Semantic similarity dissociates short- from long-term recency effects: Testing a neurocomputational model of list memory

The finding that recency effects can occur not only in immediate free recall (i.e., short-term recency) but also in the continuous-distractor task (ie., long-term recency) has led many theorists to reject the distinction between short- and long-term memory stores. Recently, we have argued that long-term recency effects do not undermine the concept of a short-term store, and we have presented a neurocomputational model that accounts for both short- and long-term recency and for a series of dissociations between these two effects. Here, we present a new dissociation between short- and long-term recency based on semantic similarity, which is predicted by our model. This dissociation is due to the mutual support between associated items in the short-term store, which takes place in immediate free recall and delayed free recall but not in continuous-distractor free recall.     

Effects of posttraining treatments in the posterior cingulate cortex on short- and long-term memory for inhibitory avoidance in rats

Adult male Wistar rats were bilaterally implanted with indwelling cannulae in the caudal region of the posterior cingulate cortex. After recovery, animals were trained in a step-down inhibitory avoidance task (3.0-s, 0.4-mA foot shock) and received, right after training, a 0.5-microl infusion of vehicle (phosphate-buffered saline, pH 7.4), of the GABA(A) receptor agonist muscimol (0.1 or 0.5 microg), of the cAMP-dependent protein kinase (PKA) stimulant Sp-cAMPS (0.1 or 0.5 microg), or of the PKA inhibitor Rp-cAMPS (0.1 or 0.5 microg). Animals were tested twice, 1.5 h and, again, 24 h after training, in order to examine the effects of these agents on short- and long-term memory, respectively. Muscimol (0.5 but not 0.1 microg) hindered retention for both short- and long-term memory (p <.05). Rp-cAMPS (0.1 or 0.5 microg) hindered retention for short-term memory (p <.05). In addition, these animals showed lower, but not significantly lower, latencies than controls in the test session for long-term memory (p >.10). A trend toward an amnesic effect on long-term memory was also observed after Sp-cAMPS infusion at 0.1 microg (p <.10). These results show that strong stimulation of GABAergic synapses in the caudal region of the rat posterior cingulate cortex right after training impairs short- and long-term memory (the latter less dramatically). The same occurs by inhibiting PKA activity with regard to STM and possibly to LTM.     

mTOR signaling in the hippocampus is necessary for memory formation

It is widely accepted that the formation of long-term memory (LTM) requires mRNA translation, but little is known about the cellular mechanisms in the brain that regulate this process. Mammalian target of rapamycin (mTOR) is a key regulator of translational efficacy and capacity. Here, we show that LTM formation of one-trial inhibitory avoidance (IA) in rats, a hippocampus-dependent fear-motivated learning task, requires mTOR activation. IA training is specifically associated with a rapid increase in the phosphorylation state of mTOR and its substrate ribosomal S6 kinase (p70S6K). Bilateral intra-CA1 infusion of rapamycin, a selective mTOR inhibitor, 15 min before, but not immediately after training completely hinders IA LTM without affecting short-term memory (STM) retention. Therefore, our findings indicate that the regulation of hippocampal mRNA translation is a major control step in memory consolidation.     

Inhibition of mTOR by rapamycin in the amygdala or hippocampus impairs formation and reconsolidation of inhibitory avoidance memory

Mammalian target of rapamycin (mTOR), a central regulator of protein synthesis in neurons, has been implicated in synaptic plasticity and memory. Here we show that mTOR inhibition by rapamycin in the basolateral amygdala (BLA) or dorsal hippocampus (DH) impairs both formation and reconsolidation of memory for inhibitory avoidance (IA) in rats. Male Wistar rats received bilateral infusions of vehicle or rapamycin into the BLA or DH before or after IA training or retrieval. Memory retention was tested at different time points after drug infusion. Rapamycin impaired long-term IA retention when given before or immediately after training or retrieval into the BLA. When infused into the DH, rapamycin produced memory impairment when given before training or immediately after retrieval. The impairing effects of post-retrieval rapamycin required memory retrieval and were not reversed by a reminder shock. The results provide the first evidence that mTOR in the BLA and DH might play a role in IA memory reconsolidation.     

