anisomycin and Amnesia

To date, the effects of protein synthesis inhibitors (PSI) in learning and memory processes have been attributed to translational arrest and consequent inhibition of de novo protein synthesis. Here we argue that amnesia produced by PSI can be the direct result of their abnormal induction of mRNA-a process termed gene superinduction. This action exerted by PSI involves an abundant and prolonged accumulation of mRNA transcripts of genes that are normally transiently induced. We summarize experimental evidence for the multiple mechanisms and signaling pathways mediating gene superinduction and consider its relevance for PSI-induced amnesia. This mechanistic alternative to protein synthesis inhibition is compared to models of electroconvulsive seizures and fragilexsyndrome associated with enhanced mRNA/protein levels and cognitive deficits.

Topics: Amnesia; Anisomycin; Extinction, Biological; Gene Expression Regulation; Genes, fos; Genes, jun; Humans; Models, Biological; Phosphoproteins; Protein Biosynthesis; Protein Synthesis Inhibitors; RNA, Messenger; Signal Transduction

Topics: Adrenocorticotropic Hormone; alpha-Methyltyrosine; Amnesia; Amphetamine; Animals; Anisomycin; Cycloheximide; Disease Models, Animal; Electroshock; Ether; Ethyl Ethers; Humans; Learning; Methyltyrosines; Phenoxybenzamine; Protein Biosynthesis; Puromycin; Reserpine; Strychnine; Tyrosine 3-Monooxygenase; Vasopressins

It is well established that newly acquired information is stabilized over time by processes underlying memory consolidation, these events can be impaired by many drug treatments administered shortly after learning. The consolidation hypothesis has been challenged by a memory integration hypothesis, which suggests that the processes underlying new memories are vulnerable to incorporation of the neurobiological alterations induced by amnesic drugs generating a state-dependent memory. The present experiments investigated the effects of amnesic drugs infused into the insular cortex of male Wistar rats on memory for object recognition training. The findings provide evidence that infusions of several amnesic agents including a protein synthesis inhibitor, an RNA synthesis inhibitor, or an NMDA receptor antagonist administered both after a specific period of time and before retrieval induce state-dependent recognition memory. Additionally, when amnesic drugs were infused outside the early consolidation window, there was amnesia, but the amnesia was not state-dependent. Data suggest that amnesic agents can induce state-dependent memory when administered during the early consolidation window and only if the duration of the drug effect is long enough to become integrated to the memory trace. In consequence, there are boundary conditions in order to induce state-dependent memory.

Topics: Amnesia; Animals; Anisomycin; Dichlororibofuranosylbenzimidazole; Extinction, Psychological; Injections, Intraventricular; Learning; Male; Memory Consolidation; Mental Recall; Nucleic Acid Synthesis Inhibitors; Protein Synthesis Inhibitors; Rats; Rats, Wistar; Recognition, Psychology; Retention, Psychology; Transcription, Genetic

The terrestrial slug Limax can form an odor-aversion memory by the single simultaneous presentation of a food odor and an aversive stimulus. We have previously demonstrated that the long-term retention of this memory was impaired by a high-dose injection of a protein synthesis inhibitor 30min prior to the conditioning. However, the onset of amnesia was delayed if the dose of the inhibitor was reduced or a less potent protein synthesis inhibitor was used. We thus speculated that the persistence of memory depends on the amount of newly synthesized protein following learning. In the present study, we further elaborated on this idea by injecting a high dose of anisomycin at different timings before or after conditioning, and tested the memory retention at 1, 2, 3, 7, or 14days after the conditioning. We found that the injection of anisomycin 6h before, or 1h after the conditioning had no effect on memory retention for 7days, and an injection at 30min before and just following the conditioning impaired the memory retention at 3days. Interestingly, the injection at 3h before and 30min after the conditioning did not impair the retention at 3days but did impair retention at 7days. Taking into account the time course of protein synthesis inhibition in the brain, our results further support the idea that the memory retention period is dependent on the amount of protein synthesized following memory acquisition.

Topics: Amnesia; Animals; Anisomycin; Avoidance Learning; Conditioning, Classical; Gastropoda; Memory, Long-Term; Protein Biosynthesis; Protein Synthesis Inhibitors; Retention, Psychology

