Consolidation Of Contextual Fear Memory Research Articles

No impairment of contextual fear memory consolidation by oxytocin receptor antagonism in male rats

Oxytocin is a peptide released into brain regions associated with the processing of aversive memory and threat responses. Given the expression of oxytocin receptors across this vigilance surveillance system of the brain, we investigated whether pharmacological antagonism of the receptor would impact contextual aversive conditioning and memory. Adult male rats were conditioned to form an aversive contextual memory. The effects of peripheral administration of either the competitive antagonist Atosiban or noncompetitive antagonist L-368,899 were compared to saline controls. Oxytocin receptor antagonism treatment did not significantly impact the consolidation of aversive contextual memory in any of the groups. We conclude that peripheral antagonism of oxytocin signalling did not impact the formation of aversive memory.

The Post-conditioning Acute Strength Exercise Facilitates Contextual Fear Memory Consolidation Via Hippocampal N-methyl-D-aspartate-receptors

The benefits of aerobic exercises for memory are known, but studies of strength training on memory consolidation are still scarce. Exercise stimulates the release of metabolites and myokines that reaching the brain stimulate the activation of NMDA-receptors and associated pathways related to cognition and synaptic plasticity. The aim of the present study was to investigate whether the acute strength exercise could promote the consolidation of a weak memory. We also investigated whether the effects of strength exercise on memory consolidation and on the BDNF and synapsin I levels depends on the activation of NMDA-receptors. Male Wistar rats were submitted to strength exercise session after a weak training in contextual fear conditioning paradigm to investigate the induction of memory consolidation. To investigate the participation of NMDA-receptors animals were submitted to contextual fear training and strength exercise and infused with MK801 or saline immediately after exercise. To investigate the participation of NMDA-receptors in BDNF and synapsin I levels the animals were submitted to acute strength exercise and infused with MK801 or saline immediately after exercise (in absence of behavior experiment). Results showed that exercise induced the consolidation of a weak memory and this effect was dependent on the activation of NMDA-receptors. The hippocampal overexpression of BDNF and Synapsin I through exercise where NMDA-receptors dependent. Our findings showed that strength exercise strengthened fear memory consolidation and modulates the overexpression of BDNF and synapsin I through the activation of NMDA-receptors dependent signaling pathways.

Increased hippocampal CREB phosphorylation after retrieval of remote contextual fear memories in Carioca high-conditioned freezing rats

The participation of the hippocampal formation in consolidation and reconsolidation of contextual fear memories has been widely recognized and known to be dependent on the activation of the cAMP response element (CRE) binding protein (CREB) pathway. Recent findings have challenged the prevailing view that over time contextual fear memories migrate to neocortical circuits and no longer require the hippocampus for retrieval of remote fearful memories. It has also recently been found that this brain structure is important for the maintenance and recall of remote fear memories associated with aversive events, a common trait in stress-related disorders such as generalized anxiety disorder (GAD), major depression, and post-traumatic stress disorder. In view of these findings, here we examined the putative role of CREB in the hippocampus of an animal model of GAD during the retrieval of remote contextual fear memories. Specifically, we evaluated CREB phosphorylation in the hippocampus of male Carioca High- and Low-conditioned Freezing rats (CHF and CLF, respectively) upon re-exposure of animals to contextual cues associated to footshocks weeks after fear conditioning. Age-matched male rats from a randomized crossbreeding population served as controls (CTL). Adrenal catecholamine levels were also measured as a biological marker of stress response. Seven weeks after contextual fear conditioning, half of the sample of CHF (n = 9), CLF (n = 10) and CTL (n = 10) rats were randomly assigned to return to the same context chamber where footshocks were previously administrated (Context condition), while the remaining animals were individually placed in standard housing cages (Control condition). Western blot results indicated that pCREB levels were significantly increased in the hippocampus of CHF rats for both Context and Control conditions when compared to the other experimental groups. CHF rats in the Context condition also exhibited significant more freezing than that observed for both CLF and CTL rats. Lastly, CHF animals in the Context condition displayed significantly higher adrenal catecholamine levels than those in the Control condition, whereas no differences in catecholamine levels were observed between Context and Control conditions for CLF and CTL rats. These findings are discussed from a perspective in which the hippocampus plays a role in the maintenance and recall of remote contextual fear memories via the CREB pathway.

