Persistence Of Long-term Memory Research Articles

Standardized extract of Ginkgo biloba enhances memory persistence over time

BackgroundPreviously, our group has shown that treatment with a standardized extract of Ginkgo biloba leaves (EGb) before acquisition/encoding of the conditioned suppression and object recognition task produced recent memory persistence by upregulating CREB-1 and BDNF in the hippocampal formation in a dose-dependent manner. Moreover, memory durability is influenced by processes that occur after encoding. Since the effects of EGb on consolidation processes and memory persistence are unknown, the characterization of these effects will help elucidate both the beneficial and harmful effects of “cognitive enhancers” treatments. MethodsWe investigated the effects of EGb treatment (250, 500 and 1000 mg Kg−1) on consolidation of conditioned lick suppression memory and its persistence, i.e., assessing fear memory retrieval and extinction, 2–4 days (recent long-term memory) or 40–42 days (remote long-term memory) after its acquisition. We also analyzed the compounds in the EGb by UHPLC-HRMS/MS and molecular networking (MN) for dereplication. ResultsWe show, for the first time, that EGb-induced persistence of conditioned suppression. Interestingly, while a higher dose promoted both recent and remote long-term memory persistence without preventing the acquisition of fear extinction memory, the lower dose induced the persistence of original fear remote memory and prevented extinction fear memory formation. The intermediate dose seems to be related to anti-anxiety effects. Furthermore, dereplication of EGb assisted by GNPS detected, besides ginkgolides A, B and D, distinct flavonoids, including quercetin, rutin and nicotiflorin. ConclusionThis study is the first to show that EGb treatment modulates recent and remote fear memory consolidation and its persistence. Additionally, our phytochemical analysis of the EGb corroborates the presence of flavonoids and terpenoids, which may account for the biological effects of EGb on the duration of memory and shed light on its potential as an adjunct to the treatment of memory decline or anxiety disorders.

Dopamine neurotransmission in the VTA regulates aversive memory formation and persistence

Dopamine (DA) neurons in the ventral tegmental area (VTA) innervating several limbic and neocortical regions of the mammalian brain have long been implicated in motivation, rewarding and aversive behaviors, and memory processing. Recently, we demonstrated that somatodendritic release of DA in the VTA regulates the formation and maintenance of appetitive long-term memories (LTM). However, less is known about the impact of DA neurotransmission in the VTA on aversive LTM. Here, we describe the modulation of negative-valence memories by D1/D5-type DA (D1R)-receptor-mediated neurotransmission in the VTA. As aversive stimuli elicit both active and passive behavioral responses, we used two single-trial aversive training protocols: inhibitory avoidance task and conditioned place aversion. We bilaterally microinfused SCH23390, an antagonist of D1R, into the VTA immediately after training and found that DA neurotransmission in the VTA modulates LTM consolidation and persistence of aversive experiences. Together with previous findings demonstrating that D1R-mediated DA neurotransmission in the medial prefrontal cortex and hippocampus is involved in the formation and persistence of LTM for aversive events, our present results indicate that memory processing of environmental stimuli with negative-valence depends on the integration of information mediated by D1R activation in both the VTA region and in selected downstream target areas.

Learning new words: Memory reactivation as a mechanism for strengthening and updating a novel word's meaning.

In the present study we explored the postlearning changes in a novel word's definition using a cue-induced memory reactivation. Native speakers of Spanish (N = 373) learned low-frequency words with their corresponding definitions. The following day, reactivated groups were exposed to a reminder and provided a subjective assessment of reactivation for each word, while control groups did not receive a reactivation. Study A demonstrated that memory reactivation enhances both explicit recall and semantic integration of new meanings. Study B investigated the effect of memory reactivation in the modification of the new meanings, through three different experiments. Results show an improvement of the updated definitions according to each word's reactivation strength. In addition, congruence with previous knowledge was suggested to be a boundary condition, while consolidation time had a positive modulatory effect. Our findings call attention to reactivation as a factor allowing for malleability as well as persistence of long-term memories for words.

