Impairment Of Memory Reconsolidation Research Articles

Non-competitive NMDA antagonist MK-801 prevents memory reconsolidation impairment caused by protein synthesis inhibitors in young chicks.

Introduction: Reactivation of already consolidated memory can initiate its destabilization, making the memory trace labile. Normally, this destabilization is followed by reconsolidation of the memory trace, enriched by newly acquired experience. Disrupting the reconsolidation process, for example, by inhibiting protein synthesis, impairs subsequent memory retrieval, leading to reminder-related amnesia. Previous studies in various species have shown that this impairment can be prevented by using NMDA receptor antagonists, which interfere with memory destabilization. Methods: In the present study we examined this phenomenon using a one-trial passive avoidance learning model in newborn chicks, the hypothesis being that inactivation of the NMDA-mediated transmission during memory reactivation would inhibit the memory trace labilization and thus prevent the reminder-related amnesia. Results: We found that reminder-associated administration of the NMDA receptor antagonist MK-801 or one of the protein synthesis inhibitors (anisomycin, cycloheximide, 2-deoxygalactose) each alone produced amnesia. However, when combined, injection of MK-801 before the reminder prevented amnesia induced by protein synthesis inhibitors. Discussion: We suggest that the observed paradoxical effect implicates the involvement of NMDA receptors in both protein synthesis-independent engram destabilization upon its retrieval and protein synthesismediated engram stabilization after its updating. This puzzling dual role of NMDA receptors in memory destabilization/restabilization requires further investigation.

Corticosterone injection into the dorsal and ventral hippocampus impairs fear memory reconsolidation in a time-dependent manner in rats

Reconsolidation is an active process induced following the reactivation of previously consolidated memories. Recent studies suggest brain corticosteroid receptors may participate in the modulation of fear memory reconsolidation. Glucocorticoid receptors (GRs), with 10-fold lower affinity than mineralocorticoid receptors (MRs), are mainly occupied during the peak of the circadian rhythm, and after stress, so they probably have a more critical role than MRs in memory phases during stressful situations. This study investigated the role of dorsal and ventral hippocampal (DH and VH) GRs and MRs on fear memory reconsolidation in rats. Male Wistar rats with surgically implanted bilaterally cannulae at the DH and VH were trained and tested in an inhibitory avoidance task. The animals received bilateral microinjections of vehicle (0.3 µl/side), corticosterone (3 ng/0.3 µl/side), the GRs antagonist RU38486 (3 ng/0.3 µl/side), or the MRs antagonist spironolactone (3 ng/0.3 µl/side) immediately after memory reactivation. Moreover, drugs were injected into VH 90 min after memory reactivation. Memory tests were performed 2, 9, 11, and 13 days after memory reactivation. Results indicated that injection of corticosterone into the DH but not VH immediately after memory reactivation significantly impaired fear memory reconsolidation. Moreover, corticosterone injection into VH 90 min after memory reactivation impaired fear memory reconsolidation. RU38486, but not spironolactone reversed these effects. These findings indicate that corticosterone injection into the DH and VH via GRs activation impairs the reconsolidation of fear memory in a time-dependent manner.

Cannabidiol attenuates fear memory expression in female rats via hippocampal 5-HT1A but not CB1 or CB2 receptors

Growing evidence from male rodent and human studies suggests that cannabidiol (CBD) modulates the expression of aversive memories and anxiety-related responses. The limited data on whether and how CBD influences these aspects in females could have therapeutic implications given the increased susceptibility of women to anxiety- and stress-related disorders relative to men. Female studies are also essential to examine inherent aspects that potentially contribute to differences in responsiveness to CBD. Here we addressed these questions in adult female rats. Contextually fear-conditioned animals acutely treated with CBD (1.0–10 mg/kg) were tested 45 min later. In subsequent experiments, we investigated the estrous cycle effects and the contribution of dorsal hippocampus (DH) serotonin 1A (5-HT1A) and cannabinoid types 1 (CB1) and 2 (CB2) receptors to CBD-induced effects on memory retrieval/expression. The effects of pre-retrieval systemic or intra-DH CBD administration on subsequent fear extinction were also assessed. Lastly, we evaluated the open arms avoidance and stretched-attend postures in females exposed to the elevated plus-maze after systemic CBD treatment. CBD 3.0 and 10 mg/kg administered before conditioned context exposure reduced females' freezing. This action remained unchanged across the estrous cycle and involved DH 5-HT1A receptors activation. Pre-retrieval CBD impaired memory reconsolidation and lowered fear during early extinction. CBD applied directly to the DH was sufficient to reproduce the effects of systemic CBD treatment. CBD 3.0 and 10 mg/kg reduced anxiety-related responses scored in the elevated plus-maze. Our findings demonstrate that CBD attenuates the behavioral manifestation of learned fear and anxiety in female rats.