In neuroscientists' attempts to understand the long-term storage of memory, topics of particular importance and interest are the cellular and system mechanisms of maintenance (e.g., those sensitive to ζ-inhibitory peptide, ZIP) and those induced by memory retrieval (i.e., reconsolidation). Much is known about each of these processes in isolation, but less is known concerning how they interact. It is known that ZIP sensitivity and memory retrieval share at least some molecular targets (e.g., recycling α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA, receptors to the plasma membrane); conversely, the fact that sensitivity to ZIP emerges only after consolidation ends suggests that consolidation (and by extension reconsolidation) and maintenance might be mutually exclusive processes, the onset of one canceling the other. Here, we use conditioned taste aversion (CTA) in rats, a cortically dependent learning paradigm, to test this hypothesis. First, we demonstrate that ZIP infusions into gustatory cortex begin interfering with CTA memory 43-45 h after memory acquisition-after consolidation ends. Next, we show that a retrieval trial administered after this time point interrupts the ability of ZIP to induce amnesia and that ZIP's ability to induce amnesia is reengaged only 45 h after retrieval. This pattern of results suggests that memory retrieval and ZIP-sensitive maintenance mechanisms are mutually exclusive and that the progression from one to the other are similar after acquisition and retrieval. They also reveal concrete differences between ZIP-sensitive mechanisms induced by acquisition and retrieval: the latency with which ZIP-sensitive mechanisms are expressed differ for the two processes.. Memory retrieval and the molecular mechanisms that are sensitive to ζ-inhibitory peptide (ZIP) are the few manipulations that have been shown to effect memory maintenance. Although much is known about their effect on maintenance separately, it is unknown how they interact. Here, we describe a model for the interaction between memory retrieval and ZIP-sensitive mechanisms, showing that retrieval trials briefly (i.e., for 45 h) interrupt these mechanisms. ZIP sensitivity emerges across a similar time window after memory acquisition and retrieval; the maintenance mechanisms that follow acquisition and retrieval differ, however, in the latency with which the impact of ZIP is expressed.

Topics: Amnesia; Animals; Anisomycin; Avoidance Learning; Cell-Penetrating Peptides; Conditioning, Classical; Female; Lipopeptides; Memory; Mental Recall; Microinjections; Protein Synthesis Inhibitors; Rats; Rats, Long-Evans; Somatosensory Cortex; Taste

Our current understanding of brain mechanisms involved in learning and memory has been derived largely from studies using experimentally naïve animals. However, it is becoming increasingly clear that not all identified mechanisms may generalize to subsequent learning. For example, N-methyl-D-aspartate glutamate (NMDA) receptors in the dorsal hippocampus are required for contextual fear conditioning in naïve animals but not in animals previously trained in a similar task. Here we investigated how animals learn contextual fear conditioning for a second time-a response which is not due to habituation or generalization. We found that dorsal hippocampus infusions of voltage-dependent calcium channel blockers or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) agonist impaired the first, not the second contextual learning. Only manipulations of the entire hippocampus led to an impairment in second learning. Specifically, inactivation of either the dorsal or ventral hippocampus caused the remaining portion of the hippocampus to acquire and consolidate the second learning. Thus, dorsal hippocampus seems necessary for initial contextual fear conditioning, but either the dorsal or ventral hippocampus is sufficient for subsequent conditioning in a different context. Together, these findings suggest that prior training experiences can change how the hippocampus processes subsequent similar learning.

Topics: 2-Amino-5-phosphonovalerate; Amnesia; Animals; Anisomycin; Calcium Channel Blockers; Conditioning, Classical; Electroshock; Excitatory Amino Acid Antagonists; Fear; Freezing Reaction, Cataleptic; GABA Agonists; Hippocampus; Male; Models, Neurological; Models, Psychological; Muscimol; Protein Synthesis Inhibitors; Rats, Sprague-Dawley; Retention, Psychology; Verapamil

When administered near the time of training, protein synthesis inhibitors such as anisomycin impair later memory. A common interpretation of these findings is that memory consolidation requires new protein synthesis initiated by training. However, recent findings support an alternative interpretation that abnormally large increases in neurotransmitter release after injections of anisomycin may be responsible for producing amnesia. In the present study, a local anesthetic was administered prior to anisomycin injections in an attempt to mitigate neurotransmitter actions and thereby attenuate the resulting amnesia. Rats received lidocaine and anisomycin injections into the amygdala 130 and 120 min, respectively, prior to inhibitory avoidance training. Memory tests 48 h later revealed that lidocaine attenuated anisomycin-induced amnesia. In other rats, in vivo microdialysis was performed at the site of amygdala infusion of lidocaine and anisomycin. As seen previously, anisomycin injections produced large increases in release of norepinephrine in the amygdala. Lidocaine attenuated the anisomycin-induced increase in release of norepinephrine but did not reverse anisomycin inhibition of protein synthesis, as assessed by c-Fos immunohistochemistry. These findings are consistent with past evidence suggesting that anisomycin causes amnesia by initiating abnormal release of neurotransmitters in response to the inhibition of protein synthesis.

Topics: Amnesia; Amygdala; Anesthetics, Local; Animals; Anisomycin; Avoidance Learning; Lidocaine; Male; Memory; Norepinephrine; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley

The mammary pheromone promotes the acquisition of novel odorants (CS1) in newborn rabbits. Here, experiments pinpoint that CS1 becomes able to support neonatal learning of other odorants (CS2). We therefore evaluated whether these first- and second-order memories remained dependent after reactivation. Amnesia induced after CS2 recall selectively blocked this memory, when recall and amnesia of CS1 left the souvenir of CS2 safe; this finding partially differed from results obtained in adult mammals. Thus, in this model of neonatal appetitive odor learning, second-order memory seems to depend on first-order memory for its formation but not for its maintenance.