BDNF as a Putative Target for Standardized Extract of Ginkgo biloba-Induced Persistence of Object Recognition Memory.

Despite considerable progress on the study of the effect of standardized extract of Gingko biloba (EGb) on memory processes, our understanding of its role in the persistence of long-term memory (LTM) and the molecular mechanism underlying its effect, particularly episodic-like memory, is limited. We here investigated the effects of EGb on the long-term retention of recognition memory and its persistence and BDNF expression levels in the dorsal hippocampal formation (DHF). Adult male Wistar rats (n = 10/group) were handled for 10 min/5 day. On day 6, the animals were treated with vehicle or 0.4 mg/kg diazepam (control groups) or with EGb (250, 500 or 100 mg/kg) 30 min before the training session (TR1), in which the animals were exposed to two sample objects. On day 7, all rats underwent a second training session (TR2) as described in the TR1 but without drug treatment. Object recognition memory (ORM) was evaluated on day 8 (retention test, T1) and day 9 (persistence test, T2). At the end of T1or T2, animals were decapitated, and DHF samples were frozen at −80 °C for analyses of the differential expression of BDNF by Western blotting. EGb-treated groups spent more time exploring the novel object in T2 and showed the highest recognition index (RI) values during the T1 and T2, which was associated with upregulation of BDNF expression in the DHF in a dose-and session-dependent manner. Our data reveal, for the first time, that EGb treatment before acquisition of ORM promotes persistence of LTM by BDNF differential expression.

The temperature sensitivity of memory formation and persistence is altered by cold acclimation in a pond snail.

There are reports on the inability of inbred, laboratory-reared Lymnaea stagnalis to perform feeding and aerial respiration in the cold. It has also been suggested that laboratory-bred snails have an inability to perform aerial respiration in winter months in the laboratory. Here, we used an inbred, laboratory-reared strain of Lymnaea (the S-strain) to demonstrate that the snails are capable of performing those behaviours in a cold (4°C) environment after a 2 day acclimation period. In addition, the inbred snails were able to perform aerial respiration during winter months at room temperature (20°C) in the laboratory. The persistence of long-term memory (LTM) was extended for at least 4 weeks by placing S-strain snails into a 4°C environment following training. Typically, the cold block (CB) procedure (1 h at 4°C) immediately after a training session blocks LTM formation in the S-strain but not in a freshly collected strain. Four weeks at 4°C transformed the S-strain phenotype into one resisting the CB procedure. Thus, with a 4week cold spell snails gain a resistance to the CB procedure, and that would explain why freshly collected snails are resistant to the procedure. However, we found that F1 progeny of a freshly collected strain reared in the laboratory were resistant to the CB procedure. This suggests that an unknown selection resulted in the S-strain being susceptible to the CB procedure.

Short-term memory reactivation of a weak CS-US association promotes long-term memory persistence in conditioned odor aversion.

In conditioned odor aversion (COA), the association of a tasteless odorized solution (the conditioned stimulus [CS]) with an intraperitoneal injection of LiCl (the unconditioned stimulus [US[), which produces visceral malaise, results in its future avoidance. The strength of this associative memory is mainly dependent on two parameters, that is, the strength of the US and the interstimuli interval (ISI). In rats, COA has been observed only with ISIs of ≤15 min and LiCl (0.15 M) doses of 2.0% of bodyweight, when tested 48 h after acquisition (long-term memory [LTM]). However, we previously reported a robust aversion in rats trained with ISIs up to 60 min when tested 4 h after acquisition (short-term memory [STM]). Since memories get reactivated during retrieval, in the current study we hypothesized that testing for STM would reactivate this COA trace, strengthening its LTM. For this, we compared the LTM of rats trained with long ISIs or low doses of LiCl initially tested for STM with that of rats tested for LTM only. Interestingly, rats conditioned under parameters sufficient to produce STM, but not LTM, showed a reliable LTM when first tested for STM. These observations suggest that under suboptimal training conditions, such as long ISIs or low US intensities, a CS–US association is established but requires reactivation in the short-term in order to persist in the long-term.

