anisomycin and Memory-Disorders

The process of memory consolidation involves the synthesis of new proteins, and interfering with protein synthesis through anisomycin can impair memory. Memory deficits due to aging and sleep disorders may also result from a reduction in protein synthesis. Rescuing memory deficits caused by protein synthesis deficiency is therefore an important issue that needs to be addressed. Our study focused on the effects of cordycepin on fear memory deficits induced by anisomycin using contextual fear conditioning. We observed that cordycepin was able to attenuate these deficits and restore BDNF levels in the hippocampus. The behavioral effects of cordycepin were dependent on the BDNF/TrkB pathway, as demonstrated by the use of ANA-12. Cordycepin had no significant impact on locomotor activity, anxiety or fear memory. Our findings provide the first evidence that cordycepin can prevent anisomycin-induced memory deficits by regulating BDNF expression in the hippocampus.

Topics: Anisomycin; Brain-Derived Neurotrophic Factor; Fear; Hippocampus; Humans; Memory Disorders

Alzheimer's disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid β (Aβ) in the brain. Although several studies reported possible mechanisms involved in Aβ pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aβ-responsive gene involved in Aβ cytotoxicity. However, we still do not know how Aβ increases the level of REDD1 and whether REDD1 mediates Aβ-induced synaptic dysfunction. To elucidate this, we examined the effect of Aβ on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aβ-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aβ-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aβ injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aβ-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aβ may increase REDD1 translation rather than transcription. Aβ activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aβ-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aβ blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aβ-induced synaptic deficits. REDD1 shRNA also blocked Aβ-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aβ pathology and could be a target for AD therapy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anisomycin; Dactinomycin; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Hippocampus; Male; MAP Kinase Signaling System; Memory and Learning Tests; Memory Disorders; Mice; Protein Biosynthesis; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-fyn; Receptor, Metabotropic Glutamate 5; Ribosomal Protein S6 Kinases; RNA, Small Interfering; Synapses; TOR Serine-Threonine Kinases; Transcription Factors; Up-Regulation

The involvement of protein synthesis in the mechanisms of conditioned food aversion memory impairment and recovery in grape snails was studied. It was found that protein synthesis inhibitor (cycloheximide) injections before a reminder by the conditioned stimulus (CS) caused amnesia development. Three days after amnesia induction, injections of cycloheximide or another protein synthesis inhibitor, anisomycin, combined with a reminder by four CSs resulted in memory retrieval, which was saved for 24 h. Cycloheximide injections and the administration of one CS as a reminder to an amnestic animals caused the memory expression only in response to this CS, while it was absent the next day. The isolated administration of a reminder or inhibitor injections without a reminder was not effective. It is suggested that amnesia is an active process and that one of its mechanisms may be a protein-dependent amnesia reactivation caused by a reminder. The administration of protein synthesis inhibitors led to impairment of amnesia reactivation and to recovery of the state formed before amnesia induction and thus to the recovery of conditioned food aversion memory.

Topics: Animals; Anisomycin; Conditioning, Classical; Cycloheximide; Disease Models, Animal; Drug Administration Schedule; Electric Stimulation; Food; Memory Disorders; Protein Synthesis Inhibitors; Recovery of Function; Signal Transduction; Snails; Statistics, Nonparametric; Time Factors

Stressful events can generate emotional memories linked to the traumatic incident, but they also can impair the formation of nonemotional memories. Although the impact of stress on emotional memories is well studied, much less is known about the influence of the emotional state on the formation of nonemotional memories. We used the novel object-recognition task as a model of nonemotional memory in mice to investigate the underlying mechanism of the deleterious effect of stress on memory consolidation. Systemic, hippocampal, and peripheral blockade of cannabinoid type-1 (CB1) receptors abolished the stress-induced memory impairment. Genetic deletion and rescue of CB1 receptors in specific cell types revealed that the CB1 receptor population specifically in dopamine β-hydroxylase (DBH)-expressing cells is both necessary and sufficient for stress-induced impairment of memory consolidation, but CB1 receptors present in other neuronal populations are not involved. Strikingly, pharmacological manipulations in mice expressing CB1 receptors exclusively in DBH(+) cells revealed that both hippocampal and peripheral receptors mediate the impact of stress on memory consolidation. Thus, CB1 receptors on adrenergic and noradrenergic cells provide previously unrecognized cross-talk between central and peripheral mechanisms in the stress-dependent regulation of nonemotional memory consolidation, suggesting new potential avenues for the treatment of cognitive aspects on stress-related disorders.