Topics: Aging; Amnesia; Animals; Animals, Newborn; Anisomycin; Conditioning, Operant; Female; Learning; Male; Memory; Mental Recall; Motivation; Odorants; Pheromones; Protein Synthesis Inhibitors; Rabbits; Smell

The NMDA glutamate receptor antagonists (MK-801 or APV) as well as protein synthesis inhibitors (cycloheximide or anisomycine) affect reactivation processes of long-term memory as studied in snail Helix lucorum with food aversion conditioning. It was found that, 24 hours after training, injection of each of the above mentioned substances initiated amnesia with duration more than 3 weeks. Repeated aversion conditioning with the same food (as at initial one) produced no memory restoration. However, amnesia was not observed in snails after simultaneous injection of protein synthesis inhibitor and NMDA glutamate receptor antagonists (MK-801 + cycloheximide or APV + anisomycin) before reminding procedure. In next experiments, cycloheximide was injected 3-9 hours after MK-801/reminding procedure. We have found development of incomplete amnesia in snails with cycloheximide injection 3 or 6 hours after MK-801/reminding procedure and, at repeated aversion conditioning with the same food, memory was quickly restored. Cycloheximide injection 9 hours after MK-801/reminding procedure led to development ofa steady-state amnesia with disruption of aversion conditioning with the same food as at repeated training. We suggest that mechanisms of "MK-801-induced amnesia" (as well as other mechanisms of long-term adaptive processes in the brain) depend on novel protein synthesis and become suppressed after inhibitors of protein synthesis application. "Time window" of amnesia induction process dependence on protein molecules synthesis remains during 6-9 hours after MK-801/reminding procedure.

Topics: Amnesia; Animals; Anisomycin; Cycloheximide; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Helix, Snails; Memory; Protein Biosynthesis; Protein Synthesis Inhibitors; Receptors, N-Methyl-D-Aspartate; Time Factors; Valine

In the adult mouse, signaling through c-Jun N-terminal kinases (JNKs) links exposure to acute stress to various physiological responses. Inflammatory cytokines, brain injury and ischemic insult, or exposure to psychological acute stressors induce activation of hippocampal JNKs. Here we report that exposure to acute stress caused activation of JNKs in the hippocampal CA1 and CA3 subfields, and impaired contextual fear conditioning. Conversely, intrahippocampal injection of JNKs inhibitors sp600125 (30 μm) or D-JNKI1 (8 μm) reduced activity of hippocampal JNKs and rescued stress-induced deficits in contextual fear. In addition, intrahippocampal administration of anisomycin (100 μg/μl), a potent JNKs activator, mimicked memory-impairing effects of stress on contextual fear. This anisomycin-induced amnesia was abolished after cotreatment with JNKs selective inhibitor sp600125 without affecting anisomycin's ability to effectively inhibit protein synthesis as measured by c-Fos immunoreactivity. We also demonstrated milder and transient activation of the JNKs pathway in the CA1 subfield of the hippocampus during contextual fear conditioning and an enhancement of contextual fear after pharmacological inhibition of JNKs under baseline conditions. Finally, using combined biochemical and transgenic approaches with mutant mice lacking different members of the JNK family (Jnk1, Jnk2, and Jnk3), we provided evidence that JNK2 and JNK3 are critically involved in stress-induced deficit of contextual fear, while JNK1 mainly regulates baseline learning in this behavioral task. Together, these results support the possibility that hippocampal JNKs serve as a critical molecular regulator in the formation of contextual fear.

Topics: Amino Acid Sequence; Amnesia; Animals; Anisomycin; Association Learning; Avoidance Learning; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Down-Regulation; Female; Hippocampus; Isoenzymes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 10; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase 9; Molecular Sequence Data; Neurons; Protein Kinase Inhibitors; Stress, Psychological

To this day, it remains unresolved whether experimental amnesia reflects failed memory storage or the inability to retrieve otherwise intact memory. Methodological as well as conceptual reasons prevented deciding between these two alternatives: The absence of recovery from amnesia is typically taken as supporting storage impairment interpretations; however, this absence of recovery does not positively demonstrate nonexistence of memory, allowing for alternative interpretations of amnesia as impairment of memory retrieval. To address this shortcoming, we present a novel approach to study the nature of amnesia that makes positive, i.e., falsifiable, predictions for the absence of memory. Applying this paradigm, we demonstrate here that infusing anisomycin into the dorsal hippocampus induces amnesia by impairing memory storage, not retrieval.

