Long-term Memory Consolidation Research Articles

Multi‐omics Studies Reveal Altered Hippocampal N‐Glycosylation in High Fat Diet‐Induced Obese Mice

BackgroundObesity is a major public health issue afflicting over 93 million people in the US and is projected to continue increasing. Impairments of cognitive abilities such as memory loss and mood disorders such as depression and anxiety are debilitating conditions associated with obesity. N‐glycosylation, an essential posttranslational modification of proteins is required for hippocampal long‐term potentiation and memory consolidation. However, whether altered N‐glycosylation is a potential mechanism involved in impaired hippocampal functioning in obesity remains unknown.AimOur goal was to develop a multi‐omics platform including glycomics, proteomics, and transcriptomics to determine the impact of high‐fat‐diet (HFD) consumption on hippocampal N‐glycosylation and expression of cell surface receptors in the context of diet‐induced obesity.HypothesisWe hypothesize that in HFD‐induced obese mice abnormal hippocampal N‐glycosylation occurs, affecting cell surface expression and signaling of key receptors.MethodsC57BL/6J male mice were fed a HFD (45% fat) for 8 weeks to induce obesity or a low‐fat diet (LFD, 10% fat) as the lean control group. Mice were euthanized, and brain tissues collected. Hippocampi were surgically dissected and processed for glycomics, proteomics, glycoproteomics, and RT‐qPCR analysis. Hippocampal cell membrane fractions (MF) were obtained, and N‐glycans released and analyzed by nano‐Liquid Chromatography‐Mass Spectrometry (nanoLC‐MS). Peptides and glycopeptides derived from MF were analyzed by nano‐LC‐FusionOrbitrap MS. Expression level of glycosyltransferase genes were obtained by qPCR.ResultsThe N‐glycome of LFD‐fed mice was dominated by highly branched fucosylated and sialylated N‐glycans (61%) while in HFD‐fed obese mice these N‐glycans were significantly decreased (51%). Correspondingly, transcript analysis of the glycosyltransferases showed that MGAT2 gene, which encodes the enzyme responsible for initiating the synthesis of complex branched N‐glycans, was significantly decreased by 50% in hippocampi of HFD‐fed obese mice compared to lean controls. Our findings show a decrease in complex branched glycans on the hippocampal cell surface of HFD‐obese mice that may be due to the downregulation of the MGAT2 gene. Proteomics and glycoproteomic analysis revealed site‐specific occupancy of over hundreds of hippocampal cell surface receptors.ConclusionsOur results suggest that chronic consumption of HFD and induced obesity results in abnormal hippocampal cell surface N‐glycosylation, and a possible enzyme associated with the altered glycosylation phenotype was identified. Aberrant N‐glycosylation may contribute to altered neuronal or glial cell function. This approach may be useful to identify novel targets for the development of new treatments for obesity‐associated mood and cognitive deficits.Support or Funding InformationFunding from National Institutes of Health, NIDDK (award 5R21DK118379) to M.B.

The super-cooling compound icilin stimulates c-Fos and Egr-1 expression and activity involving TRPM8 channel activation, Ca2+ ion influx and activation of the ternary complex factor Elk-1

The TRPM8 cation channel can be activated by the cooling compound icilin. Recently, we showed that stimulation of TRPM8 channels induces a signaling cascade leading to the activation of the transcription factor AP-1. Additionally, expression of the AP-1 constituent c-Fos has been shown to be induced following TRPM8 stimulation. c-Fos is frequently used as a marker for neuronal activity. Here, we have analyzed the mechanism connecting TRPM8 stimulation and c-Fos expression. Furthermore, we analyzed the expression of the neuronal activity-responsive transcription factor Egr-1 following TRPM8 activation. The results show that icilin-induced stimulation of TRPM8 channels increased c-Fos promoter activity and induced c-Fos expression. Moreover, icilin stimulation increased Egr-1 promoter activity and induced the expression of Egr-1. Pharmacological inhibition of TRPM8 blocked the icilin-induced expression of Egr-1 and c-Fos. An influx of Ca2+ ions into the cells via TRPM8 was necessary to stimulate Egr-1 and c-Fos expression following icilin treatment. Genetic experiments revealed that serum response elements within the Egr-1 and c-Fos promoters are crucial to couple TRPM8 stimulation with enhanced transcription of both the Egr-1 and c-Fos genes. These data were corroborated by experiments showing that TRPM8 stimulation increased the transcriptional activation potential of Elk-1, a SRE binding protein. c-Fos is important for neuronal excitability and survival. Egr-1 plays an important role in synaptic plasticity, consolidation and reconsolidation of long-term memory. Elk-1 may preserve neurons against toxic insults but may also induce depressive behaviour. The fact that TRPM8 stimulation activates the transcription factors c-Fos, Egr-1, and Elk-1 connects TRPM8 signaling with maintaining important brain functions.