Topics: Animals; Anisomycin; Dopamine beta-Hydroxylase; Electroshock; Hindlimb Suspension; Indoles; Male; Memory Consolidation; Memory Disorders; Mice, Knockout; Neurons; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Stress, Psychological

Extinction is the learned inhibition of retrieval. Recently it was shown that a brief exposure to a novel environment enhances the extinction of contextual fear in rats, an effect explainable by a synaptic tagging-and-capture process. Here we examine whether this also happens with the extinction of another fear-motivated task, inhibitory avoidance (IA), and whether it depends on dopamine acting on D1 or D5 receptors. Rats were trained first in IA and then in extinction of this task. The retention of extinction was measured 24 h later. A 5-min exposure to a novel environment 30 min before extinction training enhanced its retention. Right after exposure to the novelty, animals were given bilateral intrahippocampal infusions of vehicle (VEH), of the protein synthesis inhibitor anisomycin, of the D1/D5 dopaminergic antagonist SCH23390, of the PKA inhibitor Rp-cAMP or of the PKC inhibitor Gö6976, and of the PKA stimulator Sp-cAMP or of the PKC stimulator PMA. The novelty increased hippocampal dopamine levels and facilitated the extinction, which was inhibited by intrahippocampal protein synthesis inhibitor anisomysin, D1/D5 dopaminerdic antagonist SCH23390, or PKA inhibitor Rp-cAMP and unaffected by PKC inhibitor Gö6976; additionally, the hippocampal infusion of PKA stimulator Sp-cAMP reverts the effect of D1/D5 dopaminergic antagonist SCH 23390, but the infusion of PKC stimulator PMA does not. The results attest to the generality of the novelty effect on fear extinction, suggest that it relies on synaptic tagging and capture, and show that it depends on hippocampal dopamine D1 but not D5 receptors.

Topics: Animals; Anisomycin; Behavior, Animal; Benzazepines; Carbazoles; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dopamine; Extinction, Psychological; Fear; Hippocampus; Learning; Male; Memory; Memory Disorders; Protein Kinase C; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D5; Stress, Physiological; Thionucleotides; Time Factors

To identify an individual as familiar, rodents form a specific type of memory named social recognition memory. The olfactory bulb (OB) is an important structure for social recognition memory, while the hippocampus recruitment is still controversial. The present study was designed to elucidate the OB and the dorsal hippocampus contribution to the consolidation of social memory. For that purpose, we tested the effect of anisomycin (ANI), which one of the effects is the inhibition of protein synthesis, on the consolidation of social recognition memory. Swiss adult mice with cannulae implanted into the CA1 region of the dorsal hippocampus or into the OB were exposed to a juvenile during 5 min (training session; TR), and once again 1.5 h or 24 h later to test social short-term memory (S-STM) or social long-term memory (S-LTM), respectively. To study S-LTM consolidation, mice received intra-OB or intra-CA1 infusion of saline or ANI immediately, 3, 6 or 18 h after TR. ANI impaired S-LTM consolidation in the OB, when administered immediately or 6h after TR. In the dorsal hippocampus, ANI was amnesic only if administered 3 h after TR. Furthermore, the infusion of ANI in either OB or CA1, immediately after training, did not affect S-STM. Moreover, ANI administered into the OB did not alter the animal's performance in the buried food-finding task. Altogether, our results suggest the consolidation of S-LTM requires both OB and hippocampus participation, although in different time points. This study may help shedding light on the specific roles of the OB and dorsal hippocampus in social recognition memory.

Topics: Age Factors; Animals; Anisomycin; Conditioning, Psychological; Disease Models, Animal; Fear; Feeding Behavior; Hippocampus; Male; Memory Disorders; Mice; Nucleic Acid Synthesis Inhibitors; Olfactory Bulb; Reaction Time; Recognition, Psychology; Social Behavior; Statistics, Nonparametric; Time Factors

