects observed in previous studies using nonspecific inhibitors may be attributable to blocking the function of eNOS. The findings indicate that eNOS may play a role in memory formation for this task, which is at least distinct from any role that may be played by nNOS.     

Relative importance of nitric oxide and carbon monoxide in regulating the ACTH response to immune and non-immune signals

The present work investigated the effect of nitric oxide (NO) or carbon monoxide (CO) in the ACTH response to an immune signal [the intravenous injection of interleukin-1 β (IL-1β)] or to a neurogenic stressor (mild intermittent inescapable foot shocks). The arginine derivative N(ω)-L-arginine methylester (L-NAME), which non-specifically inhibits NO formation induced by all constitutive forms of NO synthase (NOS), significantly augmented the effect of IL-1P,but blockade of CO formation with metalloporphyrins was without effect. On the other hand, L-NAME blunted the effect of shocks on the early phase of ACTH release, while we had reported earlier that metalloporphyrins exerted a similar effect. This effect was mimicked by blockade of neuronal (n) NOS by N(ω)-Propyl-L-arginine (PA), although the resulting decrease in hormone levels was less than that induced by L-NAME. These results indicate that endogenous NO, but not CO, interferes with ACTH released by a peripheral immune signal. In contrast, NO formed by nNOS enhances the ability of shocks to induce ACTH secretion.     

Enhancement of the Post-training Cholinergic Tone Antagonizes the Impairment of Retention Induced by a Nitric Oxide Synthase Inhibitor in Mice

The present experiments examined the role of the central cholinergic system in the memory impairment induced by post-training administration of a nitric oxide synthase (NOS) inhibitor in mice. Male Swiss mice received a one-trial inhibitory avoidance training (0.8 mA, 50 Hz, 1-s footshock) followed immediately by an ip injection of the NOS inhibitor -N^G-nitroarginine methyl ester ( -NAME; 100 mg/kg). Retention (cut-off time, 300 s) was tested 48 h after training. The administration of -NAME results in memory impairment for the inhibitory avoidance task. The effects of -NAME (100 mg/kg, ip) on retention were reversed in a dose-related manner by the centrally acting anticholinesterase physostigmine (35, 70, or 150 μg/kg, sc) administered 30 min after the NOS inhibitor. Further, -NAME (100 mg/kg, ip)-induced memory impairment was completely antagonized by the centrally acting muscarinic cholinergic agonist oxotremorine (OTM; 25, 50, or 100 μg/kg, sc) when given 30 min after -NAME. The peripherally acting anticholinesterase neostigmine (150 μg/kg, sc) did not modify the memory-impairing effects of -NAME. These findings suggest that the memory impairment following post-training administration of a NOS inhibitor is mediated, at least in part, by a reduction of the activity of central muscarinic cholinergic mechanisms and are consistent with our previous view that nitric oxide may be involved in post-training neural processes underlying the storage of newly acquired information.     

Role of the NO/sGC/PKG signaling pathway of hippocampal CA1 in morphine-induced reward memory

Evidence suggests that the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP dependent protein kinase (PKG) signaling pathway plays a key role in memory processing, but the actual participation of this signaling cascade in the hippocampal CA1 during morphine-induced reward memory remains unknown. In this study, we investigated the role of the NO/sGC/PKG signaling pathway in the CA1 on morphine-induced reward memory using a conditioned place preference (CPP) paradigm. We found that rats receiving an intraperitoneal (i.p.) injection of 4mg/kg morphine exhibited CPP, whereas rats treated with only 0.2mg/kg morphine failed to produce CPP. Intra-CA1 injection of the neuronal NO synthase (nNOS) inhibitor 7-NI, the sGC inhibitor ODQ or the PKG inhibitor Rp-8-Br-PET-cGMPS had no effect on the acquisition of CPP by 4mg/kg morphine. Intra-CA1 injection of 7-NI blocked the consolidation of CPP induced by 4mg/kg morphine, and this amnesic effect of 7-NI was mimicked by ODQ and Rp-8-Br-PET-cGMPS. Intra-CA1 injection of the NOS substrate L-arg or the sGC activator YC-1 with an ineffective dose of morphine (0.2mg/kg, i.p.) elicited CPP. This response induced by L-arg or YC-1 was reversed by pre-microinjection of Rp-8-Br-PET-cGMPS in the CA1. These results indicated that the activation of the NO/sGC/PKG signaling pathway in the CA1 is necessary for the consolidation of morphine-related reward memory.     

