Recognition memory after short retention intervals in fornix-transected monkeys

Fornix-transected monkeys were impaired in recognition memory after brief retention intervals for short lists of either colours or spatial positions. The results were contrasted with the existing evidence in human amnesic patients for a neurologically separate, intact short-term memory system.     

The lifespan of time intervals in reference memory

To further explore how memory influences time judgments, we conducted two experiments on the lifespan of temporal representations in memory. Penney et al (2000, Journal of Experimental Psychology Human Perception and Performance 26 1770-1787) reported that the perceived duration of auditorily and visually marked intervals differs only when both marker-type intervals are compared directly. This finding can be explained by a 'memory-mixing' process, whereby the memory trace of previous intervals influences the perception of upcoming ones, which are then added to the memory content. In the experiments discussed here, we manipulated the mixing mode of auditory/visual signal presentations. In experiment 1, signals from the same modality were either grouped by blocks or randomised within blocks. The results showed that the auditory/visual difference decreased but remained present when modalities were grouped by blocks. In experiment 2, we used a line-segmentation task. The results showed that, after a training block was performed in one modality, the perceived duration of signals from the other modality was distorted for at least 30 trials and that the magnitude of the difference decreased as the block went on. The results of both experiments highlight the influence of memory on time judgments, providing empirical support to, and quantitative portrayal of, the memory-mixing process.     

Administration of corticosterone after memory reactivation disrupts subsequent retrieval of a contextual conditioned fear memory: dependence upon training intensity

Reactivation of stabilized memories returns them to a labile state and causes them to undergo extinction or reconsolidation processes. Although it is well established that administration of glucocorticoids after training enhance consolidation of contextual fear memories, but their effects on post-retrieval processes are not known. In this study, we first asked whether administration of corticosterone after memory reactivation would modulate subsequent expression of memory in rats. Additionally, we examined whether this modulatory action would depend upon the strength of the memory. We also tested the effect of propranolol after memory reactivation. Adult male Wistar rats were trained in a fear conditioning system using moderate (0.4 mA) or high shock (1.5 mA) intensities. For reactivation, rats were returned to the chamber for 90 s 24h later. Immediately after reactivation, rats were injected with corticosterone (1, 3 or 10mg/kg) or vehicle. One, 7 and 14 days after memory reactivation, rats were returned to the context for 5 min, and freezing behavior was scored. The findings indicated that corticosterone when injected after memory reactivation had no significant effect on recall of a moderate memory, but it impaired recall of a strong memory at a dose of 3mg/kg. Propranolol (5mg/kg) given after the reactivation treatment produced a modest impairment that persisted over three test sessions. Further, the results showed that corticosterone, but not propranolol deficit was reversed by a reminder shock. These findings provide evidence that administration of glucocorticoids following memory reactivation reduces subsequent retrieval of strong, but not moderate, contextual conditioned fear memory likely via acceleration of memory extinction. On the other hand, propranolol-induced amnesia may result from blockade of reconsolidation process. Further studies are needed to determine the underlying mechanisms.     

Reinstatement versus reactivation effects on active memory in infants

Reinstatement and reactivation are procedurally different reminder paradigms used with infants and children, but most developmental psychologists do not distinguish between them. In 4 experiments with 102 three-month-olds, we asked if they differ functionally as well. Independent groups of infants received either a reactivation or a reinstatement reminder 3 days after training, when the memory is active, but its specific details have been forgotten. In Experiment 1, we measured retention after increasing delays until infants forgot altogether. A single reinstatement protracted retention twice as long after training as a single reactivation. In Experiments 2-4, whether the reminder was the original training stimulus or a novel one differentially affected the duration and specificity of memory in the 2 procedures as well. These data demonstrate that the distinction between reinstatement and reactivation is not artificial. In addition to differing procedurally, reinstatement and reactivation differ functionally, with different memory-preserving effects.     

Differential regulation of glutamic acid decarboxylase gene expression after extinction of a recent memory vs. intermediate memory

Extinction reduces fear to stimuli that were once associated with an aversive event by no longer coupling the stimulus with the aversive event. Extinction learning is supported by a network comprising the amygdala, hippocampus, and prefrontal cortex. Previous studies implicate a critical role of GABA in extinction learning, specifically the GAD65 isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD). However, a detailed analysis of changes in gene expression of GAD in the subregions comprising the extinction network has not been undertaken. Here, we report changes in gene expression of the GAD65 and GAD67 isoforms of GAD, as measured by relative quantitative real-time RT-PCR, in subregions of the amygdala, hippocampus, and prefrontal cortex 24-26 h after extinction of a recent (1-d) or intermediate (14-d) fear memory. Our results show that extinction of a recent memory induces a down-regulation of Gad65 gene expression in the hippocampus (CA1, dentate gyrus) and an up-regulation of Gad67 gene expression in the infralimbic cortex. Extinguishing an intermediate memory increased Gad65 gene expression in the central amygdala. These results indicate a differential regulation of Gad gene expression after extinction of a recent memory vs. intermediate memory.     