Topics: Amnesia; Animals; Anisomycin; Conditioning, Operant; Extinction, Psychological; Hippocampus; Injections, Intraventricular; Male; Memory; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley

Intra-amygdala injections of anisomycin produce large increases in the release of norepinephrine (NE), dopamine (DA), and serotonin in the amygdala. Pretreatment with intra-amygdala injections of the beta-adrenergic receptor antagonist propranolol attenuates anisomycin-induced amnesia without reversing the inhibition of protein synthesis, and injections of NE alone produce amnesia. These findings suggest that abnormal neurotransmitter responses may be the basis for amnesia produced by inhibition of protein synthesis. The present experiment extends these findings to the hippocampus and adds acetylcholine (ACh) to the list of neurotransmitters affected by anisomycin. Using in vivo microdialysis at the site of injection, release of NE, DA, and ACh was measured before and after injections of anisomycin into the hippocampus. Anisomycin impaired inhibitory avoidance memory when rats were tested 48 h after training and also produced substantial increases in local release of NE, DA, and ACh. In an additional experiment, pretreatment with intrahippocampal injections of propranolol prior to anisomycin and training significantly attenuated anisomycin-induced amnesia. The disruption of neurotransmitter release patterns at the site of injection appears to contribute significantly to the mechanisms underlying amnesia produced by protein synthesis inhibitors, calling into question the dominant interpretation that the amnesia reflects loss of training-initiated protein synthesis necessary for memory formation. Instead, the findings suggest that proteins needed for memory formation are available prior to an experience, and that post-translational modifications of these proteins may be sufficient to enable the formation of new memories.

Topics: Acetylcholine; Amnesia; Animals; Anisomycin; Dopamine; Hippocampus; Injections, Intraventricular; Memory; Microdialysis; Neurotransmitter Agents; Norepinephrine; Protein Processing, Post-Translational; Protein Synthesis Inhibitors; Rats

The temporal dynamics of consolidation and reconsolidation of taste/odor aversion memory are evaluated during rat pup growth at postnatal days 3, 10, and 18. This is assessed through the temporal gradients of efficacy of a protein synthesis inhibitor (anisomycin) in inducing amnesia after either acquisition (consolidation) or reactivation (reconsolidation). The results show a progressive reduction with age of the delay during which the inhibitor is able to induce amnesia. Control experiments rule out a reduction of anisomycin efficacy due to blood brain barrier growth or decrease in protein synthesis inhibition. Thus, these results present the first evidence that the protein synthesis-dependent phase of memory stabilization requires less time with age. This decrease occurs in parallel for consolidation and reconsolidation. Such changes in the dynamics of memory processing could contribute to the cognitive improvement associated with development.

Topics: Age Factors; Amnesia; Animals; Animals, Newborn; Anisomycin; Conditioning, Psychological; Dose-Response Relationship, Drug; Memory; Protein Synthesis Inhibitors; Rats; Time Factors; Weaning

Memories are dynamic, rather than static, in nature. The reactivation of a memory through re-exposure to salient training stimuli results in its destabilization, necessitating a restabilization process known as reconsolidation, a disruption of which leads to amnesia. I found that one normal function of hippocampal memory reconsolidation in rats is to modify the strength of a contextual-fear memory as a result of further learning.

Topics: Amnesia; Analysis of Variance; Animals; Anisomycin; Behavior, Animal; Brain-Derived Neurotrophic Factor; Conditioning, Psychological; Early Growth Response Protein 1; Fear; Freezing Reaction, Cataleptic; Hippocampus; Lactones; Learning; Male; Memory; Oligodeoxyribonucleotides, Antisense; Protein Synthesis Inhibitors; Rats

Reconsolidation has proven to be a common phenomenon relevant to memory processing. However, the functional significance of this process is still a matter of debate. Previous work has shown that reconsolidation is indeed a process by which updated information is integrated, through the synthesis of proteins, to a memory trace. To further analyze the role that updated information plays in retrieved spatial memory susceptibility to disruption, we injected anisomycin bilaterally in the dorsal hippocampus of Wistar rats. Implanted animals were trained for 5 days on the Morris water maze (MWM) task and injected with anisomycin before the third or fifth training session. When memory was assessed a week later, only animals injected on the third training session showed disruption of long-term memory. Furthermore, when animals were trained for either 3 (middle-trained) or 5 (well-trained) days and a week later anisomycin was infused before a reminder session, only middle-trained rats infused with anisomycin showed reduced performance when tested for long-term memory. Finally, animals trained for 5 days and injected with anisomycin 7 days later on an extinction session showed impaired long-term extinction when tested. These results suggest that for spatial memory tasks acquisition of updated information is a necessary feature to undergo this process. We propose that reconsolidation is not an accurate term because it implies that consolidation happens again. This conception does not fit with the evidence; hence, we suggest that updating consolidation is a more descriptive term to refer to this process.

Topics: Amnesia; Animals; Anisomycin; Extinction, Psychological; Functional Laterality; Hippocampus; Male; Maze Learning; Memory; Protein Synthesis Inhibitors; Rats; Rats, Wistar; Space Perception

The cerebellum, amygdala and perirhinal cortex are involved in fear learning but the different roles that these three structures play in aversive learning are not well defined. Here we show that in adult rats amygdala or cerebellar vermis blockade causes amnesia when performed immediately, but not 1 h, after the recall of fear memories. Thus, the cerebellum, as well as the amygdala, influences long-term fear memories. These effects are long lasting, as they do not recover over time, even after a reminder shock administration. However, all of the subjects were able to form new fear memories in the absence of inactivation. By increasing the strength of conditioning, we observed that stronger fear memories are affected by the combined but not independent amygdala and cerebellar blockade. These results demonstrate that the cerebellum supports the memory processes even in the absence of a crucial site for emotions like the amygdala. Furthermore, they suggest that the amygdala is only one of the neural sites underlying long-term fear memories. Finally, the inactivation of the perirhinal cortex never alters retrieved fear traces, showing important differences between the amygdala, cerebellum and perirhinal cortex in emotional memories.