Doubts about double dissociations between short- and long-term memory

Historically, psychologists and neuroscientists have distinguished between processes supporting memory for events across retention delays of several seconds (short-term memory, STM), and those supporting memory for events across longer retention delays of minutes or more (long-term memory, LTM). Dissociations reported in some neuropsychological studies have contributed to a popular view that there must be neurally distinct memory stores that differentially support STM and LTM. In this article, we review evidence from recent studies regarding dissociations between STM and LTM. We suggest that the evidence reveals problems with claims of selective STM or LTM impairments, which in turn questions whether theories of memory need to propose neurally distinct stores for short- and long-term retention. We consider alternative ways to explain the neural mechanisms of memory across different retention intervals.     

Implicit short- and long-term memory direct our gaze in visual search

Visual attention is strongly affected by the past: both by recent experience and by long-term regularities in the environment that are encoded in and retrieved from memory. In visual search, intertrial repetition of targets causes speeded response times (short-term priming). Similarly, targets that are presented more often than others may facilitate search, even long after it is no longer present (long-term priming). In this study, we investigate whether such short-term priming and long-term priming depend on dissociable mechanisms. By recording eye movements while participants searched for one of two conjunction targets, we explored at what stages of visual search different forms of priming manifest. We found both long- and short- term priming effects. Long-term priming persisted long after the bias was present, and was again found even in participants who were unaware of a color bias. Short- and long-term priming affected the same stage of the task; both biased eye movements towards targets with the primed color, already starting with the first eye movement. Neither form of priming affected the response phase of a trial, but response repetition did. The results strongly suggest that both long- and short-term memory can implicitly modulate feedforward visual processing.     

Dissociation of short- and long-term face memory: evidence from long-term recency effects in temporal lobe epilepsy

We tested whether memory deficits in temporal lobe epilepsy (TLE) are better described by a single- or dual-store memory model. To this aim, we analyzed the influence of TLE and proactive interference (PI) on immediate and 24-h long-term recency effects during face recognition in 16 healthy participants and 18 right and 21 left non-surgical TLE patients. PI in healthy participants or TLE erased the long-term recency effect, but left the immediate recency effect unaffected. Although the immediate recency effect was still visible in right TLE patients, the number of detected recency items during immediate recognition was decreased in right TLE compared to left TLE. Right TLE was also related to decreased detection of pre-recency items during delayed recognition compared to left TLE, and decreased detection of pre-recency items during immediate recognition under PI. The results show that the temporal lobes are necessary for the long-term recency effect, but not for the immediate recency effect, and thus speak for a dissociation of short- and long-term memory for faces. Right TLE is related to more severe long-term memory deficits than left TLE and is also related to additional short-term memory deficits for faces.     

Post-training disruption of Arc protein expression in the anterior cingulate cortex impairs long-term memory for inhibitory avoidance training

The activity-regulated-cytoskeletal-associated protein (Arc) has a well established role in memory consolidation and synaptic plasticity in the hippocampus and amygdala. However the role of Arc within the anterior cingulate cortex (ACC), an area of the brain involved in processing memory for pain, has yet to be examined. Here we sought to determine if Arc protein within neurons of the rat ACC is necessary for the consolidation of a single-trial, contextual inhibitory avoidance (IA) task. Immunohistochemistry and western blotting revealed an increase in Arc protein within the ACC following IA training in a shock-specific manner, suggesting that ACC Arc expression may play a critical role in the consolidation of the aversive task. To directly test this hypothesis, male Sprague-Dawley rats were trained on the IA task and given post-training intra-ACC infusions of Arc antisense oligodeoxynucleotides (ODNs), designed to suppress Arc translation, or control scrambled ODNs that do not suppress Arc translation. Memory retention was tested 48h after training. Arc antisense-induced disruption of Arc protein expression in the ACC impaired long-term memory for the IA task as compared to rats given intra-ACC infusions of the scrambled control ODNS, suggesting that Arc expression in the ACC is important for the consolidation of emotional memory. Results further indicate that knock down of Arc 6h after training impairs IA memory. This is consistent with time course findings indicating elevated Arc expression at 3 and 6h after IA training but not 12 or 48h. Taken together, these findings support the hypothesis that Arc expression in the ACC participates in synaptic plasticity that underlies long-term memory.     