Differential effectiveness of various prior-cuing treatments in the reactivation and maintenance of memory

In 3 experiments, changes were examined in the characteristics of newly acquired and reinstated memories over time in preweanling rats. Experiment 1 indicated that forgetting after conditioning was monotonic, with the upper limit of retention at approximately 120 min posttraining. In Experiment 2, Ss were exposed to various elements of the training episode before testing, after either a 3- or a 24-hr retention interval. The results indicated that the prior-cuing treatments were differentially effective and that the effectiveness of a reactivation treatment may change as a function of the retention interval. Experiment 3 indicated that Ss expressed a conditioned aversion at much longer intervals following reactivation treatments than after initial conditioning. Furthermore the susceptibility of the reinstated memory to forgetting was dependent on the prior-cuing treatment used. The results suggest a change in the memorial representation of the conditioning episode over time.     

Remembered duration: working memory and the reproduction of intervals

On the basis of attention allocation models of time estimation, the role of working memory in prospective duration reproduction is explored. In four experiments, adult participants performed a counting task (duration, 400 sec) that allowed coordinative and sequential demands on working memory to be varied. After completing the counting task, the participants reproduced the time that they had worked on this task It emerged that (1) increased coordinative demands on working memory (but not increased sequential demands) reduced the accuracy of prospective duration reproduction (Experiments 1 and 2), (2) presenting context information during the reproduction phase enhanced the accuracy of the reproduced duration (Experiment 3), and (3) individual differences in coordinative working memory capacity affected duration reproduction in the same direction as the experimental manipulation of coordinative task demands (Experiment 4). The results suggest that attention allocation models of time estimation may benefit from taking a more differentiated view of the types of attentional demands that affect temporal cognition.     

Preserved spatial memory over brief intervals in older adults

Two studies compared young and older adults' memory for location information after brief intervals. Experiment 1 found that accuracy of intentional spatial memory for individual locations was similar in young and older participants for set sizes of 3 and 6. Both groups also encoded individual locations in relation to the larger configuration of locations. Experiment 2 showed that like young adults, older adults' latency to respond to a test probe in a letter working memory task was negatively influenced by spatial information that was irrelevant to the task. This interference effect indicated preserved incidental memory for spatial information in older adults. Together, these data suggest that initial encoding of spatial information for relatively small numbers of items is largely preserved in healthy older adults and that representations of spatial information persist over short intervals.     

Aversive memory reactivation engages in the amygdala only some neurotransmitters involved in consolidation

Consolidation refers to item stabilization in long-term memory. Retrieval renders a consolidated memory sensitive, and a "reconsolidation" process has been hypothesized to keep the original memory persistent. Some authors could not detect this phenomenon. Here we show that retrieved contextual fear memory is vulnerable to amnesic treatments and that the amygdala is critically involved. Cholinergic and histaminergic systems seem to modulate only consolidation, whereas cannabinoids are involved in both consolidation and reactivation. The lability of retrieved memory affords opportunities to treat disorders such as phobias, post-traumatic stress, or chronic pain, and these results help searching for appropriate therapeutic targets.     

Prospective memory in the rat

The content of prospective memory is comprised of representations of an action to perform in the future. When people form prospective memories, they temporarily put the memory representation in an inactive state while engaging in other activities, and then activate the representation in the future. Ultimately, successful activation of the memory representation yields an action at an appropriate, but temporally distant, time. A hallmark of prospective memory is that activation of the memory representation has a deleterious effect on current ongoing activity. Recent evidence suggests that scrub jays and non-human primates, but not other species, are capable of future planning. We hypothesized that prospective memory produces a selective deficit in performance at the time when rats access a memory representation but not when the memory representation is inactive. Rats were trained in a temporal bisection task (90 min/day). Immediately after the bisection task, half of the rats received an 8-g meal (meal group) and the other rats received no additional food (no-meal group). Sensitivity to time in the bisection task was reduced as the 90-min interval elapsed for the meal group but not for the no-meal group. This time-based prospective-memory effect was not based on response competition, an attentional limit, anticipatory contrast, or fatigue. Our results suggest that rats form prospective memories, which produces a negative side effect on ongoing activity.     