Comparative Study of the Effect of a DNA Methyltransferase Inhibitor and a Histone Deacetylase Inhibitor on Memory Formation Processes in Anterograde Amnesia.

The participation of DNA methylation and histone acetylation in the mechanisms of anterograde amnesia and memory recovery was studied on grape snails trained in conditioned food aversion. Anterograde amnesia developed 10 days after memory reconsolidation impairment with an NMDA glutamate receptor antagonist and was characterized by long-term memory formation impairment upon repeated training. DNA methyltransferase inhibitor injections to snails 1 h before repeated training, as well as 15 min or 4 h after repeated training, caused rapid formation of memory that persisted for at least 10 days. Injections of histone deacetylase inhibitor before repeated training also induced the formation of a stable long-term memory. However, administration of histone deacetylase inhibitor 15 min after repeated training initiated a temporary memory recovery. Injections of the inhibitor 4 h after repeated training were ineffective. These results indicate that histone-dependent chromatin remodeling and DNA methylation are selectively involved in the mechanisms of anterograde amnesia and memory recovery.

DNA methylation inhibition participates in the anterograde amnesia key mechanism through the suppression of the transcription of genes involved in memory formation in grape snails

The study of the amnesia mechanisms is of both theoretical and practical importance. The mechanisms of anterograde amnesia are the least studied, due to the lack of an experimental model that allows studying this amnesia type molecular and cellular mechanisms. Previously, we found that conditional food aversion memory reconsolidation impairment in snails by NMDA glutamate receptor antagonists led to the amnesia induction, in the late stages of which (>10 days) repeated training did not cause long-term memory formation. In the same animals, long-term memory aversion to a new food type was formed. We characterized this amnesia as specific anterograde amnesia. In the present work we studied the role of epigenetic DNA methylation processes as well as protein and mRNA synthesis in the mechanisms of anterograde amnesia and memory recovery. DNMT methyltransferase inhibitors (iDNMT: zebularine, RG108 (N-Phthalyl-1-tryptophan), and 5-AZA (5-Aza-2'-deoxycytidine)) were used to alter DNA methylation. It was found that in amnesic animals the iDNMT administration before or after shortened repeated training led to the rapid long-term conditional food aversion formation (Ebbinghaus saving effect). This result suggests that amnestic animals retain a latent memory, which is the basis for accelerated memory formation during repeated training. Protein synthesis inhibitors administration (cycloheximide) before or immediately after repeated training or administration of RNA synthesis inhibitor (actinomycin D) after repeated training prevented memory formation under iDNMT action. The earlier protein synthesis inhibitor effect suggests that the proteins required for memory formation are translated from the pre-existing, translationally repressed mRNAs. Thus, we have shown for the first time that the anterograde amnesia key mechanism is DNMT-dependent suppression of the transcription of genes involved in memory mechanisms. Inhibition of DNMT during repeated training reversed these genes expression blockade, opening access to them by transcription factors synthesized during training from the pre-existing mRNAs.

Evidence on the impairing effects of Ayahuasca on fear memory reconsolidation.