The extracellular protease matrix metalloproteinase-9 is activated by inhibitory avoidance learning and required for long-term memory

Matrix metalloproteinases (MMPs) are a family of extracellularly acting proteolytic enzymes with well-recognized roles in plasticity and remodeling of synaptic circuits during brain development and following brain injury. However, it is now becoming increasingly apparent that MMPs also function in normal, nonpathological synaptic plasticity of the kind that may underlie learning and memory. Here, we extend this idea by investigating the role and regulation of MMP-9 in an inhibitory avoidance (IA) learning and memory task. We demonstrate that following IA training, protein levels and proteolytic activity of MMP-9 become elevated in hippocampus by 6 h, peak at 12-24 h, then decline to baseline values by approximately 72 h. When MMP function is abrogated by intrahippocampal infusion of a potent gelatinase (MMP-2 and MMP-9) inhibitor 3.5 h following IA training, a time prior to the onset of training-induced elevation in levels, IA memory retention is significantly diminished when tested 1-3 d later. Animals impaired at 3 d exhibit robust IA memory when retrained, suggesting that such impairment is not likely attributed to toxic or other deleterious effects that permanently disrupt hippocampal function. In anesthetized adult rats, the effective distance over which synaptic plasticity is impaired by a single intrahippocampal infusion of the MMP inhibitor of the kind that blocks IA memory is approximately 1200 microm. Taken together, these data suggest that IA training induces a slowly emerging, but subsequently protracted period of MMP-mediated proteolysis critical for enabling long-lasting synaptic modification that underlies long-term memory consolidation.     

Differential effects of emotional arousal in short- and long-term memory in healthy adults

Recent studies demonstrated important differences between short- and long-term memory mechanisms. Besides, the emotional component has a crucial role in memory formation. This study was carried out to answer whether there is a differential influence of emotional arousal in short- and long-term memory in healthy adults. Thirty-one healthy volunteers were divided into two major groups. In the first group long-term memory (LTM) was evaluated, with the testing session one week after training. The second group was tested 1h after training, where short-term memory (STM) was evaluated. Each group was divided in to two subgroups. One half of the volunteers was exposed to an emotionally neutral story, and the other half of each group was exposed to a closely matched but more emotionally arousing story. The testing session consisted of a questionary containing 80 questions of multiple choices. The results were evaluated through percentage of correct answers. Results showed that correct answers were increased, in LTM measures, in the subjects that were given the emotional version of the test. In STM measures, no differences were found between the emotional and neutral version. However, the presentation of emotional story caused an emotional reaction in both groups. The lack of effect of emotional arousal in STM suggests that amygdala is not related to STM mechanisms. Further studies using different approaches are needed to elucidate if STM processes are influenced by emotional arousal.     

Endogenous BDNF is required for long-term memory formation in the rat parietal cortex

Information storage in the brain is a temporally graded process involving different memory phases as well as different structures in the mammalian brain. Cortical plasticity seems to be essential to store stable long-term memories, although little information is available at the moment regarding molecular and cellular events supporting memory consolidation in the neocortex. Brain-derived neurotrophic factor (BDNF) modulates both short-term synaptic function and activity-dependent synaptic plasticity in hippocampal and cortical neurons. We have recently demonstrated that endogenous BDNF in the hippocampus is involved in memory formation. Here we examined the role of BDNF in the parietal cortex (PCx) in short-term (STM) and long-term memory (LTM) formation of a one-trial fear-motivated learning task in rats. Bilateral infusions of function-blocking anti-BDNF antibody into the PCx impaired both STM and LTM retention scores and decreased the phosphorylation state of cAMP response element-binding protein (CREB). In contrast, intracortical administration of recombinant human BDNF facilitated LTM and increased CREB activation. Moreover, inhibitory avoidance training is associated with a rapid and transient increase in phospho-CREB/total CREB ratio in the PCx. Thus, our results indicate that endogenous BDNF is required for both STM and LTM formation of inhibitory avoidance learning, possibly involving CREB activation-dependent mechanisms. The present data support the idea that early sensory areas constitute important components of the networks subserving memory formation and that information processing in neocortex plays an important role in memory formation.     