Fos protein expression in olfactory-related brain areas after learning and after reactivation of a slowly acquired olfactory discrimination task in the rat

Fos protein immunodetection was used to investigate the neuronal activation elicited in some olfactory-related areas after either learning of an olfactory discrimination task or its reactivation 10 d later. Trained rats (T) progressively acquired the association between one odor of a pair and water-reward in a four-arm maze. Two groups of pseudotrained rats were used: PO rats were not water restricted and were submitted to the olfactory stimuli in the maze without any reinforcement, whereas PW rats were water-deprived and systematically received water in the maze without any odorous stimulation. When the discrimination task was well mastered, a significantly lower Fos immunoreactivity was observed in T rats compared to PW and PO rats in most of the analyzed brain areas, which could reflect the post-acquisition consolidation process. Following memory reactivation, differences in Fos immunoreactivity between trained and some pseudotrained rats were found in the anterior part of piriform cortex, CA3, and orbitofrontal cortex. We also observed that Fos labeling was significantly higher in trained rats after memory reactivation than after acquisition of the olfactory task in most of the brain areas examined. Our results support the assumption of a differential involvement of neuronal networks after either learning or reactivation of an olfactory discrimination task.     

The effect of zolpidem on targeted memory reactivation during sleep

According to the active system consolidation theory, memory consolidation during sleep relies on the reactivation of newly encoded memory representations. This reactivation is orchestrated by the interplay of sleep slow oscillations, spindles, and theta, which are in turn modulated by certain neurotransmitters like GABA to enable long-lasting plastic changes in the memory store. Here we asked whether the GABAergic system and associated changes in sleep oscillations are functionally related to memory reactivation during sleep. We administered the GABA_A agonist zolpidem (10 mg) in a double-blind placebo-controlled study. To specifically focus on the effects on memory reactivation during sleep, we experimentally induced such reactivations by targeted memory reactivation (TMR) with learning-associated reminder cues presented during post-learning slow-wave sleep (SWS). Zolpidem significantly enhanced memory performance with TMR during sleep compared with placebo. Zolpidem also increased the coupling of fast spindles and theta to slow oscillations, although overall the power of slow spindles and theta was reduced compared with placebo. In an uncorrected exploratory analysis, memory performance was associated with slow spindle responses to TMR in the zolpidem condition, whereas it was associated with fast spindle responses in placebo. These findings provide tentative first evidence that GABAergic activity may be functionally implicated in memory reactivation processes during sleep, possibly via its effects on slow oscillations, spindles and theta as well as their interplay.