Consolidation, reconsolidation, and extinction of contextual fear memory depend on de novo protein synthesis in the locus coeruleus

Memory consolidation is the process underlying the stabilization of labile short-term memory and the generation of long-term memory for persistent memory storage. The retrieval of contextual fear memory induces two distinct and opposite memory processes: reconsolidation and extinction. Reconsolidation re-stabilizes retrieved memory for re-storage, whereas memory extinction weakens fear memory and generates a new inhibitory memory. Importantly, the requirement for new gene expression is a critical biochemical feature of the consolidation, reconsolidation, and long-term extinction of memory. The locus coeruleus (LC) is a small nucleus in the brain stem that is composed predominantly of noradrenergic neurons that project to many brain regions. Recent studies have shown that the LC plays modulatory roles in the consolidation and extinction of auditory fear memory through its projections to brain regions contributing to memory storage. Here, we show that the LC is required for the consolidation, reconsolidation, and long-term extinction of contextual fear memory. We first observed that c-fos expression was induced in the LC following contextual fear conditioning to induce consolidation and following short and long re-exposure to the conditioning context to induce reconsolidation and long-term extinction, respectively. More importantly, inhibition of protein synthesis in the LC by a micro-infusion of anisomycin blocked the consolidation, reconsolidation, and long-term extinction of contextual fear memory. Our findings suggest that consolidation, reconsolidation, and long-term extinction occur in the LC and that the LC plays an essential role in memory storage and maintenance.

Insulin enhances contextual fear memory independently of its effect in increasing plasma adrenaline

AimsAdrenaline enhances contextual fear memory consolidation possibly by activating liver β2-adrenoceptors causing transient hyperglycaemia. Contrastingly, insulin-induced hypoglycaemia may culminate in blood adrenaline increment, hidering the separation of each hormone's action in contextual fear memory. Therefore, an adrenaline-deficient mouse model was used aiming to investigate if contextual fear memory consolidation following insulin administration requires or not subsequent increases in plasma adrenaline, which occurs in response to insulin-induced hypoglycemia. Main methodsFear conditioning was performed in wild-type (WT) and adrenaline-deficient (Pnmt-KO) male mice (129 × 1/SvJ) treated with insulin (2 U/kg, intraperitoneal (i.p.)) or vehicle (0.9 % NaCl (i.p.)). Blood glucose was quantified. Catecholamines were quantified using HPLC with electrochemical detection. Quantitative real-time polymerase chain reaction was used to assess mRNA expression of hippocampal Nr4a1, Nr4a2, Nr4a3, and Bdnf genes. Key findingsInsulin-treated WT mice showed increased freezing behaviour when compared to vehicle-treated WT mice. Also, plasma dopamine, noradrenaline, and adrenaline increased in this group. Insulin-treated Pnmt-KO animals showed increased freezing behaviour when compared with respective vehicle. However, no changes in plasma or tissue catecholamines were identified in insulin-treated Pnmt-KO mice when compared with respective vehicle. Furthermore, insulin-treated Pnmt-KO mice presented increased Bdnf mRNA expression when compared to vehicle-treated Pnmt-KO mice. SignificanceConcluding, enhanced freezing behaviour after insulin treatment, even in adrenaline absence, may indicate a key role of insulin in contextual fear memory. Insulin may cause central molecular changes promoting contextual fear memory formation and/or retrieval. This work may indicate a further role of insulin in the process of contextual fear memory modulation.

Cannabidiol modulates contextual fear memory consolidation in animals with experimentally induced type-1 diabetes mellitus.