The entorhinal cortex plays a role in extinction

In this study, we analyzed the participation of the entorhinal cortex in extinction of a learned aversive response. Rats with infusion cannulae aimed to the entorhinal cortex were trained in a one-trial step-down inhibitory avoidance task (IA) and submitted to four consecutive daily test sessions without the footshock, a procedure that induced extinction of the conditioned response in control animals. When infused into the entorhinal cortex immediately after the first extinction session at doses able to block consolidation of IA memory, the NMDA receptor antagonist, AP5 (25 nmol/side), the inhibitor of protein synthesis anisomycin (300 nmol/side) and the inhibitor of CaMKII, KN-93 (10 nmol/side), but not the MEK1/2 inhibitor PD-98059 (5 nmol/side) hindered extinction of the IA response. The same results were obtained when the interval between the first and second test session was 48 instead of 24h. The data indicate that normal functionality of the NMDA receptors, together with CaMKII activity and protein synthesis are necessary in the entorhinal cortex at the time of the first test session to generate extinction. Our results also suggest that the ERK1/2 pathway does not play a role in this process.     

Short- and long-term effects of cannabinoids on the extinction of contextual fear memory in rats

Facilitation of memory extinction by manipulation of the endocannabinoid (eCB) system has been recently studied in several paradigms. Our previous results pointed to facilitation of contextual fear memory extinction by a low dose of a cannabinoid agonist, with a suggestion of short-term effects. The aim of the present study was to further investigate the effects of cannabinoid drugs in the short- and long-term extinction of conditioned fear using an extended extinction protocol. Male Wistar rats were placed in a conditioning chamber and after 3 min received a footshock (1.5 mA, 1 s). On the next day, they received i.p. drug treatment (WIN55212-2 0.25 mg/kg, AM404 10 mg/kg, SR141716 A 1 mg/kg) and were re-exposed to the conditioning chamber for 30 min (extinction training). No-Extinction groups received the same drug treatment, but were exposed for 3 min to the conditioning chamber. A drug-free test of contextual memory (3 min) was performed 7 days later. The cannabinoid agonist WI55212-2 and the inhibitor of eCB metabolism/uptake AM404 facilitated short-term extinction. In addition, long-term effects induced by treatments with WIN55212 and AM404 were completely divergent to those of SR141716A treatment. The present results confirm and extend previous findings showing that the eCB system modulates short-term fear memory extinction with long-lasting consequences.     

Retrieval does not induce reconsolidation of inhibitory avoidance memory

It has been suggested that retrieval during a nonreinforced test induces reconsolidation instead of extinction of the mnemonic trace. Reconsolidation would preserve the original memory from the labilization induced by its nonreinforced recall through a hitherto uncharacterized mechanism requiring protein synthesis. Given the importance that such a process would have in terms of maintaining, as part of the animal behavioral repertoire, a learned response that has been devalued by experience, we analyzed its existence for the memory associated with a one-trial, step-down inhibitory avoidance task (IA), a memory whose consolidation and extinction require protein synthesis in the CA1 region of the dorsal hippocampus (CA1) and involve the participation of the basolateral amygdala (BLA) and entorhinal cortex (ENT). Rats were trained in IA, and 24 h later they were submitted either to a pure reactivation session (retrieval without stepping down), which was unable by itself to initiate extinction of the avoidance response, or to a second training session. Fifteen minutes before or 3 h after either the reactivation or the retraining sessions, animals were infused with the protein synthesis inhibitor anisomycin (ANI) into CA1, BLA, or ENT. Contrary to the prediction of the reconsolidation hypothesis, none of these treatments affected subsequent memory retention. Because reconsolidation is regarded to be a direct consequence of retrieval, one would expect that, when given before a retention test or a pure reactivation session, enhancers of memory expression should permanently improve retention and, therefore, facilitate retrieval both in that and in subsequent sessions. Using two well-known retrieval enhancers, noradrenaline and adrenocorticotropin(1-24), we could not find any evidence suggestive of reconsolidation. Hence, our results indicate that there is no retrieval-induced, protein synthesis-dependent process that would cause reconsolidation of IA memory.     