Expression of long-lasting synaptic plasticity and long-term memory requires protein synthesis, which can be repressed by phosphorylation of eukaryotic initiation factor 2 α-subunit (eIF2α). Elevated phosphorylation of eIF2α has been observed in the brains of Alzheimer's disease patients and Alzheimer's disease model mice. Therefore, we tested whether suppressing eIF2α kinases could alleviate synaptic plasticity and memory deficits in Alzheimer's disease model mice. Genetic deletion of eIF2α kinase PERK prevented enhanced phosphorylation of eIF2α and deficits in protein synthesis, synaptic plasticity and spatial memory in mice that express familial Alzheimer's disease-related mutations in APP and PSEN1. Similarly, deletion of another eIF2α kinase, GCN2, prevented impairments of synaptic plasticity and defects in spatial memory exhibited by the Alzheimer's disease model mice. Our findings implicate aberrant eIF2α phosphorylation as a previously unidentified molecular mechanism underlying Alzheimer's disease-related synaptic pathophysioloy and memory dysfunction and suggest that PERK and GCN2 are potential therapeutic targets for treatment of individuals with Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anisomycin; Disease Models, Animal; eIF-2 Kinase; Female; Hippocampus; Humans; In Vitro Techniques; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neuronal Plasticity; Presenilin-1; Protein Synthesis Inhibitors; Recognition, Psychology

Neuropsychological analyses of amnesic patients, as well as lesion experiments, indicate that the temporal lobe is essential for the encoding, storage, and expression of object recognition memory (ORM). However, temporal lobe structures directly involved in the consolidation and reconsolidation of these memories are not yet well-defined. We report here that systemic administration of a protein synthesis inhibitor before or up to 4 h after training or reactivation sessions impairs consolidation and reconsolidation of ORM, without affecting short-term memory. We have also observed that ORM reconsolidation is sensitive to protein synthesis inhibition, independently of the ORM trace age. Using bdnf and egr-1 gene expression analysis, we defined temporal lobe areas related to consolidation and reconsolidation of ORM. Training and reactivation 21 days after ORM acquisition sessions provoked changes in bdnf mRNA in somatosensory, perirhinal, and hippocampal cortices. Reactivation 2 days after the training session elicited changes in bdnf and egr-1 mRNA in entorhinal and prefrontal cortices, while reactivation 9 days post-training provoked an increase in egr-1 transcription in somatosensory and entorhinal cortices. The differences in activated circuits and in the capacity to recall the memory trace after 9 or 21 days post-training suggest that memory trace suffers functional changes in this period of time. All these results indicate that the functional state of the recognition memory trace, from acquisition to forgetting, can be specifically defined by behavioral, circuitry, and molecular properties.

Topics: 4-Aminopyridine; Age Factors; Animals; Anisomycin; Behavior, Animal; Brain; Brain-Derived Neurotrophic Factor; Discrimination Learning; Early Growth Response Protein 1; Exploratory Behavior; Gene Expression Regulation; Imidazoles; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Neural Pathways; Potassium Channel Blockers; Protein Synthesis Inhibitors; Proto-Oncogene Proteins c-fos; Pyridines; Recognition, Psychology; RNA, Messenger; Time Factors

Protein synthesis inhibitor antibiotics are widely used to produce amnesia, and have been recognized to inhibit general or global mRNA translation in the basic translational machinery. For instance, anisomycin interferes with protein synthesis by inhibiting peptidyl transferase or the 80S ribosomal function. Therefore, de novo general or global protein synthesis has been thought to be necessary for long-term memory formation. However, it is unclear which mode of translation-gene-specific translation or general/global translation-is actually crucial for the memory consolidation process in mammalian brains. Here, we generated a conditional transgenic mouse strain in which double-strand RNA-dependent protein kinase (PKR)-mediated phosphorylation of eIF2alpha, a key translation initiation protein, was specifically increased in hippocampal CA1 pyramidal cells by the chemical inducer AP20187. Administration of AP20187 significantly increased activating transcription factor 4 (ATF4) translation and concomitantly suppressed CREB-dependent pathways in CA1 cells; this led to impaired hippocampal late-phase LTP and memory consolidation, with no obvious reduction in general translation. Conversely, inhibition of general translation by low-dose anisomycin failed to block hippocampal-dependent memory consolidation. Together, these results indicated that CA1-restricted genetic manipulation of particular mRNA translations is sufficient to impair the consolidation and that consolidation of memories in CA1 pyramidal cells through eIF2alpha dephosphorylation depends more on transcription/translation of particular genes than on overall levels of general translation. The present study sheds light on the critical importance of gene-specific translations for hippocampal memory consolidation.