To uncover whether psychedelic drugs attenuate fear memory responses would advance the development of better psychedelic-based treatments for posttraumatic stress disorder (PTSD). Ayahuasca (AYA), a psychedelic brew containing indolamine N, N-dimethyltryptamine (DMT) and β-carbolines, facilitates fear extinction and improves neural plasticity. Upon retrieval, fear memory undergoes labilization and reconsolidation; however, the effects of AYA on this memory stabilization phase are unknown. We aimed to investigate the effects of AYA treatment on fear memory reconsolidation. Fear-conditioned Wistar rats received AYA (60, 120, or 240mg/kg) or H2O orally via gavage o.g. 20min before, immediately, or 3h after a short retrieval session. Analysis of AYA through liquid chromatography-tandem mass spectrometry was used to determine the content of DMT and β-carbolines in AYA. AYA impaired fear memory reconsolidation when given 20min before or 3h after memory retrieval, with the dose of 60mg/kg being effective at both moments. This dose of AYA was devoid of anxiolytic effect. Importantly, during retrieval, AYA did not change fear expression. The lack of retrieval abolished the reconsolidation impairing effect of AYA. The effects of AYA treatment 20min before or 3h aftermemory retrieval lasted at least 22days, suggesting no spontaneous recovery of fear memory. Fear memory impairments induced by AYA treatment, at both moments, do not show reinstatement. Our findings support the view that a low dose of AYA treatment impairs early and late stages of memory reconsolidation instead of facilitating fear extinction.

Role of prediction error and the cholinergic system on memory reconsolidation processes in mice

The ability to make predictions based on stored information is a general coding strategy. A prediction error (PE) is a mismatch between expected and current events. Our memories, like ourselves, are subject to change. Thus, an acquired memory can become active and update its content or strength by a labilization-reconsolidation process. Within the reconsolidation framework, PE drives the updating of consolidated memories. In the past our lab has made key progresses showing that a blockade in the central cholinergic system during reconsolidation can cause memory impairment, while reinforcement of cholinergic activity enhances it. In the present work we determined that PE is a necessary condition for memory to reconsolidate in an inhibitory avoidance task using both male and female mice. Depending on the intensity of the unconditioned stimulus (US) used during training, a negative (higher US intensity) or positive (lower US intensity/no US) PE on a retrieval session modified the behavioral response on a subsequent testing session. Furthermore, we demonstrated that the cholinergic system modulates memory reconsolidation only when PE is detected. In this scenario administration of oxotremorine, scopolamine or nicotine after memory reactivation either enhanced or impaired memory reconsolidation in a sex-specific manner.

NMDA Receptors Antagonist Prevents Memory Deficit Produced by Reconsolidation Impairment in Young Chicks

Alzheimer's disease is the most common cause of dementia. Despite numerous studies of its pathogenesis, processes leading to memory decay in Alzheimer's disease and tactics for its prevention are still in infancy. Here we propose a new hypothesis of memory autodegradation process in the brain compromised by neurodegeneration. A retrieval of an old consolidated memory, especially under conditions of novelty can render it to a labile form. This requires subsequent repeated consolidation, or reconsolidation. We argue that when an old memory is retrieved in the brain where reconsolidation processes are impaired by neurodegeneration, the original memory does not stabilize and degrades. Thus, being activated in a pathologically altered brain, memory trace weakens itself. If this suggestion is correct, then autodegradation of old memory in the impaired brain can be prevented by inhibiting its labilization during the retrieval. We started testing this hypothesis by employing a behavioral model of memory deficit produced by pharmacological impairment of memory reconsolidation in a one-trial passive avoidance learning model in young chicks (Gallus gallus domesticus). In previous experiments we demonstrated that retrieval of the passive avoidance memory paired with administration of a protein synthesis inhibitor anisomycin (ANI) or a glycosylation inhibitor 2-deoxygalactose (2DGal) resulted in the recall deficit. Here, we tested whether this memory impairment could be rescued by prevention of the memory labilization process. Two-days old chicks were trained in the passive avoidance learning model. Two hours after the training they were presented with a reminder paired with bilateral intraventricular administration of ANI (80 mkg) or 2DGal (3.28 mg) 5 min prior to the reminder. Additionally, 30 min before the reminder the animals received systemic administration of a non-competitive NMDA receptors antagonist MK801 (0.3 mg/kg) in order to access the possibility to prevent memory labilization and its effect. The control groups received physiological saline intraventricularly and intraperitoneally. The avoidance recall was tested 2 h after the reminder. The avoidance recall was significantly impaired in the animals which received ANI or 2DGal 5 min before the reminder as compared with control groups receiving no reminder or reminder coupled with physiological saline injection. Thus, inhibition of protein synthesis or glycoprotein fucosylation prevented reconsolidation of the reactivated memory producing amnesia. However, administration of NMDA antagonist MK801 prior to the inhibitor/reminder treatment prevented memory impairment resulting in high avoidance level that did not differ from the control groups recall. Thus, we have shown that memory deficit produced by memory retrieval under conditions of impaired protein synthesis can be protected by the preceding administration of NMDA receptor antagonist. We suggest that this effect might be due to prevention of reminder-induces memory trace destabilization which preserved the integrity of the original memory trace.