Cholinergic activity in the insular cortex is necessary for acquisition and consolidation of contextual memory

Experiences with a high emotional content (aversive) tend to be stored as long-term memories; however, there are also contextual recollections, which form a significant part of our memories. Different research has shown that the insular cortex (IC) plays an important role during aversive memory formation, yet its role during incidental/non-aversive learning like pre-exposure contextual memory formation has received little attention. The objective of this research was to establish the role of cholinergic activity in the IC through its muscarinic receptors during the formation of inhibitory avoidance (IA) memory, as well as during pre-exposure contextual memory, using a paradigm such as latent inhibition (LI). Rats with bilateral cannulae directed into the IC were trained in the LI paradigm of IA or IA task alone. The muscarinic antagonist receptor scopolamine was infused bilaterally into the IC 5 min before the pre-exposure into the dark chamber of the IA cage, one day before the conventional IA training or during the IA training day. During the IA test, the entrance latency into the dark chamber of the IA cage was measured as an index of contextual memory. The results showed that scopolamine infused before and after IA training disrupts inhibitory avoidance memory. Also, it showed that the pre-exposed saline-infused animals (LI) had a lower entrance latency compared to the group not pre-exposed (IA). However, the group that received scopolamine into the IC before, but not after, the pre-exposure to the dark chamber, presented a similar latency to the IA group, showing a blockade of the latent inhibition of the IA. These results suggest that cholinergic activity in the insular cortex is necessary during the acquisition and consolidation of avoidance memory, but appears necessary only during the acquisition of pre-exposure non-aversive contextual memory.     

Modulation of working, short- and long-term memory by nicotinic receptors in the basolateral amygdala in rats

Male Wistar rats were exposed to one-trial step-down inhibitory avoidance training using a 0.5 mA footshock. Through bilaterally implanted indwelling cannulae, they received bilateral 0.5 microL infusions of saline, mecamylamine (1.0 or 10.0 microg/side), or nicotine (0.6 or 3.0 microg/side) into the basolateral complex of the amygdaloid nucleus (BLA). Infusions were either 10 min before training (Experiment 1) or 4 min after training (Experiment 2). In Experiment 1, the animals were tested three times: first for working memory (WM) 5 s after training, then for short-term memory (STM) 90 min later, and finally for long-term memory (LTM) 24 h later. Mecamylamine depressed and nicotine enhanced WM, STM, and LTM. In Experiment 2, the treatments were given after WM was presumably over. Again, mecamylamine inhibited and nicotine enhanced STM and LTM. The results indicate that nAChRs in BLA participate in the regulation of WM formation and STM and LTM acquisition and consolidation.     

Memory traces compete under regimes of limited Arc protein synthesis: Implications for memory interference

Recently encoded information can be lost in the presence of new information, a process called 'retrograde interference'. Retrograde interference has been extensively described for more than a century; however, little is known about its underlying mechanisms. Different approaches agree on the need of the synthesis of plasticity related proteins (PRPs) to consolidate a long-term memory (LTM). Our hypothesis is that when PRPs are limited, interference of a task over LTM formation of another may be due to the utilization of protein resources common to both tasks. Here, by combining the tasks of inhibitory avoidance (IA) and open field (OF) exploration in rats, we show that memory traces compete for their stabilization if PRPs are limited. As a result, LTM is formed for only one of the tasks with a consequent decrease in the memory for the other. Furthermore, infusing Arc antisense oligonucleotide into the dorsal hippocampus, we found that Arc is necessary for LTM formation of these two types of learning tasks and is one of the PRPs that can be shared between them when animals are trained in both OF and IA. In sum, these findings suggest that under conditions of reduced protein availability, a learning task interferes with LTM formation of another by using the available PRPs.     