Effect of pristine fullerene on acquisition, consolidation and retrieval memory in wistar rats

The present study evaluated the effect of fullerene (C60) under in vitro conditions, in hippocampus homogenates from rats and on the induction of behavioral disabilities. Exposure to in vitro C60 led to an increase in the concentration of reactive oxygen species (ROS) and lipid peroxidation (LPO) of hippocampus treated with of fullerene and suspension. These results indicate that the oxidative stress caused by the exposure to C60 was in part related to an absence of an antioxidant response. In this sense, one-trial inhibitory avoidance task were performed and results showed that fullerene at 0.2 and 0.45 μm impaired the acquisition and consolidation of short and long-term memory. Further, enzymatic analysis in rat hippocampus were not significantly different, however, there was an increase in the content of LPO and ROS produced by fullerene. Overall, the results indicates that fullerene possess neurotoxic properties that impairs behavior and promotes oxidative stress.

Differential Phosphorylation of the Glucocorticoid Receptor in Hippocampal Subregions Induced by Contextual Fear Conditioning Training.

Aversive events induce the release of glucocorticoid stress hormones that facilitate long-term memory consolidation, an effect that depends on the activation of glucocorticoid receptors (GRs). GRs are distributed widely in the hippocampus. The dorsal region of the hippocampus has been related to cognitive functions and the ventral region to stress and emotion. GR acts as a transcription factor which after hormone binding becomes phosphorylated, affecting its cellular distribution and transcriptional activity. Two functionally well-described GR phosphorylation sites are serine 232 (pSer232), which enhances gene expression, and serine 246 (pSer246), having the opposite effect. Since gene expression is one of the plastic mechanisms needed for memory consolidation, we investigated if an aversive learning task would induce GR phosphorylation in the dorsal (DH) and the ventral (VH) hippocampus. We trained rats in contextual fear conditioning (CFC) using different foot-shock intensities (0.0, 0.5, or 1.5 mA). One subgroup of animals trained with each intensity was sacrificed 15 min after training and blood was collected to quantify corticosterone (CORT) levels in serum. Another subgroup was sacrificed 1 h after training and brains were collected to evaluate the immunoreactivity (IR) to GR, pSer232 and pSer246 by SDS-PAGE/Western blot in DH and VH, and by immunohistochemistry in dorsal and ventral CA1, CA2, CA3, and dentate gyrus (DG) hippocampal regions. The conditioned freezing response increased in animals trained with 0.5 and 1.5 mA during training and extinction sessions. The degree of retention and CORT levels were directly related to the intensity of the foot-shock. Although total GR-IR remained unaffected after conditioning, we observed a significant increase of pSer246-IR in the dorsal region of CA1 and in both dorsal and ventral DG. The only region in which pSer232-IR was significantly elevated was ventral CA3. Our results indicate that fear conditioning training is related to GR phosphorylation in specific subregions of the hippocampus, suggesting that its transcriptional activity for gene expression is favored in ventral CA3, whereas its repressor activity for gene-silencing is increased in dorsal CA1 and in both dorsal and ventral DG.

Elucidating the role of protein synthesis in hippocampus‐dependent memory consolidation across the day and night

It is widely acknowledged that de novo protein synthesis is crucial for the formation and consolidation of long‐term memories. While the basal activity of many signaling cascades that modulate protein synthesis fluctuates in a circadian fashion, it is unclear whether the temporal dynamics of protein synthesis‐dependent memory consolidation vary depending on the time of day. More specifically, it is unclear whether protein synthesis inhibition affects hippocampus‐dependent memory consolidation in rodents differentially across the day (i.e., the inactive phase with an abundance of sleep) and night (i.e., the active phase with little sleep). To address this question, male and female C57Bl6/J mice were trained in a contextual fear conditioning task at the beginning or the end of the light phase. Animals received a single systemic injection with the protein synthesis inhibitor anisomycin or vehicle directly, 4, 8 hr, or 11.5 hr following training, and memory was assessed after 24 hr. Here, we show that protein synthesis inhibition impaired the consolidation of context–fear memories selectively when the protein synthesis inhibitor was administered at the first three time points, irrespective of timing of training. Even though the basal activity of signaling pathways regulating de novo protein synthesis may fluctuate across the 24‐hr cycle, these results suggest that the temporal dynamics of protein synthesis‐dependent memory consolidation are similar for day‐time and night‐time learning.