Protein synthesis inhibitor administration before a reminder caused recovery from amnesia induced by memory reconsolidation impairment with NMDA glutamate receptor antagonist

Memory recovery in amnestic animals is one of the most poorly studied processes. In this paper, we examine the role of protein synthesis and a reminder in the mechanisms of amnesia and memory recovery in grape snails trained to conditioned food aversion. Amnesia was induced by the impairment of memory reconsolidation using NMDA (N-methyl d-aspartate) glutamate receptor antagonists. In an early stage of amnesia (day 3), injections of protein synthesis inhibitors into animals combined with a reminder by a conditioned stimulus (CS) led to the recovery of aversive reactions to its presentation. Two types of changes in reactions to CS were revealed. In most animals, a persistent recovery of memory retrieval was found that lasted for at least 10 days. In other snails, aversive responses to CS persisted for 24 h. Isolated injections of inhibitors, injections of inhibitors and a reminder by the learning environment (without presenting a CS), usage of a differentiating stimulus instead of a CS, or inhibitor injections after the reminder did not affect the development of amnesia. The administration of protein synthesis inhibitors and a reminder in the late period after amnesia induction (10 days) did not affect its development or caused a short-term memory recovery. We suggest that amnesia is an active process that develops over time. The reminder induces the reactivation of the amnesia process dependent on protein synthesis, while the administration of protein synthesis inhibitors leads to the impairment of amnesia reactivation and recovery of the state formed before amnesia induction (i.e., recovery of conditioned food aversion memory).

Nucleus reuniens of the thalamus controls fear memory reconsolidation

The nucleus reuniens has been shown to support the acquisition, consolidation, maintenance, destabilization upon retrieval, and extinction of aversive memories. However, the direct participation of this thalamic subregion in memory reconsolidation is yet to be examined. The present study addressed this question in contextually fear-conditioned rats. Post-reactivation infusion of the GABAA receptor agonist muscimol, the glutamate N2A-containing NMDA receptor antagonist TCN-201, or the protein synthesis inhibitor anisomycin into the NR induced significant impairments in memory reconsolidation. Administering muscimol or TCN-201 and anisomycin locally, or associating locally infused muscimol or TCN-201 with systemically administered clonidine, an α2-receptor adrenergic agonist that attenuates the noradrenergic tonus associated with memory reconsolidation, produced no further reduction in freezing times when compared with the muscimol-vehicle, TCN-201-vehicle, vehicle-anisomycin, and vehicle-clonidine groups. This pattern of results indicates that such treatment combinations produced no additive/synergistic effects on reconsolidation. It is plausible that NR inactivation and antagonism of glutamate N2A-containing NMDA receptors weakened/prevented the subsequent action of anisomycin and clonidine because they disrupted the early stages of signal transduction pathways involved in memory reconsolidation. It is noteworthy that these pharmacological interventions, either alone or combined, induced no contextual memory specificity changes, as assessed in a later test in a novel and unpaired context. Besides, omitting memory reactivation precluded the impairing effects of muscimol, TCN-201, anisomycin, and clonidine on reconsolidation. Together, the present findings demonstrate interacting mechanisms through which the NR can regulate contextual fear memory restabilization.

The role of prelimbic and anterior cingulate cortices in fear memory reconsolidation and persistence depends on the memory age.

Reconsolidation is a time-limited process under which reactivated memory content can be modified. Works focused on studying reconsolidation mainly restrict intervention to the moments immediately after reactivation and to recently acquired memories. However, the brain areas activated during memory retrieval depend on when it was acquired, and it is relatively unknown how different brain sites contribute to reconsolidation and persistence of reactivated recent and remote fear memories. Here, we sought to investigate the participation of prelimbic (PL) and anterior cingulate cortices (ACC) in recent (1 d old) and remote (21 d old) fear memory reconsolidation and persistence. Male Wistar rats were submitted to the contextual fear conditioning protocol. Tamoxifen (TMX), an estrogen receptor modulator known to inhibit protein kinase C activity was used to interfere with these processes. When infused into the PL cortex, but not into the ACC, TMX administration immediately or 6 h after recent fear memory reactivation impaired memory reconsolidation and persistence, respectively. TMX administered immediately after remote memory reactivation impaired memory reconsolidation when infused into the PL cortex and ACC. However, remote memory persistence was only affected when TMX was infused 6 h after memory reactivation into the ACC and no effect was observed when TMX was infused 6 h after memory reactivation into PL cortex. Together, the findings provide further evidence on the participation of PL cortex and ACC in reconsolidation of recent and remote fear memories and suggest that the persistence of a reactivated fear memory becomes independent on the PL cortex with memory age and dependent on the ACC.