Sleep supports the consolidation of newly acquired memories (Mednick et al. 2011; Klinzing et al. 2019). According to the active system consolidation theory, new memories and their associated neuronal activation patterns become spontaneously reactivated (replayed) following learning in the sleeping brain (Wilson and McNaughton 1994; Diekelmann and Born 2010). These reactivations allow for the redistribution and integration of the memory representations from hippocampal to neocortical sites for long-term storage (Rasch and Born 2007; Klinzing et al. 2019). Memory reactivation during sleep has been proposed to rely on the synchronized interplay of electrophysiological oscillations characteristic of non–rapid eye movement (NREM) sleep, mainly neocortical slow oscillations (SOs, <1 Hz), thalamocortical spindles (9–15 Hz), and hippocampal ripples (80–200 Hz) (Mölle et al. 2009; Staresina et al. 2015; Helfrich et al. 2018; Ngo et al. 2020). Particularly, sleep spindles and their intricate phase coupling to SO have been suggested to be mechanistically involved in memory consolidation processes during sleep (Ulrich 2016; Antony et al. 2019). It has been proposed that memories become reinstated by spindle events, specifically during the up-state of slow oscillations, allowing for the flow of information between different brain sites as well as the induction of lasting structural and functional plastic changes in the learning-associated neuronal networks (Rosanova and Ulrich 2005; Peyrache and Seibt 2020). In addition to sleep spindles, neocortical and hippocampal theta activity (4–8 Hz) is also phase-locked to SO during NREM sleep (Gonzalez et al. 2018; Cox et al. 2019; Krugliakova et al. 2020), and this coupling has been related to memory consolidation during sleep (Schreiner et al. 2018).A number of neuromodulators seem to be involved in the generation of sleep spindles, SO and associated memory processing, most notably GABA (γ-aminobutyric acid), which is the major inhibitory neurotransmitter (Lancel 1999; Ulrich et al. 2018). Sleep spindles and sleep-dependent memory processing can be boosted by targeting the GABAergic system pharmacologically (Mednick et al. 2013). Zolpidem is one of the most frequently used drugs in this regard, binding to GABA_A receptors at the same location as benzodiazepines, thereby acting as a GABA_A receptor agonist (Lemmer 2007). Zolpidem increases the time spent in slow-wave sleep (SWS) and reduces the amount of rapid eye movement (REM) sleep (Kanno et al. 2000; Uchimura et al. 2006; Zhang et al. 2020). Zolpidem also increases the density and power of sleep spindles (Dijk et al. 2010; Lundahl et al. 2012; Mednick et al. 2013; Niknazar et al. 2015; Zhang et al. 2020) as well as the coupling of spindles to SO (Niknazar et al. 2015; Zhang et al. 2020), and it was further found to enhance declarative memory consolidation during sleep, with postsleep performance improvements being associated with higher spindle density and spindle power as well as with SO–spindle coupling (Kaestner et al. 2013; Mednick et al. 2013; Zhang et al. 2020).However, it remains unclear whether the changes in sleep stages, sleep spindles, and SO–spindle coupling after pharmacological manipulation with zolpidem are functionally related to the mechanisms underlying sleep-dependent memory consolidation such as memory reactivation. Over the last few years, targeted memory reactivation (TMR) has been increasingly applied to manipulate memory reactivation during sleep experimentally by presenting learning-associated reminder cues like odors or sounds (Oudiette and Paller 2013; Hu et al. 2020; Klinzing and Diekelmann 2020). TMR biases sleep-related neuronal replay events toward the reactivated memory contents (Lewis and Bendor 2019) and enhances subsequent recall performance (Rudoy et al. 2009; Diekelmann et al. 2011; Schreiner et al. 2015; Cairney et al. 2018). Although a few studies observed modulations of SOs (Rihm et al. 2014), sleep spindles (Cox et al. 2014), and SO–spindle coupling (Bar et al. 2020) with TMR during sleep, studies on the role of specific neurotransmitters and particularly on the role of GABAergic neurotransmission and associated changes in sleep oscillations for targeted memory reactivation are entirely lacking. One previous study tested the effect of pharmacologically increased GABAergic activity by administering the benzodiazepine clonazepam after cued reactivation of a declarative memory during wakefulness (Rodríguez et al. 2013). Clonazepam increased memory performance when it was administered after reactivation with an incomplete reminder cue, suggesting that increasing GABAergic neurotransmission may enhance the restabilization of reactivated declarative memories in humans during wakefulness.In the present study, we tested the effect of modulating GABAergic activity with zolpidem on targeted memory reactivation during sleep and associated changes in sleep spindles as well as SO–spindle and SO–theta coupling. We hypothesized that zolpidem enhances the beneficial effects of targeted memory reactivation on memory performance and that this enhancement is associated with increases in spindle density, spindle power, SO–spindle coupling, and possibly SO–theta coupling, and the amount of SWS. Participants were trained on a memory task including 30 sound–word associations in the evening (Forcato et al. 2020) and received an oral dose of 10 mg zolpidem (n = 11) or placebo (n = 11) after training before a full night of sleep in the sleep lab (Fig. 1). During the night, incomplete reminder cues (sounds + first syllable of the associated words) were played again via in-ear headphones during SWS. The next morning, participants were trained on an interference memory task to probe the stability of the original memory, which was tested 30 min later.Open in a separate windowFigure 1.Experimental design and memory task. (A) All subjects took part in a training session at ∼22.30, were administered with placebo (n = 11) or 10 mg of zolpidem (n = 11) before going to bed at 23:00, and received targeted memory reactivation during the first SWS period. After ∼8 h of sleep, in the morning, subjects learned an interference task and were tested on the original memory task in a testing session 30 min after the interference task. (B) Training: First, subjects were presented with 30 sound–word associations for learning. For each association, the sound was presented first for 2900 msec. The sound then continued accompanied by the word written on the screen and spoken aloud for 1500 msec. After a 4000-msec break, the next association was presented in the same way. After all associations were presented once, participants completed an immediate cued recall test. For each association, the sound was presented for 2900 msec. The sound then continued accompanied by the first syllable of the associated word for 1500 msec. Participants were then given 5000 msec to say the complete word aloud (sound continued during the entire period). Independently of their response, the correct answer was then presented on the screen and via headphones for 1500 msec. Reactivation: Each sound was first presented alone for an average of 2900 msec; the sound then continued accompanied by the first syllable of each word for another 1500 msec. After a 7000-msec break, the next sound–syllable pair was presented until all 30 pairs had been presented once. Testing: Each sound was presented for 500 msec and then the sound continued and subjects had 5000 msec to say the associated word aloud. After a break of 4000 msec, the procedure continued for the rest of the 30 associations. Adapted from Forcato et al. (2020).     