Emotionally Stimulated Persistent Memory

Most things in life are forgotten. Emotional stimulation can improve the storage of memory, which helps people to selectively build lasting memories of important experiences. Nervous system-mediated emotional arousal and memory are very closely linked. The adrenaline and corticosterone released during emotional stimulation can regulate the consolidation of long-term memory. The amygdala plays a key role in regulating the effects of these stress hormones on the body. Stress-induced activation of the amygdala and its interaction with other relevant brain regions that process memory are the key to ensuring that emotionally meaningful experiences are remembered.

Involvement of medial prefrontal cortex NMDA and AMPA/kainate glutamate receptors in social recognition memory consolidation.

Social recognition memory (SRM) enables the distinction between familiar and strange conspecifics, a fundamental ability for sociable species, such as rodents and humans. There is mounting evidence that the medial prefrontal cortex plays a prominent role both in shaping social behavior and in recognition memory. Glutamate is the major excitatory neurotransmitter in the brain, and activity of its ionotropic receptors is known to mediate both synaptic plasticity and consolidation of various types of memories. However, whether these receptors are required in the medial prefrontal cortex (mPFC) for SRM consolidation remains elusive. To address this issue, we submitted rats to a social discrimination paradigm, administered infusions of NMDA- and AMPA/kainate-receptors antagonists into the prelimbic (PrL) subdivision of the mPFC at different post-encoding time points and evaluated long-term memory retention twenty-four hours later. We found that blocking NMDA receptors immediately after the sample phase, but not 3h later, impaired SRM consolidation, whereas the blockade of AMPA/kainate receptors immediately and 3h, but not 6h after the sample phase, prevented long-term memory consolidation. These results highlight the importance of the mPFC in social cognition and may contribute towards the understanding of the dysfunctional social information processing that underlies multiple neuropsychiatric disorders.

Long-term verbal memory deficit and associated hippocampal alterations in 22q11.2 deletion syndrome

ABSTRACTChromosome 22q11.2 deletion syndrome (22q11.2DS) is a genetic disease associated with an increased risk for schizophrenia and a specific cognitive profile. In this paper, we challenge the current view of spared verbal memory in 22q11.2DS by investigating verbal memory consolidation processes over an extended time span to further qualify the neuropsychological profile. Our hypotheses are based on brain anomalies of the medial temporal lobes consistently reported in this syndrome.Eighty-four participants (45 with 22q11.2DS), aged 8–24 years old, completed a verbal episodic memory task to investigate long-term memory on four different time delays. We compared trajectories of forgetting between groups (22q11.2DS vs. controls) and analyzed performance inside the 22q11.2DS sample through cluster analyses. Potential links between memory performance and volume of the hippocampal subfields were examined.We showed accelerated long-term forgetting (ALF) in the 22q11.2DS group, visible after a delay of one day. Using mixed models, we showed significant differences in the shape of memory trajectories between subgroups of participants with 22q11.2DS. These sub-groups differed in terms of memory recognition, intellectual functioning, positive psychotic symptoms and grey matter volume of hippocampal subfields but not in terms of age.In conclusion, by investigating memory processes on longer delays than standardized memory tasks, we identified deficits in long-term memory consolidation leading to ALF in 22q11.2DS. Nevertheless, we showed that a subgroup of patients had larger memory consolidation deficit associated with lower intellectual functioning, higher rates of positive psychotic symptoms and hippocampal alterations.

The Effects of Acute Exercise on Retroactive Memory Interference.

Retroactive interference involves the disruption of previously encoded information from newly learned information and thus may impair the consolidation of long-term memory. The objective of this study was to evaluate whether acute exercise can attenuate retroactive memory interference. Three experimental studies were employed. Experiment 1 employed a between-subject randomized control trial (RCT) involving moderate-intensity walking (15 minutes). Experiment 2 employed a between-subject RCT involving high-intensity jogging (15 minutes). Experiment 3 employed a within-subject RCT involving moderate-intensity walking (15 minutes). University setting. One hundred twelve young adults. After exercise, memory interference was evaluated from an episodic word-list memory task, involving the recall of 2 word lists. The pooled effect size (standard difference in means: -0.35; 95% confidence interval: -0.64 to -0.06) across the 3 experiments was statistically significant (P = .01). We provide suggestive evidence that acute, short-duration exercise may help attenuate a retroactive memory interference effect. Implications of these findings for exercise to improve memory and attenuate memory decay are discussed.