Early \u03b2 adrenoceptor dependent time window for fear memory persistence in APPswe/PS1dE9 mice

In this study we demonstrate that 2 month old APPswe/PS1dE9 mice, a transgenic model of Alzheimer’s disease, exhibited intact short-term memory in Pavlovian hippocampal—dependent contextual fear learning task. However, their long-term memory was impaired. Intra-CA1 infusion of isoproterenol hydrochloride, the β-adrenoceptor agonist, to the ventral hippocampus of APPswe/PS1dE9 mice immediately before fear conditioning restored long-term contextual fear memory. Infusion of the β-adrenoceptor agonist + 2.5 h after fear conditioning only partially rescued the fear memory, whereas infusion at + 12 h post conditioning did not interfere with long-term memory persistence in this mouse model. Furthermore, Intra-CA1 infusion of propranolol, the β-adrenoceptor antagonist, administered immediately before conditioning to their wildtype counterpart impaired long-term fear memory, while it was ineffective when administered + 4 h and + 12 h post conditioning. Our results indicate that, long-term fear memory persistence is determined by a unique β-adrenoceptor sensitive time window between 0 and + 2.5 h upon learning acquisition, in the ventral hippocampal CA1 of APPswe/PS1dE9 mice. On the contrary, β-adrenoceptor agonist delivery to ventral hippocampal CA1 per se did not enhance innate anxiety behaviour in open field test. Thus we conclude that, activation of learning dependent early β-adrenoceptor modulation underlies and is necessary to promote long-term fear memory persistence in APPswe/PS1dE9.

Epicatechin increases the persistence of long-term memory formed by conditioned taste aversion in Lymnaea.

We examined the effects of epicatechin (Epi), a flavonoid abundant in green tea and cocoa, on long-term memory (LTM) formed following conditioned taste aversion (CTA) training in Lymnaeastagnalis In CTA training, the snails learnt to avoid a food that initially they liked (i.e. sucrose). Twenty-four hours after CTA training, 67% of the trained snails showed a significant decrease in the feeding behaviour elicited by sucrose. Placing snails in the Epi solution in CTA training did not alter the percentage of snails exhibiting LTM, but it significantly increased LTM persistence. We also examined changes following Epi exposure in spontaneous activity of the cerebral giant cells (CGCs) that modulate feeding behaviour and are necessary for CTA-LTM. Our data suggest that Epi causes a decrease in CGC activity and increases LTM persistence, possibly via a GABAergic mechanism.

Behavioral tagging and capture: long-term memory decline in middle-aged rats.

Decline in cognitive functions, including hippocampus-dependent spatial memory, is commonly observed at a later stage of aging (e.g., >20 months old in rodents) and typically studied after a discrete learning event. How normal aging, particularly at an early stage, affects the modulatory aspect of memory persistence is underinvestigated. Previous studies in young animals show that weak, fading memories can last longer if a modulating event, such as spatial novelty, is introduced around memory encoding. This is known as behavioral tagging and capture (BTC). Here, we investigated how early aging (10–13 months old) affects BTC in an appetitive delayed-matching-to-place task. We trained rats when they were young and middle aged and found that novelty facilitated long-term memory persistence in young but not in middle-aged rats. However, re-exposure to the encoded environment after learning improved memory persistence in middle-aged rats. BTC, combined with memory reactivation, facilitated memory persistence through reconsolidation. Our results point toward a weakened tagging and capture mechanism before reduction of plasticity-related proteins at an early stage of aging.

Fluoxetine Inhibits Natural Decay of Long-Term Memory via Akt/GSK-3β Signaling.