Topics: Amnesia; Amygdala; Animals; Anisomycin; Avoidance Learning; Cerebellum; Fear; Male; Memory; Nerve Net; Nerve Tissue Proteins; Neural Pathways; Parahippocampal Gyrus; Protein Synthesis Inhibitors; Rats; Rats, Wistar; Sodium Channel Blockers; Tetrodotoxin; Time; Time Factors

Amnesia produced by protein synthesis inhibitors such as anisomycin provides major support for the prevalent view that the formation of long-lasting memories requires de novo protein synthesis. However, inhibition of protein synthesis might disrupt other neural functions to interfere with memory formation. Intraamygdala injections of anisomycin before inhibitory avoidance training impaired memory in rats tested 48 h later. Release of norepinephrine (NE), dopamine (DA), and serotonin, measured at the site of anisomycin infusions, increased quickly by approximately 1,000-17,000%, far above the levels seen under normal conditions. NE and DA release later decreased far below baseline for several hours before recovering at 48 h. Intraamygdala injections of a beta-adrenergic receptor antagonist or agonist, each timed to blunt effects of increases and decreases in NE release after anisomycin, attenuated anisomycin-induced amnesia. In addition, similar to the effects on memory seen with anisomycin, intraamygdala injections of a high dose of NE before training impaired memory tested at 48 h after training. These findings suggest that altered release of neurotransmitters may mediate amnesia produced by anisomycin and, further, raise important questions about the empirical bases for many molecular theories of memory formation.

Topics: Adrenergic Agonists; Adrenergic Antagonists; Amnesia; Amygdala; Animals; Anisomycin; Dopamine; Male; Norepinephrine; Protein Biosynthesis; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Serotonin; Time Factors

Systemic or intra-hippocampal administration of the protein synthesis inhibitor anisomycin generally leads to impairments in memory tested 24 hr or more after training but spares memory for a few hours after training. Thus, amnesia does not appear immediately after training but develops with time, findings most often interpreted as evidence for distinct short- and long-term memory processes. However, time courses for the onset of amnesia vary substantially after treatment with protein synthesis inhibitors. Some of the variability across experiments may reflect task-related differences or, perhaps relatedly, may reflect memory processing mediated by different neural systems. In the present experiments, anisomycin was infused into either the hippocampus or the amygdala 20 min before inhibitory avoidance training. Similar to previous findings, intra-hippocampus injections of anisomycin impaired memory tested 48 hr after training yet spared memory tested 4 hr after training. In contrast, intra-amygdala injections of anisomycin impaired memory tested at 0.5, 4, and 48 hr after training, revealing no evidence for spared memory at short times after training. The distinct temporal properties for amnesia following anisomycin injections into the hippocampus or amygdala may reflect different consequences for memory of perturbations of the neural system in which the manipulation is made.

Topics: Amnesia; Amygdala; Animals; Anisomycin; Avoidance Learning; Behavior, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Hippocampus; Male; Protein Synthesis Inhibitors; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Reaction Time; Statistics, Nonparametric; Time Factors

The effects of protein synthesis inhibitors on the reactivation of an associative skill consisting of refusing a particular food by common snails were studied. Animals were given single injections of a protein synthesis inhibitor (cycloheximide at 0.6 mg/snail or anisomycin at 0.4 mg) 24 h after three days of training, and were then presented with a "reminding" stimulus (the "conditioned reflex" food-banana) and tested for retention of the skill. Observations revealed an impairment of reproduction of the acquired skill 2.5 h after the "reminder," with spontaneous restoration at 4.5-5.5 h. Other snails were given single 1.8-mg doses of cycloheximide or three 0.6-mg doses with intervals of 2 h. "Reminders" were presented after each injection. In these conditions, impairment of reproduction of the conditioned reflex also appeared 2.5 h after the first "reminder," though amnesia lasted at least 30 days and repeat training of the animals produced only partial recovery of the skill. Thus, we have provided the first demonstration that recovery of a long-term memory "trace" on exposure to relatively low doses of protein synthesis inhibitors produces transient and short-lived amnesia, lasting 2-3 h, while long-term, irreversible amnesia occurs after longer-lasting or more profound suppression of protein synthesis. These results suggest that the "reminding" process induces reconsolidation of the " initial" memory, suppression of which by protein synthesis inhibitors leads to "erasure" of the memory "trace" and impairs consolidation on repeat training.