The amnestic agent anisomycin disrupts intrinsic membrane properties of hippocampal neurons via a loss of cellular energetics.

The nearly axiomatic idea that de novo protein synthesis is necessary for long-term memory consolidation is based heavily on behavioral studies using translational inhibitors such as anisomycin. Although inhibiting protein synthesis has been shown to disrupt the expression of memory, translational inhibitors also have been found to profoundly disrupt basic neurobiological functions, including the suppression of ongoing neural activity in vivo. In the present study, using transverse hippocampal brain slices, we monitored the passive and active membrane properties of hippocampal CA1 pyramidal neurons using intracellular whole cell recordings during a brief ~30-min exposure to fast-bath-perfused anisomycin. Anisomycin suppressed protein synthesis to 46% of control levels as measured using incorporation of radiolabeled amino acids and autoradiography. During its application, anisomycin caused a significant depolarization of the membrane potential, without any changes in apparent input resistance or membrane time constant. Anisomycin-treated neurons also showed significant decreases in firing frequencies and spike amplitudes, and showed increases in spike width across spike trains, without changes in spike threshold. Because these changes indicated a loss of cellular energetics contributing to maintenance of ionic gradients across the membrane, we confirmed that anisomycin impaired mitochondrial function by reduced staining with 2,3,5-triphenyltetrazolium chloride and also impaired cytochrome c oxidase (complex IV) activity as indicated through high-resolution respirometry. These findings emphasize that anisomycin-induced alterations in neural activity and metabolism are a likely consequence of cell-wide translational inhibition. Critical reevaluation of studies using translational inhibitors to promote the protein synthesis dependent idea of long-term memory is absolutely necessary.NEW & NOTEWORTHY Memory consolidation is thought to be dependent on the synthesis of new proteins because translational inhibitors produce amnesia when administered just after learning. However, these agents also disrupt basic neurobiological functions. We show that blocking protein synthesis disrupts basic membrane properties of hippocampal neurons that correspond to induced disruptions of mitochondrial function. It is likely that translational inhibitors cause amnesia through their disruption of neural activity as a result of dysfunction of intracellular energetics.

β-adrenergic modulation of discrimination learning and memory in the auditory cortex.

Despite vast literature on catecholaminergic neuromodulation of auditory cortex functioning in general, knowledge about its role for long‐term memory formation is scarce. Our previous pharmacological studies on cortex‐dependent frequency‐modulated tone‐sweep discrimination learning of Mongolian gerbils showed that auditory‐cortical D1/5‐dopamine receptor activity facilitates memory consolidation and anterograde memory formation. Considering overlapping functions of D1/5‐dopamine receptors and β‐adrenoceptors, we hypothesised a role of β‐adrenergic signalling in the auditory cortex for sweep discrimination learning and memory. Supporting this hypothesis, the β1/2‐adrenoceptor antagonist propranolol bilaterally applied to the gerbil auditory cortex after task acquisition prevented the discrimination increment that was normally monitored 1 day later. The increment in the total number of hurdle crossings performed in response to the sweeps per se was normal. Propranolol infusion after the seventh training session suppressed the previously established sweep discrimination. The suppressive effect required antagonist injection in a narrow post‐session time window. When applied to the auditory cortex 1 day before initial conditioning, β1‐adrenoceptor‐antagonising and β1‐adrenoceptor‐stimulating agents retarded and facilitated, respectively, sweep discrimination learning, whereas β2‐selective drugs were ineffective. In contrast, single‐sweep detection learning was normal after propranolol infusion. By immunohistochemistry, β1‐ and β2‐adrenoceptors were identified on the neuropil and somata of pyramidal and non‐pyramidal neurons of the gerbil auditory cortex. The present findings suggest that β‐adrenergic signalling in the auditory cortex has task‐related importance for discrimination learning of complex sounds: as previously shown for D1/5‐dopamine receptor signalling, β‐adrenoceptor activity supports long‐term memory consolidation and reconsolidation; additionally, tonic input through β1‐adrenoceptors may control mechanisms permissive for memory acquisition.

Initiated by CREB: Resolving Gene Regulatory Programs in Learning and Memory: Switch in Cofactors and Transcription Regulators between Memory Consolidation and Maintenance Network.