Topics: Analysis of Variance; Animals; Anisomycin; Avoidance Learning; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Biophysics; Conditioning, Psychological; CREB-Binding Protein; Dose-Response Relationship, Drug; Electric Stimulation; Enzyme Activation; Eukaryotic Initiation Factor-2; Fear; Gene Expression Regulation; Hippocampus; In Vitro Techniques; Long-Term Potentiation; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Microtubule-Associated Proteins; Mutation; Patch-Clamp Techniques; Phosphorylation; Protein Kinases; Protein Synthesis Inhibitors; Proto-Oncogene Proteins c-fos; Pyramidal Cells; Signal Transduction; Statistics, Nonparametric; Stilbamidines; Tacrolimus; Transcription Factor 4

Cognitive impairment is one of the most important negative consequences associated with cannabis consumption. We found that CB1 cannabinoid receptor (CB1R) activation transiently modulated the mammalian target of rapamycin (mTOR)/p70S6K pathway and the protein synthesis machinery in the mouse hippocampus, which correlated with the amnesic properties of delta9-tetrahydrocannabinol (THC). In addition, non-amnesic doses of either the mTOR blocker rapamycin or the protein synthesis inhibitor anisomycin abrogated the amnesic-like effects of THC, pointing to a mechanism involving new protein synthesis. Moreover, using pharmacological and genetic tools, we found that THC long-term memory deficits were mediated by CB1Rs expressed on GABAergic interneurons through a glutamatergic mechanism, as both the amnesic-like effects and p70S6K phosphorylation were reduced in GABA-CB1R knockout mice and by NMDA blockade.

Topics: Animals; Anisomycin; Central Nervous System Agents; Cognition; Dronabinol; gamma-Aminobutyric Acid; Glutamic Acid; Hippocampus; Male; Memory; Memory Disorders; Mice; Mice, Knockout; Neurons; Protein Kinases; Protein Synthesis Inhibitors; Receptor, Cannabinoid, CB1; Receptors, N-Methyl-D-Aspartate; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Conditioned odor aversion (COA) results from the association between a novel odor and a delayed visceral illness. Basolateral amygdala is crucial for COA learning but its importance in COA consolidation remains to be demonstrated. We investigated whether infusion of anisomycin, a protein synthesis inhibitor, in the basolateral amygdala impaired COA consolidation. COA was greatly impaired when anisomycin was infused immediately before odor-malaise pairing, but not between odor and malaise. This suggests that the formation of odor representation, rather than malaise integration, within the amygdala has been disrupted. Anisomycin infusion before acquisition did not affect short-term memory (tested 4 h after odor-malaise pairing) but dramatically impaired long-term COA memory (tested 3 days later). This indicates specific consolidation impairment. Control experiments indicated that anisomycin infusion did not affect amygdala functionality and olfactory perception and did not induce cell death in the amygdala. Moreover, anisomycin treatment induced an important decrease (65-70%) of LiCl-induced Fos protein expression in the basolateral and the central nuclei of the amygdala but not in adjacent piriform cortex indicating a reliable and localized protein synthesis inhibition. These findings suggest the pivotal role of the basolateral amygdala, and possibly the central amygdala, in COA memory consolidation.

Topics: Amygdala; Animals; Anisomycin; Avoidance Learning; Behavior, Animal; Male; Memory Disorders; Odorants; Oncogene Proteins v-fos; Phosphopyruvate Hydratase; Protein Synthesis Inhibitors; Rats; Rats, Wistar; Time Factors

In experiments examining the potential reconsolidation of drug-associated contextual memories, rats were given a single pairing of cocaine with a specific context, and the ability of the protein synthesis inhibitor anisomycin administered following a context-only memory retrieval trial to impair conditioned locomotor sensitization was tested. Rats receiving 150 mg/kg anisomycin immediately following a 5-min reexposure to the cocaine-conditioned context showed decreased activity compared with the vehicle control group in response to a low-dose cocaine challenge during a subsequent test for conditioned sensitization. This effect was not seen when anisomycin was administered following a 30-min reexposure to the context or when anisomycin was administered 25 min after a 5-min reexposure. These results are consistent with a growing literature suggesting that following retrieval, associative contextual memories may undergo a transient protein synthesis-dependent reconsolidation phase that normally serves to maintain memory.

Topics: Analysis of Variance; Animals; Anisomycin; Association Learning; Behavior, Animal; Cocaine; Conditioning, Classical; Dopamine Uptake Inhibitors; Drug Interactions; Male; Memory Disorders; Motor Activity; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley

Previous studies indicated that stress levels of glucocorticoid hormones (cortisol in humans, and corticosterone in rodents) induce impairment of long-term memory retrieval, but the underlying mechanisms (genomic or nongenomic) are not clear. To clarify this issue, we investigated the involvement of brain corticosteroid receptors and protein synthesis in the corticosterone-induced impairment of memory retrieval. Young rats were trained in the water maze task with six trials per day for 6 consecutive days. Retention of the spatial training was assessed 24 h after the last training session with a 60-s probe trial. Experiments included intraventricular injections of anisomycin, a specific protein synthesis inhibitor or specific antagonists for both types of corticocosteroid receptors (mineralocorticoid receptor, MR, and glucocorticoids receptor, GR) before corticosterone administration shortly before retention testing. The results showed that administration of anisomycin did not change the corticosterone response. Administration of the MR, but not GR, antagonist blocked the corticosterone-induced response dose dependently. These findings provide evidence for the view that glucocorticoids impair memory retrieval through nongenomic mechanisms involving an interaction with central MRs.