Acute Nicotine Treatment Alleviates LPS-Induced Impairment of Fear Memory Reconsolidation Through AMPK Activation and CRTC1 Upregulation in Hippocampus.

BackgroundFear memory is a fundamental capability for animals and humans to survive. Its impairment results in the disability to avoid danger. When memory is reactivated, a reconsolidation process, which can be disrupted by various stimuli, including inflammation, is required to become permanent. Nicotine has been shown to improve cognitive deficits induced by inflammation and other stimuli. Therefore, in the present study, we investigated the effect of nicotine on lipopolysaccharide (LPS)-induced impairment of fear memory reconsolidation and the underlying mechanism.MethodsStep-through inhibitory avoidance task was recruited to study fear memory of rat, i.p. LPS (0.5 mg/kg) treatment was used to induce inflammation, and western blot and immunostaining were applied to detect protein expression and distribution in medial prefrontal cortex and hippocampus.ResultsOur data showed that LPS induced fear memory reconsolidation impairment without affecting retrieval. In addition, LPS significantly increased inflammation factors tumor necrosis factor-α and interleukin-1 beta and decreased CREB-regulated transcription coactivator 1 (CRTC1) expression and adenosine monophosphate-activated protein kinase (AMPK) activation in hippocampus. More importantly, LPS significantly decreased CRTC1 expression and AMPK activation in neurons by activating microglia cells. Of note, either nicotine treatment or activation of AMPK by intracerebroventricular infusion of metformin reduced LPS-induced impairment of fear memory reconsolidation and ameliorated inflammation factor tumor necrosis factor-α and interleukin-1 beta as well as the expression of CRTC1.ConclusionsIn conclusion, our results showed that acute nicotine treatment alleviates LPS-induced impairment of fear memory reconsolidation through activation of AMPK and upregulation of CRTC1 in hippocampus.

Peculiarities in Synthesis of Proteins Implicated in Memory Reconsolidation and Induction of Amnesia.

The peculiarities of implication of NMDA glutamate receptors and protein synthesis into the mechanisms responsible for impairment of memory reconsolidation were studied in edible snails conditioned to food aversion. Injections of NMDA glutamate receptor antagonists or protein synthesis inhibitor prior to reminding with conditioned food stimulus provoked development of amnesia after different latent periods. NMDA glutamate receptor antagonists gradually weakened the aversive reactions to conditioned stimulus presented in parallel with reminder during 1 h. The protein synthesis inhibitor cycloheximide provoked the development of amnesia only 2.5 h after the onset of reminding procedure. Combined injections of protein synthesis inhibitor and NMDA glutamate receptor antagonist prior to reminding completely prevented the development of amnesia. The data agree with hypothesis that memory reconsolidation and amnesia are distinct processes, which need activation of synthesis of specific proteins.

Regulation of Garcinol on Histone Acetylation in the Amygdala and on the Reconsolidation of a Cocaine-Associated Memory.