Distinctiveness of processing,processing time and memory performance

The research reported here, explored the conditions where processing time can be used as a predictive measure for retention performance. The results showed that, in similar but quantitatively different tasks, both processing time and retention performance increased with increasing task difficulty. The strongly suggests that processing time can be used as an independent measure for extensiveness of processing, and as a predictor for later retention performance. This relationship, however, is restricted to the comparison of similar processing tasks that differ only in the amount of processing necessary to perform the task.It is hypothesized that longer processing times are indicative of more extensive processing, leading to the formation of more distinctive memory representations. These, in turn, cause higher retention performance because they allow better discrimination from other memory traces, and because they are retrieved more easily.Although distinctiveness of memory representations is an important variable in determining retention performance, it is not the only one. In a recall test, semantic relations between items had an effect on performance independent of distinctiveness.     

工作记忆广度：资源限制、记忆消退还是转换机制？

为了检验工作记忆广度有限性的3种假说,即资源限制假说、记忆消退假说和转换机制假说,实验要求被试首先完成一项转换效率任务,然后完成工作记忆广度任务。结果发现,加工负荷对工作记忆广度具有重要影响,保持时间不影响工作记忆广度,转换效率与工作记忆广度也没有显著相关。实验结果支持工作记忆广度受认知资源限制的观点     

On the nature of the relationship between processing activity and item retention in children

The concept of working memory emphasizes the interrelationship between the transient retention of information and concurrent processing activity. Three experiments address this relationship in children between 8 and 17 years of age by examining forgetting when a processing task is interpolated between presentation and recall of the memory items. Unlike previous studies, delivery of interpolated stimuli was under computer control and responses to these stimuli were timed. There were consistent effects of the duration of the interpolated task, but no effects of either its difficulty or similarity to memory material and no qualitative developmental differences in task performance. The absence of an effect of difficulty provides no support for models of working memory in which limited capacity is shared between the dual functions of processing and storage, but is compatible with an alternative "task switching" account. However, task switching did not explain developmental differences in recall. Other aspects of the results suggest that there can be interactions between processing and storage but it is argued that these cannot be straightforwardly explained in terms of either task switching or resource sharing.     

Central ghrelin increases anxiety in the Open Field test and impairs retention memory in a passive avoidance task in neonatal chicks

Ghrelin (Grh) is an endogenous ligand for the growth hormone secretagogue receptor. Although Ghr stimulates feeding in rats, it inhibits feeding in neonatal chicks. However, little is known about other central behavioral effects of Ghr. Therefore, we investigated the Ghr effects, injected intracerebroventricularly, on anxiety and memory retention of neonatal chicks in an Open Field test and in a one-trial passive avoidance task, respectively. In the Open Field test, the administration of Ghr in a dose-dependent manner increased the latency to ambulate but decreased ambulation activity, indicating an anxiogenic effect. Furthermore, chicks trained on a passive avoidance task and injected with a dose of 30 pmol of Ghr immediately after training showed an impairment of memory retention. However, there were no significant effects on the number of pecks during the pretraining, training, retention and discrimination. In addition, different doses of Ghr produced an inhibition in food intake at different times after injection. Our results indicate that Ghr induces anxiogenesis in chicks. Moreover, we have shown for the first time that Ghr can decrease memory retention in a non-mammalian species, suggesting that Ghr may play an important role in the processes of memory retention in birds.     

D-Lactate inhibition of memory in a single trial discrimination avoidance task in the young chick

L-Lactate is a metabolite possibly able to meet some neuronal energy demands. However, a clear role for L-lactate in behaviour remains elusive. Administration of the inactive isomer D-lactate (1.75 mM; ic), immediately post-training, resulted in a persistent retention loss from 40 min post-training when used in conjuction with a single trial discrimination avoidance task designed for the young chick. Furthermore, 1mM noradrenaline (ic) administered 20 min post-training overcame the retention loss induced by D-lactate. Although not directly demonstrated in the current study, it is plausible that D-lactate inhibited memory processing by competing with L-lactate for uptake into neurons. The time of onset of the retention loss induced by D-lactate is in accord with findings where the action of noradrenaline is inhibited. The successful challenge of D-lactate inhibition by a high concentration of noradrenaline may suggest a relationship by some unidentified mechanism.     