Topics: Amnesia; Animals; Anisomycin; Association Learning; Conditioning, Classical; Cycloheximide; Dose-Response Relationship, Drug; Feeding Behavior; Helix, Snails; Memory; Protein Synthesis Inhibitors

Memory traces, once established, are no longer sensitive to disruption by metabolic inhibitors. However, memories reactivated by reminder are once again vulnerable, in a time-dependent manner, to amnestic treatment. To determine whether the metabolic events following a reminder recapitulate those following initial training we examined the temporal dynamics of amnesia induced by the protein synthesis inhibitor anisomycin and the glycosylation inhibitor 2-deoxygalactose. The effects of both were transient and dependent on time of reminder post-training and time of injection relative to reminder, and differed from those following initial training. 2-[(14)C]-deoxyglucose uptake increased in two brain regions, the intermediate medial hyperstriatum ventrale (IMHV) and lobus parolfactorius (LPO) following reminder as it did following training, but the increase was bilateral rather than confined to the left hemisphere and was more marked in LPO than IMHV. C-fos expression after reminder was increased only in the LPO, the chick brain region associated with a late phase of memory processing and recall. Thus although, like initial consolidation, memory processing after reminder is sensitive to inhibitors of protein synthesis and glycosylation, the temporal and pharmacological dynamics indicate differences between these two processes.

Topics: Amnesia; Analysis of Variance; Animals; Anisomycin; Avoidance Learning; Behavior, Animal; Brain; Carbon Isotopes; Cell Count; Chickens; Enzyme-Linked Immunosorbent Assay; Female; Functional Laterality; Galactose; Immunohistochemistry; Male; Memory; Protein Synthesis Inhibitors; Proto-Oncogene Proteins c-fos; Retention, Psychology; Time Factors

Information storage in the brain is a temporally graded process involving different memory types or phases. It has been assumed for over a century that one or more short-term memory (STM) processes are involved in processing new information while long-term memory (LTM) is being formed. It has been repeatedly reported that LTM requires de novo RNA synthesis around the time of training. Here we show that LTM formation of a one-trial inhibitory avoidance training in rats, a hippocampal-dependent form of contextual fear conditioning, depends on two consolidation periods requiring synthesis of new mRNAs. By injecting the RNA polymerase II inhibitors 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole or alpha-amanitin into the CA1 region of the dorsal hippocampus at various times before and after training, we found that hippocampal gene expression is critical in two time windows: around the time of training and 3-6 hr after training. Interestingly, these two periods of sensitivity to transcriptional inhibitors are similar to those observed using the protein synthesis inhibitor anisomycin. These findings underscore the parallel dependence of LTM formation of contextual fear on mRNA and protein synthesis in the hippocampus and suggest that the two time periods of anisomycin-induced amnesia depend at least in part on new mRNA synthesis.

Topics: Amanitins; Amnesia; Animals; Anisomycin; Avoidance Learning; Catheterization; Dichlororibofuranosylbenzimidazole; Drug Administration Routes; Enzyme Inhibitors; Fear; Gene Expression; Hippocampus; Male; Memory; Motivation; Nucleic Acid Synthesis Inhibitors; Rats; Rats, Wistar; RNA Polymerase II; RNA, Messenger; Time Factors

The terrestrial slug Limax avoids the odor of innately preferred food after it is presented with the aversive taste of quinidine. This type of associative memory persists for several weeks. We investigated effects of protein synthesis inhibitors on the retention of this odor-taste associative memory. Anisomycin or cycloheximide applied to the slug 30 min prior to conditioning impaired the memory retention as late as two or more days after the conditioning, while the retention of a short-term memory was normal for up to 24 h. In contrast, the inhibition of protein synthesis by these inhibitors decays within several hours. In Limax, the onset of amnesia is unusually delayed when protein synthesis is suppressed at the time of conditioning.

Topics: Amnesia; Animals; Anisomycin; Association Learning; Avoidance Learning; Chi-Square Distribution; Cycloheximide; Memory; Mollusca; Nerve Tissue Proteins; Odorants; Protein Synthesis Inhibitors; Taste; 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

Long-term memory formation for passive-avoidance learning in the day-old chick is known to have two distinct time windows of protein synthesis (F.M. Freeman, S.P.R. Rose, A.B. Scholey, 1995. Two time windows of anisomycin-induced amnesia for passive-avoidance training in the day-old chick. Neurobiol. Learn. Mem. 63, 291-295). The lobus parolfactorius (LPO) is thought to be an important site for the second wave of protein synthesis which occurs 4-5 h after training. Birds received bilateral intracranial injections of agonists and antagonists for the mu-, delta-, kappa-opioid receptors and the opioid receptor-like (ORL(1)) receptor directly into the LPO at 5 h post-training and were tested for recall 24 h later. Also, 100 microM beta-funaltrexamine (beta-FAN), a mu-opioid receptor antagonist, significantly impaired memory formation (P<0.01). The delta-opioid receptor was also involved in memory formation at this time-point since antagonism of this receptor by 1 mM ICI-174,864 caused amnesia (P<0.01) which was reversed by the agonist, DPLPE. The kappa-opioid receptor appeared not to be involved during the second phase of neuronal activity since neither stimulation by dynorphin nor inhibition by nor-BIN caused amnesia for the task. The ORL(1) receptor agonist orphanin FQ also had no effect suggesting that this receptor was not involved at this 5-h time-point. Cytosolic and mitochondrial protein synthesis has been shown to be important in passive-avoidance learning in the day-old chick. Both chloramphenicol (CAP) and anisomycin (ANI), inhibitors of mitochondrial and cytosolic protein synthesis, respectively, caused disruption when injected 5 h post-training into the LPO (P<0.05). Endomorphin-2 (Endo-2), a mu-opioid receptor agonist, reversed both the ANI- and CAP-sensitivity. However, DPLPE, a delta-opioid receptor agonist, only reversed the effect due to CAP. Possible mechanisms for these effects are discussed.