Understanding the mechanisms underlying the natural decay of long-term memory can help us find means of extending the duration of long-term memory. However, the neurobiological processes involved in the decay of long-term memory are poorly understood. In the present study, we examined the effect of acute and chronic treatment of fluoxetine on natural decay of long-term memory and the possible mechanism. Late administration of fluoxetine prolonged the persistence of long-term memory in mice, as demonstrated by object location recognition and Barnes maze tests. Fluoxetine altered Akt/glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling in the hippocampus. Late short- and long-term pharmacological inhibition of GSK-3β mimicked the effect of fluoxetine on memory persistence. Pharmacological inhibition of Akt blocked the effect of fluoxetine on memory persistence. Finally, late infusion of fluoxetine increased hippocampal long-term potentiation (LTP) and pharmacological inhibition of GSK-3β blocked the natural decline in LTP. These results demonstrate that GSK-3β might be a key molecule in memory decay process, and fluoxetine extends the period of long-term memory maintenance via Akt/GSK-3β signaling.

The differential role of cortical protein synthesis in taste memory formation and persistence.

The current dogma suggests that the formation of long-term memory (LTM) is dependent on protein synthesis but persistence of the memory trace is not. However, many of the studies examining the effect of protein synthesis inhibitors (PSIs) on LTM persistence were performed in the hippocampus, which is known to have a time-dependent role in memory storage, rather than the cortex, which is considered to be the main structure to store long-term memories. Here we studied the effect of PSIs on LTM formation and persistence in male Wistar Hola (n⩾5) rats by infusing the protein synthesis inhibitor, anisomycin (100 μg, 1 μl), into the gustatory cortex (GC) during LTM formation and persistence in conditioned taste aversion (CTA). We found that local anisomycin infusion to the GC before memory acquisition impaired LTM formation (P=8.9E−5), but had no effect on LTM persistence when infused 3 days post acquisition (P=0.94). However, when we extended the time interval between treatment with anisomycin and testing from 3 days to 14 days, LTM persistence was enhanced (P=0.01). The enhancement was on the background of stable and non-declining memory, and was not recapitulated by another amnesic agent, APV (10 μg, 1 μl), an N-methyl-D-aspartate receptor antagonist (P=0.54). In conclusion, CTA LTM remains sensitive to the action of PSIs in the GC even 3 days following memory acquisition. This sensitivity is differentially expressed between the formation and persistence of LTM, suggesting that increased cortical protein synthesis promotes LTM formation, whereas decreased protein synthesis promotes LTM persistence.

Awake reactivation of emotional memory traces through hippocampal–neocortical interactions

Emotionally arousing experiences are typically well remembered not only due to immediate effects at encoding, but also through further strengthening of subsequent consolidation processes. A large body of research shows how neuromodulatory systems promote synaptic consolidation. However, how emotionally arousing experiences alter systems-level interactions, presumably a consequence of modifications at a synaptic level, remains unclear. Animal models predict that memory traces are maintained by spontaneous reactivations across hippocampal–neocortical circuits during “offline” periods such as post-learning rest, and suggest this might be stronger for emotional memories. The present study was designed to test this hypothesis in humans using functional Magnetic Resonance Imaging. Participants underwent a two-category localizer paradigm followed by a categorical differential delay fear conditioning paradigm interleaved with blocks of awake rest. Counterbalanced across participants, exemplars of one category (CS+), but not the other (CS−), were paired with mild electrical shocks. Fear recall (differential conditioned pupil dilation) was tested 24h later. Analyses of the localizer paradigm replicate earlier work showing category-specific response patterns in neocortical higher-order visual regions. Critically, we show that during post-learning rest, spontaneous reactivation of these neocortical patterns was stronger for the CS+ than the CS− category. Furthermore, hippocampal connectivity with the regions exhibiting these reactivations predicted strength of fear recall 24h later. We conclude that emotional arousal during learning promotes spontaneous post-learning reactivation of neocortical representations of recent experiences, which leads to better memory when coinciding with hippocampal connectivity. Our findings reveal a systems-level mechanism that may explain the persistence of long-term memory for emotional experiences.

Blocking Synaptic Removal of GluA2-Containing AMPA Receptors Prevents the Natural Forgetting of Long-Term Memories.