In view of the neuroprotective characteristic of cannabidiol (CBD) and its beneficial action on aversive memory in non-diabetic animals, we aimed to investigate in animals with experimentally induced type-1 diabetes mellitus (T1DM) whether CBD treatment would be able to impair the contextual fear memory consolidation, its generalisation and whether the effect would be lasting. We also investigated the CBD effect on anxiety-like responses. After T1DM induction, animals received single or more prolonged treatment with CBD and were submitted to the contextual fear conditioning test. As expression of activity-regulated cytoskeletal-associated (Arc) protein is necessary for memory consolidation, we evaluated its expression in the dorsal hippocampus (DH). For evaluating anxiety-related responses, animals were submitted to the elevated plus maze test (EPMT), in which the time and number of entries in the open arms were used as anxiety index. A single injection of CBD impaired the contextual fear memory consolidation and its generalisation, which was evaluated by exposing the animal in a neutral context. This single injection was able to reduce the elevated expression of Arc in the DH from these animals. Interestingly, more prolonged treatment with CBD also impaired the persistence of context-conditioned fear memory and induced an anxiolytic-like effect, as the treated group spent more time in the open arms of the EPMT. CBD interferes with contextual fear memory and the dosage regimen of treatment seems to be important. Moreover, we cannot rule out the involvement of emotional aspects in these processes related to fear memory.

Neocortical synaptic engrams for remote contextual memories

While initial encoding of contextual memories involves the strengthening of hippocampal circuits, these memories progressively mature to stabilized forms in neocortex and become less hippocampus dependent. Although it has been proposed that long-term storage of contextual memories may involve enduring synaptic changes in neocortical circuits, synaptic substrates of remote contextual memories have been elusive. Here we demonstrate that the consolidation of remote contextual fear memories in mice correlated with progressive strengthening of excitatory connections between prefrontal cortical (PFC) engram neurons active during learning and reactivated during remote memory recall, whereas the extinction of remote memories weakened those synapses. This synapse-specific plasticity was CREB-dependent and required sustained hippocampal signals, which the retrosplenial cortex could convey to PFC. Moreover, PFC engram neurons were strongly connected to other PFC neurons recruited during remote memory recall. Our study suggests that progressive and synapse-specific strengthening of PFC circuits can contribute to long-term storage of contextual memories.

Atypical hypnotic compound ML297 restores sleep architecture immediately following emotionally valenced learning, to promote memory consolidation and hippocampal network activation during recall.

Sleep plays a critical role in consolidating many forms of hippocampus-dependent memory. While various classes of hypnotic drugs have been developed in recent years, it remains unknown whether, or how, some of them affect sleep-dependent memory consolidation mechanisms. We find that ML297, a recently developed candidate hypnotic agent targeting a new mechanism (activating GIRK1/2-subunit containing G-protein coupled inwardly rectifying potassium [GIRK] channels), alters sleep architecture in mice over the first 6 hr following a single-trial learning event. Following contextual fear conditioning (CFC), ML297 reversed post-CFC reductions in NREM sleep spindle power and REM sleep amounts and architecture, renormalizing sleep features to what was observed at baseline, prior to CFC. Renormalization of post-CFC REM sleep latency, REM sleep amounts, and NREM spindle power were all associated with improved contextual fear memory (CFM) consolidation. We find that improvements in CFM consolidation due to ML297 are sleep-dependent, and are associated with increased numbers of highly activated dentate gyrus (DG), CA1, and CA3 neurons during CFM recall. Together our findings suggest that GIRK1/2 channel activation restores normal sleep architecture- including REM sleep, which is normally suppressed following CFC-and increases the number of hippocampal neurons incorporated into the CFM engram during memory consolidation.

MTORC1 function in hippocampal parvalbumin interneurons: regulation of firing and long-term potentiation of intrinsic excitability but not long-term contextual fear memory and context discrimination