Exposure to drug-related cues often disrupts abstinence from cocaine use by triggering memories of drug effects, leading to craving and possible relapse. One prospective method of treatment is weakening cocaine-associated memories via impairment of memory reconsolidation. Previous experiments have shown that systemic injection of the amnestic agent garcinol impairs the reconsolidation of cocaine-cue memories in a temporally constrained, cue-specific, and persistent manner. Here, we investigated garcinol’s effect on cocaine-cue memory reconsolidation when administered to the lateral nucleus of the amygdala (LA), as well as its epigenetic activity following systemic garcinol administration and also when given in conjunction with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor. Rats received 12 days of cocaine self-administration training during which time an active lever press resulted in an i.v. cocaine infusion that was concurrently paired with the presentation of a light/tone cue. After 8 days of lever extinction, rats received a memory reactivation session followed by a cue-induced reinstatement test. Intra-LA garcinol following memory reactivation significantly impaired reconsolidation only if the memory was reactivated. Additional studies revealed a significant reduction in histone H3 K27 acetylation and reduced expression of the immediate-early genes Arc and Egr-1 in the LA. When administered alone, TSA enhanced the reinstatement of a cocaine-cue memory, an effect that was prevented when garcinol was concurrently administered. These data indicate the LA is a key structure responsive to garcinol, suggest that one of garcinol’s mechanisms of action is through the reduction of memory-related gene expression in the LA, implicate changes in histone acetylation in memory reconsolidation, and support garcinol as a potential therapeutic tool for sustaining abstinence.

Proteins or RNA synthesis inhibitors suppressed induction of amnesia developing under impairment of memory reconsolidation by serotonin receptors antagonist

Studies have shown that retrieval of long-term memory can cause memory reconsolidation, and impaired reconsolidation leads to amnesia development. However, the mechanisms of amnesia induction due to impaired memory reconsolidation remains poorly described. Using experiments involving grape snails trained to conditioned food aversion, we studied the role of translation and transcription processes and the role of serotonin receptors in the mechanisms of amnesia induction. We found that administration of a serotonin receptor antagonist or a protein synthesis inhibitor before the administration of a reminder using a conditioned food stimulus induced amnesia development, whereas injections of mRNA synthesis inhibitor did not affect memory safety. Moreover, combined injections of an antagonist of serotonin receptor and inhibitors of protein or mRNA synthesis before reminder administration completely prevented amnesia development. In addition, inhibitors of protein or mRNA synthesis prevented amnesia development 3 h but not 9 h after the administration of a serotonin receptor antagonist/reminder. We hypothesize that the mechanisms of amnesia induction caused by impaired memory reconsolidation depend on protein and mRNA syntheses within a certain time window, similar to the mechanisms of induction of other long-term plastic brain rearrangements.

Administration of Protein Synthesis Inhibitor before Reminder Reverses Amnesia Induced by Memory Reconsolidation Impairment with 5-HT Receptors Antagonist.

Administration of 5-HT receptor antagonist to snails trained in conditioned food aversion prior to reminding of the conditioning stimulus caused amnesia. At the early period of amnesia (day 3), injections of protein synthesis inhibitor cycloheximide without reminder or reminder alone were ineffective. At the same time, injections of the inhibitor combined with reminder led to memory recovery; this effect in most animals persisted for at least 10 days. In the rest snails, aversive responses to presentations of the conditioning stimulus persisted for 2 days. Cycloheximide injection and reminder in 10 days after induction of amnesia did not affect its development or caused a transient memory recovery (2 days). We hypothesized that amnesia is an active process unfolding in time. One of mechanism of this process is reminder-induced and protein synthesis-depended reactivation of amnesia. Inhibitor of protein synthesis disturbed this reactivation and led to recovery of the initial memory of conditioned food aversion.

NMDA or 5-HT receptor antagonists impair memory reconsolidation and induce various types of amnesia

Elucidation of amnesia mechanisms is one of the central problems in neuroscience with immense practical application. Previously, we found that conditioned food presentation combined with injection of a neurotransmitter receptor antagonist or protein synthesis inhibitor led to amnesia induction. In the present study, we investigated the time course and features of two amnesias: induced by impairment of memory reconsolidation using an NMDA glutamate receptor antagonist (MK-801) and a serotonin receptor antagonist (methiothepin, MET) on snails trained with food aversion conditioning. During the early period of amnesia (<10th day), the unpaired presentation of conditioned stimuli (CS) or unconditioned stimuli (US) in the same training context did not have an effect on both types of amnesia. Retraining an on 1st or 3rd day of amnesia induction facilitated memory formation, i.e. the number of CS + US pairings was lower than at initial training. On the 10th or 30th day after the MET/reminder, the number of CS + US pairings did not change between initial training and retraining. Retraining on the 10th or 30th day following the MK-801/reminder in the same or a new context of learning resulted in short, but not long-term, memory, and the number of CS + US pairings was higher than at the initial training. This type of amnesia was specific to the CS we used at initial training, since long-term memory for another kind of CS could be formed in the same snails. The attained results suggest that disruption of memory reconsolidation using antagonists of serotonin or NMDA glutamate receptors induced amnesias with different abilities to form long-term memory during the late period of development.