The neurobiological mechanisms involved in the natural forgetting of long-term memory and its possible functions are not fully understood. Based on our previous work describing the role of GluA2-containing AMPA receptors in memory maintenance, here, we tested their role in forgetting of long-term memory. We found that blocking their synaptic removal after long-term memory formation extended the natural lifetime of several forms of memory. In the hippocampus, it preserved spatial memories and inhibited contextual fear generalization; in the infralimbic cortex, it blocked the spontaneous recovery of extinguished fear. These findings suggest that a constitutive decay-like forgetting process erases long-term memories over time, which, depending on the memory removed, may critically contribute to developing adaptive behavioral responses.

Rapamycin restores BDNF-LTP and the persistence of long-term memory in a model of Down's syndrome

Down's syndrome (DS) is the most prevalent genetic intellectual disability. Memory deficits significantly contribute to the cognitive dysfunction in DS. Previously, we discovered that mTOR-dependent local translation, a pivotal process for some forms of synaptic plasticity, is deregulated in a DS mouse model. Here, we report that these mice exhibit deficits in both synaptic plasticity (i.e., BDNF-long term potentiation) and the persistence of spatial long-term memory. Interestingly, these deficits were fully reversible using rapamycin, a Food and Drug Administration-approved specific mTOR inhibitor; therefore, rapamycin may be a novel pharmacotherapy to improve cognition in DS.

The CPEB3 Protein Is a Functional Prion that Interacts with the Actin Cytoskeleton.

The mouse cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a translational regulator implicated in long-term memory maintenance. Invertebrate orthologs of CPEB3 in Aplysia and Drosophila are functional prions that are physiologically active in the aggregated state. To determine if this principle applies to the mammalian CPEB3, we expressed it in yeast and found that it forms heritable aggregates that are the hallmark of known prions. In addition, we confirm in the mouse the importance of CPEB3's prion formation for CPEB3 function. Interestingly, deletion analysis of the CPEB3 prion domain uncovered a tripartite organization: two aggregation-promoting domains surround a regulatory module that affects interaction with the actin cytoskeleton. In all, our data provide direct evidence that CPEB3 is a functional prion in the mammalian brain and underline the potential importance of an actin/CPEB3 feedback loop for the synaptic plasticity underlying the persistence of long-term memory.

The Persistence of Hippocampal-Based Memory Requires Protein Synthesis Mediated by the Prion-like Protein CPEB3

Consolidation of long-term memories depends on de novo protein synthesis. Several translational regulators have been identified, and their contribution to the formation of memory has been assessed in the mouse hippocampus. None of them, however, has been implicated in the persistence of memory. Although persistence is a key feature of long-term memory, how this occurs, despite the rapid turnover of its molecular substrates, is poorly understood. Here we find that both memory storage and its underlying synaptic plasticity are mediated by the increase in level and in the aggregation of the prion-like translational regulator CPEB3 (cytoplasmic polyadenylation element-binding protein). Genetic ablation of CPEB3 impairs the maintenance of both hippocampal long-term potentiation and hippocampus-dependent spatial memory. We propose a model whereby persistence of long-term memory results from the assembly of CPEB3 into aggregates. These aggregates serve as functional prions and regulate local protein synthesis necessary for the maintenance of long-term memory.

Persistence of Long-Term Memory in Vitrified and Revived Caenorhabditis elegans.

Can memory be retained after cryopreservation? Our research has attempted to answer this long-standing question by using the nematode worm Caenorhabditis elegans, a well-known model organism for biological research that has generated revolutionary findings but has not been tested for memory retention after cryopreservation. Our study's goal was to test C. elegans' memory recall after vitrification and reviving. Using a method of sensory imprinting in the young C. elegans, we establish that learning acquired through olfactory cues shapes the animal's behavior and the learning is retained at the adult stage after vitrification. Our research method included olfactory imprinting with the chemical benzaldehyde (C6H5CHO) for phase-sense olfactory imprinting at the L1 stage, the fast-cooling SafeSpeed method for vitrification at the L2 stage, reviving, and a chemotaxis assay for testing memory retention of learning at the adult stage. Our results in testing memory retention after cryopreservation show that the mechanisms that regulate the odorant imprinting (a form of long-term memory) in C. elegans have not been modified by the process of vitrification or by slow freezing.