Hippocampal CA1 parvalbumin-expressing interneurons (PV INs) play a central role in controlling principal cell activity and orchestrating network oscillations. PV INs receive excitatory inputs from CA3 Schaffer collaterals and local CA1 pyramidal cells, and they provide perisomatic inhibition. Schaffer collateral excitatory synapses onto PV INs express Hebbian and anti-Hebbian types of long-term potentiation (LTP), as well as elicit LTP of intrinsic excitability (LTPIE). LTPIE requires the activation of type 5 metabotropic glutamate receptors (mGluR5) and is mediated by downregulation of potassium channels Kv1.1. It is sensitive to rapamycin and thus may involve activation of the mammalian target of rapamycin complex 1 (mTORC1). LTPIE facilitates PV INs recruitment in CA1 and maintains an excitatory-inhibitory balance. Impaired CA1 PV INs activity or LTP affects network oscillations and memory. However, whether LTPIE in PV INs plays a role in hippocampus-dependent memory remains unknown. Here, we used conditional deletion of the obligatory component of mTORC1, the Regulatory-Associated Protein of mTOR (Raptor), to directly manipulate mTORC1 in PV INs. We found that homozygous, but not heterozygous, conditional knock-out of Rptor resulted in a decrease in CA1 PV INs of mTORC1 signaling via its downstream effector S6 phosphorylation assessed by immunofluorescence. In whole-cell recordings from hippocampal slices, repetitive firing of CA1 PV INs was impaired in mice with either homozygous or heterozygous conditional knock-out of Rptor. High frequency stimulation of Schaffer collateral inputs that induce LTPIE in PV INs of control mice failed to do so in mice with either heterozygous or homozygous conditional knock-out of Rptor in PV INs. At the behavioral level, mice with homozygous or heterozygous conditional knock-out of Rptor showed similar long-term contextual fear memory or contextual fear memory discrimination relative to control mice. Thus, mTORC1 activity in CA1 PV INs regulates repetitive firing and LTPIE but not consolidation of long-term contextual fear memory and context discrimination. Our results indicate that mTORC1 plays cell-specific roles in synaptic plasticity of hippocampal inhibitory interneurons that are differentially involved in hippocampus-dependent learning and memory.

MiRNA-126a-3p participates in hippocampal memory via alzheimer’s disease-related proteins

Memory formation and consolidation necessitate gene expression and new protein synthesis. MicroRNAs (miRNAs), a family of small noncoding RNAs that inhibit target gene mRNA expression, are involved in new memory formation. In this study, elevated miR-126a-3p (miR-126) levels were found to contribute to the consolidation of contextual fear memory. Using different commonly mined algorithms and luciferase reporter assay, we found two Alzheimer's disease (AD)-related proteins, namely EFHD2 and BACE1, but not ADAM9, were the targets downregulated by miR-126 after CFC training. Moreover, we indicated that upregulated miR-126 could promote the formation of contextual fear memory by modulating its target EFHD2. Finally, we demonstrated that miR-126 overexpression in dentate gyrus of hippocampus could reduce Aβ plaque area and neuroinflammation, as well as rescue the hippocampal memory deficits in APP/PS1 mice. This study adds to the growing body of evidence for the role of miRNAs in memory formation and demonstrates the implication of EFHD2 protein regulated by miR-126 in the adult brain.

Effects of hippocampal IP3R inhibition on contextual fear memory consolidation, retrieval, reconsolidation and extinction

Intracellular calcium stores (ICS) play a dynamic role in neuronal calcium (Ca2+) homeostasis both by buffering Ca2+ excess in the cytoplasm or providing an additional source of Ca2+ when concentration increase is needed. However, in spite of the large body of evidence showing Ca2+ as an essential second messenger in many signaling cascades underlying synaptic plasticity, the direct involvement of the intracellular Ca2+-release channels (ICRCs) in memory processing has been highly overlooked. Here we investigated the role of the ICRC inositol 1,4,5-trisphosphate receptor (IP3R) activity during different memory phases using pharmacological inhibition in the dorsal hippocampus during contextual fear conditioning. We first found that post-training administration of the IP3R antagonist 2-aminoethyl diphenylborinate (2-APB) impaired memory consolidation in a dose and time-dependent manner. Inhibiting IP3Rs also disrupted memory retrieval. Contextual fear memory reconsolidation or extinction, however, were not sensitive to IP3R blockade. Taken together, our results indicate that hippocampal IP3Rs play an important role in contextual fear memory consolidation and retrieval.