Traces of times past: Representations of temporal intervals in memory

Theories of time perception typically assume that some sort of memory represents time intervals. This memory component is typically underdeveloped in theories of time perception. Following earlier work that suggested that representations of different time intervals contaminate each other (Grondin, 2005; Jazayeri & Shadlen, 2010; Jones & Wearden, 2004), an experiment was conducted in which subjects had to alternate in reproducing two intervals. In two conditions of the experiment, the duration of one of the intervals changed over the experiment, forcing subjects to adjust their representation of that interval, while keeping the other constant. The results show that the adjustment of one interval carried over to the other interval, indicating that subjects were not able to completely separate the two representations. We propose a temporal reference memory that is based on existing memory models (Anderson, 1990). Our model assumes that the representation of an interval is based on a pool of recent experiences. In a series of simulations, we show that our pool model fits the data, while two alternative models that have previously been proposed do not.     

Short-term flavour memory in the rat

In a series of experiments, rats were exposed twice to a flavour at times T1 and T2, and the second of these exposures was followed by toxicosis. The level of the subsequent aversion was viewed as an index of whether the flavour had been recognised as familiar at T2, with a familiar flavour accruing less aversiveness than an unfamiliar one. A flavour was recognised as familiar at time T2 after a long flavour-exposure at time T1 (Experiment Ia) when moderate (3·5 h) and long (27·5 h) T1-T2 intervals were employed but was so recognised after a brief exposure at T1 (Experiment Ib) only when a moderate T1-T2 interval was employed. The memorial processes underlying flavour recognition after a brief flavour exposure were assumed, therefore, to be transient. The remaining experiments employed a brief flavour exposure at T1 and moderate T1-T2 intervals in various attempts to disrupt flavour recognition. Recognition at T2, however, was not disrupted when one (Experiment II), or three (Experiment IV) distractor flavours were interpolated between the target flavour's presentations at T1 and T2. This failure was not due to the distractor having proactively interfered with the associability of the target flavour with illness at T2 (Experiment III). Further, recognition was not disrupted when the position of the target flavour's presentation at T1 was varied across a list of distractor flavours (Experiment V), nor when the similarity of the distractor and the target flavour was varied (Experiment VI). The results indicate that the processes subserving recognition after a brief presentation of that flavour, although transient, are resistant to interference and were discussed in terms of current theories of short-term memory in animals.     

Linking somatic and symbolic representation in semantic memory: the dynamic multilevel reactivation framework

Biological plausibility is an essential constraint for any viable model of semantic memory. Yet, we have only the most rudimentary understanding of how the human brain conducts abstract symbolic transformations that underlie word and object meaning. Neuroscience has evolved a sophisticated arsenal of techniques for elucidating the architecture of conceptual representation. Nevertheless, theoretical convergence remains elusive. Here we describe several contrastive approaches to the organization of semantic knowledge, and in turn we offer our own perspective on two recurring questions in semantic memory research: (1) to what extent are conceptual representations mediated by sensorimotor knowledge (i.e., to what degree is semantic memory embodied)? (2) How might an embodied semantic system represent abstract concepts such as modularity, symbol, or proposition? To address these questions, we review the merits of sensorimotor (i.e., embodied) and amodal (i.e., disembodied) semantic theories and address the neurobiological constraints underlying each. We conclude that the shortcomings of both perspectives in their extreme forms necessitate a hybrid middle ground. We accordingly propose the Dynamic Multilevel Reactivation Framework—an integrative model predicated upon flexible interplay between sensorimotor and amodal symbolic representations mediated by multiple cortical hubs. We discuss applications of the dynamic multilevel reactivation framework to abstract and concrete concept representation and describe how a multidimensional conceptual topography based on emotion, sensation, and magnitude can successfully frame a semantic space containing meanings for both abstract and concrete words. The consideration of ‘abstract conceptual features’ does not diminish the role of logical and/or executive processing in activating, manipulating and using information stored in conceptual representations. Rather, it proposes that the materials upon which these processes operate necessarily combine pure sensorimotor information and higher-order cognitive dimensions involved in symbolic representation.