Modeling maintenance of long-term potentiation in clustered synapses: long-term memory without bistability.

Memories are stored, at least partly, as patterns of strong synapses. Given molecular turnover, how can synapses maintain strong for the years that memories can persist? Some models postulate that biochemical bistability maintains strong synapses. However, bistability should give a bimodal distribution of synaptic strength or weight, whereas current data show unimodal distributions for weights and for a correlated variable, dendritic spine volume. Thus it is important for models to simulate both unimodal distributions and long-term memory persistence. Here a model is developed that connects ongoing, competing processes of synaptic growth and weakening to stochastic processes of receptor insertion and removal in dendritic spines. The model simulates long-term (>1 yr) persistence of groups of strong synapses. A unimodal weight distribution results. For stability of this distribution it proved essential to incorporate resource competition between synapses organized into small clusters. With competition, these clusters are stable for years. These simulations concur with recent data to support the “clustered plasticity hypothesis” which suggests clusters, rather than single synaptic contacts, may be a fundamental unit for storage of long-term memory. The model makes empirical predictions and may provide a framework to investigate mechanisms maintaining the balance between synaptic plasticity and stability of memory.

Zeta inhibitory peptide (ZIP) erases long-term memories in a cockroach

Recent efforts to identify the molecules that are involved in the maintenance of long-term memories in mammals have focused attention on atypical isoforms of protein kinase C (PKC). Inhibition of these kinases by either the general PKC inhibitor, chelerythrine, or the more specific inhibitor, zeta inhibitory peptide (ZIP), can abolish both long-term potentiation in the hippocampus and as well as spatial, fear, appetitive, and sensorimotor memories. These inhibitors can also abolish long-term facilitation and long-term sensitization in the mollusk Aplysia californica. We have extended these results to an insect, the cockroach Leucophaea maderae. We show that systemic injections of either chelerythrine or ZIP erase long-term olfactory memories in the cockroach, but have no effect on memory acquisition during conditioning. We also show that inhibition of either protein kinase A (PKA) or protein synthesis can block memory acquisition but neither has an effect on the memory once it is formed. The results suggest that sustaining memories in insects requires the persistent activity of one or more isoforms of PKC and point to a strong evolutionary conservation of the molecular mechanisms that underlie the persistence of long-term memories in the central nervous system.

Effect of morphine on the persistence of long-term memory in rats.

Current evidence suggests that pharmacological manipulation around 12 h after training alters the persistence of long-term memory. However, no study has addressed whether opioids modulate the persistence of fear. The current study examined whether morphine alters the persistence of the memory of contextual fear conditioning. Male adult Wistar rats were injected with saline (NaCl 0.9 %, intraperitoneally (i.p.)) or morphine (3 and/or 10 mg/kg, i.p.) 6, 9, 12, or 24 h post-training and tested 2 or 7 days after training, when freezing responses were assessed. The involvement of state dependence and opioid receptors in the effect of morphine was investigated by respectively injecting naloxone (1 mg/kg, i.p.) 30 min before morphine, and morphine (10 mg/kg, i.p.) 30 min before testing. Morphine (10 mg/kg, i.p., 12 h post-training) did not alter freezing to context in animals tested 2 days after training but impaired freezing to context when testing was carried out 7 or 14 days after training. Morphine (10 mg/kg, i.p.) administration 6, 9, or 24 h post-training did not alter freezing measured 2 or 7 days after training. Pre-test morphine improved recall but did not alter the deleterious effect of 12 h post-training morphine. The deleterious effect of morphine was prevented by naloxone, indicating that opioid receptors are involved in this effect. Our findings indicate an inhibitory role for opioid receptors in memory persistence. This is relevant from both the experimental and clinical point of views, since it may have implications for the prevention of post-traumatic stress disorder (PTSD).