Topics: Age Factors; Amnesia; Analgesics, Opioid; Animals; Anisomycin; Avoidance Learning; Brain Chemistry; Chickens; Chloramphenicol; Conditioning, Psychological; Dynorphins; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine; Female; Male; Memory; Naltrexone; Narcotic Antagonists; Neurons; Nociceptin; Oligopeptides; Opioid Peptides; Protein Synthesis Inhibitors; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Vasodilator Agents

'New' memories are initially labile and sensitive to disruption before being consolidated into stable long-term memories. Much evidence indicates that this consolidation involves the synthesis of new proteins in neurons. The lateral and basal nuclei of the amygdala (LBA) are believed to be a site of memory storage in fear learning. Infusion of the protein synthesis inhibitor anisomycin into the LBA shortly after training prevents consolidation of fear memories. Here we show that consolidated fear memories, when reactivated during retrieval, return to a labile state in which infusion of anisomycin shortly after memory reactivation produces amnesia on later tests, regardless of whether reactivation was performed 1 or 14 days after conditioning. The same treatment with anisomycin, in the absence of memory reactivation, left memory intact. Consistent with a time-limited role for protein synthesis production in consolidation, delay of the infusion until six hours after memory reactivation produced no amnesia. Our data show that consolidated fear memories, when reactivated, return to a labile state that requires de novo protein synthesis for reconsolidation. These findings are not predicted by traditional theories of memory consolidation.

Topics: Amnesia; Amygdala; Animals; Anisomycin; Conditioning, Classical; Electroshock; Fear; Male; Memory; Mental Recall; Nerve Tissue Proteins; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley

The antibiotic anisomycin (ANI), a protein synthesis inhibitor, was used to investigate the time-related changes in protein synthesis following passive avoidance training in the day-old chick. Retention of memory for this simple learning task is known to be prevented by protein synthesis inhibitors within the first hour post-training. Here we report a second, later time window during which inhibition of protein synthesis results in amnesia following one-trial passive avoidance training. Birds were given bilateral intracranial injections of ANI (10 microliters/hemisphere of a 30 mM solution) at various times relative to training and tested 24 h later. Injections given between 0.5 h prior to 1.5 h post-training or 4-5 h post-training, but not at later or at intervening times, resulted in amnesia. These results are discussed in the context of earlier findings, using the inhibitor of glycoprotein synthesis 2-deoxygalactose, that memory formation shows two glycoprotein-synthesis-dependent periods of sensitivity (Scholey, Rose, Zamani, Bock, & Schachner, 1993). The time windows of susceptibility of ANI and 2-Dgal are consistent with a model in which there are two waves of neural activity following training; during the second, commencing 4 h after training, proteins are synthesized and then glycosylated as part of the establishment of an enduring memory trace.

Topics: Amnesia; Animals; Animals, Newborn; Anisomycin; Avoidance Learning; Behavior, Animal; Chickens; Female; Male; Time Factors

It has recently been suggested that intraperitoneal (IP) injection of anisomycin (ANI) in the chick produces amnesia for a one-trial passive avoidance task in a state-dependent manner. We have examined the behavioral and biochemical effects of IP and intracranial (IC) injections of ANI in chicks trained on a one-trial passive avoidance task. IC injection of ANI produced 35% brain protein synthesis inhibition whereas IP injection produced only negligible amounts of protein synthesis inhibition in the brain. IC injection of ANI produced amnesia and was not state-dependent. Patterns of behavior consistent with state-dependent effects were produced by IP injection of ANI. These experiments indicate that there are differences in the pattern of results produced by IP and IC injection of ANI and support the hypothesis that the expression of long-term memory in chicks is associated with protein synthesis.