Consolidation of long-term memory is a highly and precisely regulated multistep process. The transcription regulator cAMP response element-binding protein (CREB) plays a key role in initiating memory consolidation. With time processing, first the cofactors are changed and, secondly, CREB gets dispensable. This ultimately changes the expressed gene program to genes required to maintain the memory. Regulation of memory consolidation also requires epigenetic mechanisms and control at the RNA level. At the neuronal circuit level, oscillation in the activity of CREB and downstream factor define engram cells. Together the combination of all regulation mechanisms allows correct memory processing while keeping the process dynamic and flexible to adjust to different contexts. Also see the video abstract here https://youtu.be/BhSCSmorpEc.

Learning Induces Transient Upregulation of Brevican in the Auditory Cortex during Consolidation of Long-Term Memories.

It is a daily challenge for our brains to establish new memories via learning while providing stable storage of remote memories. In the adult vertebrate brain, bimodal regulation of the extracellular matrix (ECM) may regulate the delicate balance of learning-dependent plasticity and stable memory formation. Here, we trained adult male mice in a cortex-dependent auditory discrimination task and measured the abundance of ECM proteins brevican (BCN) and tenascin-R over the course of acquisition learning, consolidation, and long-term recall in two learning-relevant brain regions; the auditory cortex and hippocampus. Although early training led to a general downregulation of total ECM proteins, successful retrieval correlated with a region-specific and transient upregulation of BCN levels in the auditory cortex. No other parameter such as arousal or stress could account for the transient and region-specific BCN upregulation. This performance-dependent biphasic regulation of the ECM may assist transient plasticity to facilitate initial learning and subsequently promote the long-term consolidation of memory.SIGNIFICANCE STATEMENT The capacity to learn throughout life and at the same time guarantee lifelong storage and remote recall of established memories is a daily challenge. Emerging evidence suggests an important function of the extracellular matrix (ECM), a conglomerate of secreted proteins and polysaccharides in the adult vertebrate brain. We trained mice in an auditory long-term memory task and measured learning-related dynamic changes of the ECM protein brevican. Specifically, in the auditory cortex brevican is downregulated during initial learning and subsequently upregulated in exclusively those animals that have learned the task, suggesting a performance-dependent regulation in the service of memory consolidation and storage. Our data may provide novel therapeutic implications for several neuropsychiatric diseases involving dysregulation of the ECM.

The Beneficial Effects of Postnatal Caffeine on Spatial Learning in Adult Mice

Background: Prenatal caffeine adversely affects learning and memory in adult offspring, whereas its administration to adolescent humans improves consolidation of long-term memory. The effects of po...

Writing to Learn Increases Long-term Memory Consolidation: A Mental-chronometry and Computational-modeling Study of “Epistemic Writing”

Writing to Learn Increases Long-term Memory Consolidation: A Mental-chronometry and Computational-modeling Study of “Epistemic Writing”

Drosophila Acquires a Long-Lasting Body-Size Memory from Visual Feedback

Grasping an object or crossing a trench requires the integration of information on the operating distance of our limbs with precise distance estimation. The reach of our hands and step size of our legs are learned by the visual feedback we get during our actions. This implicit knowledge of our peripersonal space is first acquired during infancy but will be continuously updated throughout our whole life [1]. In contrast, body size of holometabolous insects does not change after metamorphosis; nevertheless, they do have to learn their body reaches at least once. The body size of Drosophila imagines can vary by about 15% depending on environmental factors like food quality and temperature [2]. To investigate how flies acquire knowledge about and memorize their body size, we studied their decisions to either refrain from or initiate climbing over gaps exceeding their body size [3]. Naive (dark-reared) flies overestimate their size and have to learn it from the parallax motion of the retinal images of objects in their environment while walking. Naive flies can be trained in a striped arena and manipulated to underestimate their size, but once consolidated, this memory seems to last for a lifetime. Consolidation of this memory is stress sensitive only in the first 2h after training but cannot be retrieved for the next 12 h. We have identified a set of intrinsic, lateral neurons of the protocerebral bridge of the central complex [4, 5] that depend on dCREB2 transcriptional activity for long-term memory consolidation and maintenance.