Sulfur dioxide derivatives attenuates consolidation of contextual fear memory in mice

Post-traumatic stress disorder (PTSD) is characterized by an enhancement of traumatic memory. Intervention strategies based on the different stages of memory have been shown to be effective in the prevention and control of PTSD. The endogenous gaseous molecule, sulfur dioxide (SO2), has been reported to significantly exert neuromodulatory effects; however, its regulation of learning and memory remains unestablished. This study aimed to investigate the effects of exogenous SO2 derivatives administration on the formation, consolidation, reconsolidation, retention, and expression of contextual fear memory. Behavioral results showed that both intraperitoneal injection (50 mg/kg, ip) and hippocampal infusion (5 μg/side) of SO2 derivatives (a mixture of sodium sulfite and sodium bisulfite, Na2SO3/NaHSO3, 3:1 M/M) significantly impaired consolidation but had no effect on reconsolidation and retention of contextual fear memory. These findings suggest that the attenuating effects of SO2 on the consolidation of fear memory involves, at least partially, the region of the hippocampus. The findings of this study provide direct evidence for the development of new strategies for PTSD prevention and treatment involving the use of gaseous SO2.

Molecular motor KIF3B in the prelimbic cortex constrains the consolidation of contextual fear memory

Molecular and cellular mechanisms underlying the role of the prelimbic cortex in contextual fear memory remain elusive. Here we examined the kinesin family of molecular motor proteins (KIFs) in the prelimbic cortex for their role in mediating contextual fear, a form of associative memory. KIFs function as critical mediators of synaptic transmission and plasticity by their ability to modulate microtubule function and transport of gene products. However, the regulation and function of KIFs in the prelimbic cortex insofar as mediating memory consolidation is not known. We find that within one hour of contextual fear conditioning, the expression of KIF3B is upregulated in the prelimbic but not the infralimbic cortex. Importantly, lentiviral-mediated knockdown of KIF3B in the prelimbic cortex produces deficits in consolidation while reducing freezing behavior during extinction of contextual fear. We also find that the depletion of KIF3B increases spine density within prelimbic neurons. Taken together, these results illuminate a key role for KIF3B in the prelimbic cortex as far as mediating contextual fear memory.

SALM4 negatively regulates NMDA receptor function and fear memory consolidation

Many synaptic adhesion molecules positively regulate synapse development and function, but relatively little is known about negative regulation. SALM4/Lrfn3 (synaptic adhesion-like molecule 4/leucine rich repeat and fibronectin type III domain containing 3) inhibits synapse development by suppressing other SALM family proteins, but whether SALM4 also inhibits synaptic function and specific behaviors remains unclear. Here we show that SALM4-knockout (Lrfn3−/−) male mice display enhanced contextual fear memory consolidation (7-day post-training) but not acquisition or 1-day retention, and exhibit normal cued fear, spatial, and object-recognition memory. The Lrfn3−/− hippocampus show increased currents of GluN2B-containing N-methyl-d-aspartate (NMDA) receptors (GluN2B-NMDARs), but not α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors (AMPARs), which requires the presynaptic receptor tyrosine phosphatase PTPσ. Chronic treatment of Lrfn3−/− mice with fluoxetine, a selective serotonin reuptake inhibitor used to treat excessive fear memory that directly inhibits GluN2B-NMDARs, normalizes NMDAR function and contextual fear memory consolidation in Lrfn3−/− mice, although the GluN2B-specific NMDAR antagonist ifenprodil was not sufficient to reverse the enhanced fear memory consolidation. These results suggest that SALM4 suppresses excessive GluN2B-NMDAR (not AMPAR) function and fear memory consolidation (not acquisition).