Retrieval-Induced Upregulation of Tet3 in Pyramidal Neurons of the Dorsal Hippocampus Mediates Cocaine-Associated Memory Reconsolidation.

BackgroundMemory retrieval refers to reexposure to information previously encoded and stored in the brain. Following retrieval, a once-consolidated memory destabilizes and undergoes reconsolidation, during which gene expression changes to restabilize memory. Investigating epigenetic regulation during reconsolidation could provide insights into normal memory formation and pathological memory associated with psychiatric disorders.MethodsWe used cocaine-induced conditioned place preference to assess the cocaine-associated memory of mice and used chemogenetic methods to manipulate the activity of the pyramidal neurons in the dorsal hippocampus. We isolated the ribosome-associated transcripts from the excitatory neurons in the dorsal hippocampus by RiboTag purification to identify the potential epigenetic regulators, and we specifically knocked down gene expression in pyramidal neurons with a Cre-dependent lentivirus.ResultsChemogenetically silencing the activity of the pyramidal neurons in the dorsal hippocampus immediately after memory retrieval markedly impaired memory reconsolidation, and the ribosome-associated mRNA level of the ten-eleven translocation (Tet) family methylcytosine dioxygenase Tet3, but not Tet1 or Tet2, was dramatically upregulated 10 minutes after memory retrieval. The protein level of Tet3 in the dorsal hippocampus but not in the anterior cingulate cortex was dramatically increased 1 hour after memory retrieval. Specifically, knockdown of Tet3 in pyramidal neurons in the dorsal hippocampus decreased the activation of pyramidal neurons and impaired the reconsolidation of cocaine-associated memory.ConclusionsOur findings highlight the new function of the DNA demethylation regulator Tet3 in pyramidal neurons of the dorsal hippocampus in regulating the reconsolidation of cocaine-associated memory.

Involvement of Glycogen Synthase Kinase-3 in the Mechanisms of Conditioned Food Aversion Memory Reconsolidation.

Experiments were performed on the snails trained in conditioned food aversion for 3 days. Injection of TDZD-8 (glycogen synthase kinase-3 inhibitor, 2 mg/kg) in combination with reminder (presentation of a conditioned food stimulus) led to memory impairment developing 3 days after inhibitor/reminder exposure and followed by spontaneous recovery in 10 days. Injections of TDZD-8 in a dose of 4 or 20 mg/kg before reminder were shown to cause amnesia that persisted for more than 10 days. Memory recovery during repeated training was observed at the earlier period than after initial training. The impairment of memory reconsolidation by TDZD-8 after training of snails for 1 day was less pronounced than under standard training conditions (3 days). The effect of a glycogen synthase kinase-3 inhibitor during memory reconsolidation is probably followed by impairment of memory retrieval and/or partial loss, which can be compensated spontaneously or after repeated training.

Bidirectional Effects of Cannabidiol on Contextual Fear Memory Extinction.

Cannabidiol (CBD) has been established to have both acute and long-lasting effects to reduce fear memory expression. The long-lasting impact might be mediated by an enhancement of memory extinction or an impairment of memory reconsolidation. Here, we directly compared the effects of i.p. injections of cannabidiol (10 mg/kg) with those of the NMDA receptor antagonist MK-801 (0.1 mg/kg) and partial agonist D-cycloserine (DCS; 15 mg/kg) in order to determine the mnemonic basis of long-term fear reduction. We showed that under conditions of strong fear conditioning, CBD reduced contextual fear memory expression both acutely during the extinction session as well as later at a fear retention test. The latter test reduction was replicated by DCS, but MK-801 instead elevated test freezing. In contrast, when initial conditioning was weaker, CBD and MK-801 had similar effects to increase freezing at the fear retention test relative to vehicle controls, whereas DCS had no observable impact. This pattern of results is consistent with CBD enhancing contextual fear memory extinction when the initial conditioning is strong, but impairing extinction when conditioning is weak. This bidirectional effect of CBD may be related to stress levels induced by conditioning and evoked at retrieval during extinction, rather than the strength of the memory per se.