Hemispheric dissociation of the involvement of NOS isoforms in memory for discriminated avoidance in the chick

Previous research has indicated a role for both the neuronal (nNOS) and endothelial (eNOS) nitric oxide isoforms in memory formation. In addition, two distinct periods of activity of nitric oxide activity, dissociated by hemispheric localization, are implicated following passive avoidance training in the chick. In the present study, we trained black Australorp-white Leghorn chicks on a color discrimination avoidance task. Diphenyleneiodonium chloride (1 microM) or N-propyl-l-arginine (50 microM) was administered into either the left or right hemisphere of the chick brain in an attempt to differentiate the effects of inhibiting eNOS or nNOS, respectively. The memory loss previously observed following administration of diphenyleneiodonium chloride between 10 and 20 min posttraining was found to be lateralized to the right hemisphere, although administration of this agent into the left hemisphere around the time of training was also amnestic. In contrast, N-propyl-l-arginine caused memory loss only when administered to the left hemisphere around the time of training. These findings suggest that activation of both eNOS and nNOS isoforms may be essential for long-term memory consolidation of this task. Further, these two periods of activity are defined temporally and by hemisphere localization, although confirmation with more selective inhibitors when they become available is advised.     

The impact of object working memory on timing

Nontemporal information processing involving short-term memory requirements disturbs time estimation. Previous studies mostly used letters or digits, which are maintained in working memory by phonological loops. Since verbal and nonverbal information are processed by separate working-memory subsystems, how do nonverbal, object-based memory tasks affect time estimation? We manipulated visual object memory load using the magic cube materials. Participants were divided into three groups, who completed a reaction-time task (control task), a memory-recognition task interposed by an attempt to produce a 2500-ms time interval (active processing), and a memory-recognition task following time interval production (passive retention). The produced time increased with increasing memory-object size under both the active processing and passive retention conditions; mean produced time interval did not significantly differ between the two experimental conditions. By comparing the reaction times and error rates of a relevant task, we excluded any speed–accuracy tradeoff during timing. This result suggests that when the working-memory information to be processed includes objects requiring attention for retention, the production of time intervals is also affected by memory item maintenance.     

Reactivated memory of an inhibitory avoidance response in mice is sensitive to a nitric oxide synthase inhibitor

It is accepted that once consolidation is completed memory becomes permanent. However, it has also been suggested that reactivation (retrieval) of the original memory, again, makes it sensitive to the same treatments that affect memory consolidation when given after training. Previous results demonstrated that the immediate post-training intraperitoneal administration of N^ω-nitro-l-arginine methyl ester (L-NAME), a non-specific inhibitor of nitric oxide synthase (NOS), impairs retention test performance of a one-trial step-through inhibitory avoidance response in adult mice. The effect of L-NAME on retention was attributed to an action on memory consolidation of the original learning. For the first time, we report that the administration of L-NAME after the first retention test (memory reactivation) of the inhibitory avoidance response impairs retention performance over six consecutive days. This impairment effect is dose-and-time dependent and could not be attributed to a retrieval deficit since a mild footshock did not reinstate the original avoidance response and no spontaneous recovery was observed at least 21 days after training. Further support for a storage deficit interpretation as opposed to a retrieval deficit was obtained from the fact that L-NAME’s effects after retrieval were not due to state-dependency. The impairment effect of L-NAME was dependent on the age of the original memory. That is, there was an inverse correlation between the susceptibility of the memory trace when reactivated and the time elapsed between training and the first retrieval session. We suggest an action of L-NAME on memory reactivation-induced processes that are different from memory extinction of the original learning extending the biological significance of nitric oxide on memory.     

Interference between storage and processing in working memory: Feature overwriting,not similarity-based competition

Eight experiments with the complex span paradigm are presented to investigate why concurrent processing disrupts short-term retention. Increasing the pace of the processing task led to worse recall, supporting the hypothesis that the processing task distracts attention from maintenance operations. Neither phonological nor semantic similarity between memory items and processing-task material impaired memory. In contrast, the degree of phonological overlap between memory items and processing-task material affected recall negatively, supporting feature overwriting as one source of interference in the complex span paradigm. When compared directly, phonological overlap impaired memory, but similarity had a beneficial effect. These findings rule out response competition or confusion as a mechanism of interference between storage and processing.     

Capacity and retention capability of working memory modify the strength of the RT/IQ correlation: a short note

The limited capacity theory assumes that working memory (WM) has limited capacity to process information and, at the same time, to store other pieces of information, necessary for further processing. Quick processing of data is supposed to be the only way to solve the task without the risk of losing vital pieces of information. We predicted, then, that the correlation between mental speed, measured by reaction time (RT), and the intelligence quotient (IQ) should not appear in the case of persons who possess a relatively capacious WM store, or who show increased retention capability of their WM store. Such persons do not need to be fast, whereas, for people who show poorer indices of capacity or retention capability of WM, mental speed is the only way to tackle a complex and difficult intellectual task. As predicted, the RT/IQ correlation appeared much stronger in the group of subjects characterized by lower retention capability and capacity of WM.