028 Sleep loss disrupts hippocampal memory consolidation via an acetylcholine- and somatostatin interneuron-mediated inhibitory gate

Abstract Introduction Sleep loss profoundly disrupts consolidation of hippocampus-dependent memory. To better characterize effects of learning and sleep loss on the hippocampal circuit, we quantified activity-dependent phosphorylation of ribosomal subunit S6 (pS6) across the dorsal hippocampus of mice. Methods We first measured pS6 throughout the hippocampus after learning (single trial contextual fear conditioning; CFC), and after subsequent sleep or sleep deprivation (SD). To characterize cell populations with activity affected by SD, we used translating ribosome affinity purification (TRAP)-seq to identify cell type-specific transcripts on pS6 ribosomes after SD vs. sleep. We next used pharmacogenetics to mimic the effects of SD, selectively activating hippocampal Sst+ interneurons or cholinergic inputs to hippocampus from the medial septum (MS) while mice slept in the hours following CFC. We also inhibited these neuronal populations to assess effects on memory consolidation. Results We find that pS6 in enhanced in the dentate gyrus (DG) following single-trial CFC, but is reduced throughout the hippocampus after brief SD – a manipulation which disrupts contextual fear memory (CFM) consolidation. Cell type-specific enrichment analysis (CSEA) of these transcripts revealed that hippocampal somatostatin-expressing (Sst+) interneurons, and cholinergic and orexinergic inputs to hippocampus, are selectively activated after SD. We used TRAP targeted to hippocampal Sst+ interneurons to identify cellular mechanisms mediating SD-driven Sst+ interneuron activation. . We find that activation of Sst+ interneurons is sufficient to disrupt CFM consolidation, by gating activity in surrounding pyramidal neurons, while inhibition of Sst+ interneurons enhances memory consolidation. Similarly, pharmacogenetic activation of cholinergic input to hippocampus from the MS disrupted CFM. Inhibition of MS cholinergic neurons promoted CFM consolidation and disinhibited neurons in the DG, increasing pS6 expression among DG granule cells. Conclusion Our data suggest that state-dependent gating of DG activity during SD is mediated by cholinergic input. Together these data provide evidence for an inhibitory gate on hippocampal information processing, which is activated by sleep loss. Support (if any) R01-NS118440 to SJA from NINDS, DP2-MH104119 to SJA from the NIH Director’s Office, and a Human Frontiers Science Program Young Investigator Award

054 Characterization of Sleep Phenotypes and Sleep-Dependent Memory Consolidation in a Mouse Model of Fragile X Syndrome

Abstract Introduction Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by disruption of Fmr1 gene function, leading to intellectual disability. FXS individuals report increased incidence of sleep disruptions such as loss of NREM sleep, irregular sleep/wake cycles, and circadian rhythm disturbances that warrant pharmacological intervention. Since sleep has critical roles in the promotion of memory consolidation, it is unknown whether disrupted cognitive function in FXS is exacerbated by abnormal sleep. We characterized the link between sleep loss phenotypes and cognition in FXS mice (Fmr1 KO). We hypothesized that normalizing sleep in Fmr1 KO mice could improve sleep-dependent cognitive function. Because direct activation of G-protein inward rectifying potassium (GIRK) channels by ML297 has been found to promote NREM sleep, we tested how ML297 affected sleep and memory consolidation phenotypes in Fmr1 KO mice. Methods Wild type (WT) and Fmr1 KO were implanted with electrodes for electroencephalogram/electromyogram (EEG/EMG) recording of wakefulness, NREM and REM sleep. Sleep-dependent memory consolidation was measured using single-trial contextual fear conditioning (CFC). ML297 or vehicle was administered after CFC training to measure the effects on sleep and fear memory consolidation. Results Fmr1 KO mice showed reduced sleep in the hours following CFC learning compared to wild type littermates, and reduced contextual fear memory consolidation. Post-CFC sleep deprivation disrupted memory consolidation in wild type littermates, but not Fmr1 KO mice. Both NREM sleep time and NREM bout length were reduced in Fmr1 KO mice, and preliminary data suggest reduced NREM delta (0.5–4 Hz) power in the prefrontal cortex. These deficits were present at baseline and also following CFC. Post-CFC training administration of ML297 rescued NREM sleep and contextual fear memory deficits in Fmr1 KO mice. Conclusion Our study showed a strong link between NREM sleep loss and cognitive deficits in Fmr1 KO mice. Critically, normalization of NREM sleep through direct activation of GIRK channels rescues cognitive deficits seen in Fmr1 KO mice, suggesting a new therapeutic approach to treating cognitive deficits associated with FXS. Support (if any) This work was supported by a Rackham Merit Fellowship to JDM.