Different importance of the volatile and non-volatile fractions of an olfactory signature for individual social recognition in rats versus mice and short-term versus long-term memory

When tested in the olfactory cued social recognition/discrimination test, rats and mice differ in their retention of a recognition memory for a previously encountered conspecific juvenile: Rats are able to recognize a given juvenile for approximately 45 min only whereas mice show not only short-term, but also long-term recognition memory (≥ 24 h). Here we modified the social recognition/social discrimination procedure to investigate the neurobiological mechanism(s) underlying the species differences. We presented a conspecific juvenile repeatedly to the experimental subjects and monitored the investigation duration as a measure for recognition. Presentation of only the volatile fraction of the juvenile olfactory signature was sufficient for both short- and long-term recognition in mice but not rats. Applying additional volatile, mono-molecular odours to the "to be recognized" juveniles failed to affect short-term memory in both species, but interfered with long-term recognition in mice. Finally immunocytochemical analysis of c-Fos as a marker for cellular activation, revealed that juvenile exposure stimulated areas involved in the processing of olfactory signals in both the main and the accessory olfactory bulb in mice. In rats, we measured an increased c-Fos synthesis almost exclusively in cells of the accessory olfactory bulb. Our data suggest that the species difference in the retention of social recognition memory is based on differences in the processing of the volatile versus non-volatile fraction of the individuals' olfactory signature. The non-volatile fraction is sufficient for retaining a short-term social memory only. Long-term social memory - as observed in mice - requires a processing of both the volatile and non-volatile fractions of the olfactory signature.     

A power-law model of psychological memory strength in short- and long-term recognition

A classic law of cognition is that forgetting curves are closely approximated by power functions. This law describes relations between different empirical dependent variables and the retention interval, and the precise form of the functional relation depends on the scale used to measure each variable. In the research reported here, we conducted a recognition task involving both short- and long-term probes. We discovered that formal memory-strength parameters from an exemplar-recognition model closely followed a power function of the lag between studied items and a test probe. The model accounted for rich sets of response time (RT) data at both individual-subject and individual-lag levels. Because memory strengths were derived from model fits to choices and RTs from individual trials, the psychological power law was independent of the scale used to summarize the forgetting functions. Alternative models that assumed different functional relations or posited a separate fixed-strength working memory store fared considerably worse than the power-law model did in predicting the data.     

Glucocorticoid-mediated effects of systemic oxytocin upon memory retrieval

During the last decade, a considerable amount of evidence has accumulated to show that oxytocin (OT) is involved with functions other than its classical roles in reproduction-associated processes, such as social recognition, maternal behavior and neuroendocrine regulation of the stress response. It has been shown, for instance, that post-training systemic administration of oxytocin in mice produces an amnestic effect on the step-through inhibitory avoidance. Since it is still unclear how systemic levels of OT may affect CNS memory processes, our aim here was to investigate the hypothesis that systemic OT effects on memory retrieval might be mediated through an oxytocin-induced decrease in glucocorticoid release. In our first experiment, we have found an amnestic effect of i.p. pre-test 0.4 microg/kg of OT upon memory retrieval in the inhibitory avoidance task (IA); this OT dose was shown to (a) significantly decrease plasma corticosterone levels when compared to the saline group, and (b) not to cause any anxiety effects by itself in a plus-maze task. At last, an ineffective-by-itself dose of dexamethasone was able to reverse the amnestic effect of this OT dose. Our results suggest that the amnestic effect of systemically administered oxytocin upon memory retrieval in the inhibitory avoidance task was probably caused by an oxytocin-induced decrease in glucocorticoid release from the adrenal gland.