Topics: Animals; Anisomycin; Behavior, Animal; Corticosterone; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Hormone Antagonists; Male; Maze Learning; Memory Disorders; Mifepristone; Protein Synthesis Inhibitors; Rats; Rats, Wistar; Receptors, Mineralocorticoid; Spironolactone; Swimming

Learning of new information is transformed into long-lasting memory through a process known as consolidation, which requires protein synthesis. Classical theory held that once consolidated, memory was insensitive to disruption. However, old memories that are insensitive to protein synthesis inhibitors can become vulnerable if they are recalled (reactivated). These findings led to a new hypothesis that when an old memory is reactivated, it again becomes labile and, similar to a newly formed memory, requires a process of reconsolidation in order to be maintained. Here, we show that the requirement for protein synthesis of a reactivated memory is evident only when the memory is recent. In fact, memory vulnerability decreases as the time between the original training and the recall increases.

Topics: Amygdala; Animals; Anisomycin; Brain; Hippocampus; Learning; Male; Memory; Memory Disorders; Nerve Tissue Proteins; Neural Pathways; Protein Synthesis Inhibitors; Rats; Rats, Long-Evans; Reaction Time; Synapses; Synaptic Transmission; Time Factors

Cellular theories of memory consolidation posit that new memories require new protein synthesis in order to be stored. Systems consolidation theories posit that the hippocampus has a time-limited role in memory storage, after which the memory is independent of the hippocampus. Here, we show that intra-hippocampal infusions of the protein synthesis inhibitor anisomycin caused amnesia for a consolidated hippocampal-dependent contextual fear memory, but only if the memory was reactivated prior to infusion. The effect occurred even if reactivation was delayed for 45 days after training, a time when contextual memory is independent of the hippocampus. Indeed, reactivation of a hippocampus-independent memory caused the trace to again become hippocampus dependent, but only for 2 days rather than for weeks. Thus, hippocampal memories can undergo reconsolidation at both the cellular and systems levels.

Topics: Amnesia, Retrograde; Animals; Anisomycin; Conditioning, Psychological; Fear; Hippocampus; Male; Memory; Memory Disorders; Memory, Short-Term; Models, Neurological; Nerve Tissue Proteins; Neural Pathways; Neurons; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley; Reaction Time; Time Factors

It is generally accepted that memory formation involves an irreversible passage via labile phases to the stable form of 'long-term memory' impervious to amnestic agents such as protein synthesis inhibitors. However, recent experiments demonstrate that reactivation of memory by way of a reminder renders it labile to such inhibitors, suggesting that such retrieval is followed by a so-called reconsolidation process similar or identical in its cellular and molecular correlates to that occurring during the initial consolidation. We compared the effects of the protein synthesis inhibitor anisomycin and the glycoprotein synthesis inhibitor 2-deoxygalactose on the temporal dynamics and pharmacological sensitivity of initial consolidation and memory expression following a reminder in a one-trial passive-avoidance task in day-old chicks. This comparison revealed three differences between the action of the inhibitors on newly formed compared with reactivated memory. First, the recall deficit after the reminder was temporary, whilst the amnesia following inhibitor treatment during training was stable. Second, the sensitive period for the effect of anisomycin was shorter in the reminder than in the training situation. Third, the effective dose for either inhibitor for reminder-associated amnesia was several times lower than for amnesia developing after training. Thus though like initial consolidation, memory expression at delayed periods following reminder depends on protein and glycoprotein synthesis, the differences between the temporal and pharmacological dynamics in the two situations point to the distinct character of the molecular processes involved in postreminder effects.

Topics: Amnesia; Animals; Anisomycin; Avoidance Learning; Brain; Chickens; Cues; Dose-Response Relationship, Drug; Female; Fucose; Glycoproteins; Male; Memory; Memory Disorders; Nerve Tissue Proteins; Nucleic Acid Synthesis Inhibitors; Protein Synthesis Inhibitors; Time Factors