Fear generalization immediately after contextual fear memory consolidation in mice

Fear generalization is a symptom of anxiety-related disorders, including acute stress disorder and post-traumatic stress disorder. Using a contextual fear conditioning paradigm, we found that mice exposed to a similar neutral context but not a different neutral context soon after training showed fear generalization immediately after contextual fear memory consolidation (i.e., 6 h after training). This fear generalization was reflected by a change not only in the total amount but also the pattern of freezing between conditioned and generalized contexts. These results provide insight into the factors that influence fear generalization and can facilitate future studies investigating the underlying pathophysiological mechanisms of anxiety-related disorders.

Habenula GPR139 is associated with fear learning in the zebrafish

G-protein coupled receptor 139 (GPR139) is an evolutionarily conserved orphan receptor, predominantly expressing in the habenula of vertebrate species. The habenula has recently been implicated in aversive response and its associated learning. Here, we tested the hypothesis that GPR139 signalling in the habenula may play a role in fear learning in the zebrafish. We examined the effect of intraperitoneal injections of a human GPR139-selective agonist (JNJ-63533054) on alarm substance-induced fear learning using conditioned place avoidance paradigm, where an aversive stimulus is paired with one compartment, while its absence is associated with the other compartment of the apparatus. The results indicate that fish treated with 1 µg/g body weight of GPR139 agonist displayed no difference in locomotor activity and alarm substance-induced fear response. However, avoidance to fear-conditioned compartment was diminished, which suggests that the agonist blocks the consolidation of contextual fear memory. On the other hand, fish treated with 0.1 µg/g body weight of GPR139 agonist spent a significantly longer time in the unconditioned neutral compartment as compared to the conditioned (punished and unpunished) compartments. These results suggest that activation of GPR139 signalling in the habenula may be involved in fear learning and the decision-making process in the zebrafish.

Metabolic fingerprints of fear memory consolidation during sleep

Metabolites underlying brain function and pathology are not as well understood as genes. Here, we applied a novel metabolomics approach to further understand the mechanisms of memory processing in sleep. As hippocampal dentate gyrus neurons are known to consolidate contextual fear memory, we analyzed real-time changes in metabolites in the dentate gyrus in different sleep–wake states in mice. Throughout the study, we consistently detected more than > 200 metabolites. Metabolite profiles changed dramactically upon sleep–wake state transitions, leading to a clear separation of phenotypes between wakefulness and sleep. By contrast, contextual fear memory consolidation induced less obvious metabolite phenotypes. However, changes in purine metabolites were observed upon both sleep–wake state transitions and contextual fear memory consolidation. Dietary supplementation of certain purine metabolites impaired correlations between conditioned fear responses before and after memory consolidation. These results point toward the importance of purine metabolism in fear memory processing during sleep.

МЕХАНИЗМЫ ПАМЯТИ ПСИХОЛОГИЧЕСКОГО СТРЕССА И ВОЗДЕЙСТВИЯ НА НИХ В ЛЕЧЕНИИ СИНДРОМА ПОСТТРАВМАТИЧЕСКОГО СТРЕССА И БОЛЬШОГО ДЕПРЕССИВНОГО РАССТРОЙСТВА

Стресс, особенно его психологический компонент, связанный с невозможностью управлять им, или избежать его воздействия, вызывает тревожные или депрессивные расстройства в виде синдрома посттравматического стресса и большого депрессивного расстройства. В формировании этих заболеваний существенную роль играют формирование, воспроизведение и генерализация памяти страха и памяти отчаяния, которые нарушают деятельность синапсов, нейронов, нейронных сетей и поведения.В этом обзоре рассмотрены механизмы формирования и воспроизведения памяти контекстуального условного страха и отчасти памяти не избегаемого психологического стресса (памяти отчаяния). Проанализировано влияние традиционных и быстродействующих антидепрессантов на эти формы памяти, как одно из направлений фармакотерапии указанных аффективных расстройств.