Renewal of extinguished behavior in pigeons (Columba livia) does not require memory consolidation of acquisition or extinction in a free-operant appetitive conditioning paradigm

Extinction learning is a fundamental capacity for adaptive and flexible behavior. As extinguished conditioned responding is prone to relapse under certain conditions, the necessity of memory consolidation for recovery phenomena to occur has been highlighted recently. Several studies have demonstrated that both acquisition and extinction training need to be properly consolidated for a relapse of the original acquired memory trace to occur. Does this imply that extinguished responses cannot relapse before memory consolidation? To answer this question, we investigated the renewal effect subsequent to an immediate or a delayed (24 h) extinction in a discriminative operant conditioning paradigm. In three different experiments, we could show (1) that acquisition learning does not need to be long-term consolidated for the occurrence of renewal, (2) that the offset of extinction training is a reliable marker for extinction recall in a free-operant extinction learning paradigm where organisms undergo consecutive acquisition training, extinction training as well as testing of conditioned responding and (3), that immediate and long-term consolidated renewal do not demonstrate any qualitative difference in terms of the behavioral output. Our results indicate on the behavioral level that the inhibitory nature of extinction is already present in free-operant learning paradigms and that it does not seem to be affected by the absence of long-term memory consolidation.

Sleep influences cognitive performance in lemurs.

Primates spend almost half their lives asleep, yet little is known about how sleep influences their waking cognition. We hypothesized that diurnal and cathemeral lemurs differ in their need for consistent, non-segmented sleep for next-day cognitive function-including long-term memory consolidation, self-control, foraging efficiency, and sociality. Specifically, we expected that strictly diurnal Propithecus is more reliant on uninterrupted sleep for cognitive performance, as compared to four other lemur species that are more flexibly active (i.e., cathemeral). We experimentally inhibited sleep and tested next-day performance in 30 individuals of 5 lemur species over 960 total nights at the Duke Lemur Center in Durham, North Carolina. Each set of pair-housed lemurs experienced a sleep restriction and/or deprivation protocol and was subsequently tested in a variety of fitness-relevant cognitive tasks. Within-subject comparisons of performance on these tasks were made by switching the pair from the experimental sleep inhibited condition to a normal sleep environment, thus ensuring cognitive equivalency among individuals. We validated effectiveness of the protocol via actigraphy and infrared videography. Our results suggest that 'normal' non-disrupted sleep improved memory consolidation for all lemurs. Additionally, on nights of normal sleep, diurnal lemurs performed better in foraging efficiency tasks than cathemeral lemurs. Social behaviors changed in species-specific ways after exposure to experimental conditions, and self-control was not significantly linked with sleep condition. Based on these findings, the links between sleep, learning, and memory consolidation appear to be evolutionarily conserved in primates.

Sleep deprivation enhances false memory on the Deese-Roediger-McDermott (DRM) task

False memories are memories that people report to be true with high confidence, even though they had never encountered the fact behind the memory in reality. Such memories possess strong semantic association with already existing encoded memories which hence appear to be familiar. Sleep is known to provide optimal conditions for the consolidation of long-term memories whereas the deprivation of sleep is known to hinder memory’s consolidation process. The role of sleep in the formation and enhancement of false memories was tested. The Deese-Roediger-McDermott (DRM) task was used to induce false memory in thirty-nine male volunteers who either slept or remained awake following learning. Following a night of recovery sleep both groups returned for retrieval of memory. It was found that sleep deprivation in comparison to sleep led to higher false memory.

PKM-ζ Expression Is Important in Consolidation of Memory in Prelimbic Cortex Formed by the Process of Behavioral Tagging

Memories are acquired and stored in two forms, short-term memory (STM) and long-term memory (LTM). For the consolidation of LTM, de novo protein synthesis is required, which are also known as plasticity related proteins. Long-term potentiation is a form of synaptic plasticity and it is considered as a cellular model of learning and memory. One of the Long-term potentiation specific plasticity related proteins, PKM-ζ, is required for the formation of LTM as well as for the maintenance of Long-term potentiation. In our study, we have shown that for the consolidation of LTM, in addition to Long-term potentiation -specific plasticity related proteins, synaptic tags are required to interact with each other. In the present study, we investigated the involvement of Long-term potentiation -specific PKM-ζ and learning tags within a critical time window, which are required for the formation of LTM without affecting STM. Behavioral tagging is an established model for the assessment of some forms of learning and memory. Despite being studied for LTM formation for many years, no studies so far have investigated the role of PKM-ζ in Behavioral tagging model. Hence, by using these two different memories based tasks (i.e., Inhibitory avoidance and Novel object recognition tasks), we observed how PKM-ζ activated by exposing a novel arena after a weak training and led to the consolidation of memory. These findings thus show how the process of behavioral tagging activates Long-term potentiation -specific PKM-ζ for the formation of LTM.