Topics: Amnesia; Animals; Anisomycin; Avoidance Learning; Chickens; Frontal Lobe; Injections, Intraperitoneal; Microinjections; Pyrrolidines

Many studies suggest that protein synthesis is required for formation of long-term memory. To test whether the protein synthesis inhibitor anisomycin (ANI) actually inhibits long-term memory formation or whether apparent amnesia could be attributed to state-dependency, chicks were both trained and tested under the influence of anisomycin (ANI). Two-day-old cockerels were trained in a 1-trial passive avoidance task. Intracerebral injections (10 microliters per hemisphere) of either saline (SAL) or 11.0 mM ANI were made into the medial hyperstriatum ventrale 5 min pretraining and 5 min pretest. The ANI inhibited cerebral protein synthesis by 70-80%, a level necessary to cause amnesia. Chicks that pecked a small bead dipped in methylanthranilate (MeA) and were injected with SAL both pretraining and pretest avoided pecking at test, showing memory for the bitter substance; chicks given ANI pretraining and SAL pretest pecked at the bead during test, which suggests amnesia. However, those given ANI both pretraining and pretest showed marked avoidance at test. Chicks trained to peck at a small bead dipped in water and given injections of either SAL or ANI pretraining and SAL pretest pecked readily at test. However, water-trained chicks given ANI pretest, regardless of pretraining injection, showed significantly higher avoidance at test. We conclude that peck aversion in the ANI-MeA-ANI group was not due to state-dependency but to generalized avoidance induced by pretest ANI.

Topics: Amnesia; Animals; Anisomycin; Avoidance Learning; Brain; Chickens; Nerve Tissue Proteins; Pyrrolidines

Two experiments investigated the effects of lithium chloride (LiCl) and anisomycin (ANI) in a water reward Y-maze task. In Experiment 1, male CD-1 mice given weak or strong training were injected post-training with either saline or LiCl (150 mg/kg), which has been reported to produce conditioned aversion in mice. One day after training, both LiCl groups avoided the rewarded arm of the maze and drank less water than saline-injected controls. Two days after training, the strongly trained LiCl mice showed avoidance, while both LiCl groups drank less water. In Experiment 2, weakly trained mice given pre- and post-training ANI (30 mg/kg) were amnesic on the second test day compared to mice that received post-trial saline. However, water consumption was increased on the test day for both groups. LiCl produced a different pattern of results than ANI in this task. On the basis of these results, it is suggested that amnesia produced by ANI is due to impaired memory formation and not to conditioned aversion.

Topics: Amnesia; Animals; Anisomycin; Appetitive Behavior; Avoidance Learning; Chlorides; Drinking Behavior; Lithium; Lithium Chloride; Male; Memory; Mice; Mice, Inbred Strains; Pyrrolidines

A series of biochemical and behavioral experiments tested the hypothesis that anisomycin (ANI), a protein synthesis inhibitor, produced decrements in long-term memory by raising free tyrosine levels and by the accumulation of catecholamines (CAs) rather than by its primary effect on protein synthesis. We compared the effects of ANI and three catecholamine synthesis inhibitors (CAIs)--diethyldithiocarbamic acid, alpha-methyl-p-tyrosine, and tetrabenazine--on cerebral concentrations of tyrosine and CAs and on the rate of accumulation of CAs. ANI had a relatively small effect, whereas the CAIs resulted in large reductions. When ANI and a CAI were used in combination, effects on CA levels were determined mainly by the CAI. The amnestic effects of ANI and the CAIs were also compared across seven experimental paradigms. Pretraining administration of any of the four drugs could result in amnesia for passive avoidance training, but only when training was weak. With an increase in training strength, a series of three injections of ANI (one pre- and two post-training) caused amnesia, but a similar series of CAI injections did not. Substituting one CAI injection for the second of three successive ANI injections did not cause amnesia, but substituting cycloheximide, another protein synthesis inhibitor, resulted in amnesia. With an active avoidance test, ANI caused amnesia while AMPT did not; d-amphetamine blocked the amnestic effect of ANI but caused amnesia in AMPT injected mice. Whereas ANI lengthened the temporal gradient over which electroconvulsive shock produced amnesia, AMPT or DDC did not. DDC caused only transient amnesia for passive avoidance training, while the amnestic effect of ANI remained constant at 24-hr and 1-week retention tests. We conclude that ANI and CAIs have distinctly different abilities to produce amnesia. These experiments provide additional support for the hypothesis that protein synthesis is required for formation of long-term memory.

Topics: Amnesia; Animals; Anisomycin; Avoidance Learning; Behavior, Animal; Brain Chemistry; Catecholamines; Cycloheximide; Dextroamphetamine; Dopamine; Electroshock; Male; Mice; Norepinephrine; Protein Biosynthesis; Spectrometry, Fluorescence; Time Factors; Tyrosine

The amnesia induced by cycloheximide (CXM) injected SC and by CXM or anisomycin injected ICV immediately after the training test was antagonized in combination with an opiate antagonist, naloxone (NLX). This antagonism occurred on both the passive avoidance- and escape-learning responses in a dose-dependent manner in mice. NLX alone (0.3-10.0 mg/kg) did not alter the performances of these tasks. Furthermore, the decrease in retention performance on shuttle avoidance in rats induced by CXM was also antagonized by NLX. Treatment with CXM and/or NLX did not affect spontaneous locomotor activity. The interaction of these drugs on the performance of the passive avoidance- and escape-learning and the shuttle avoidance tasks may be related to neurochemical memory processes. These results suggest that an opioid system may participate in the amnesic actions induced by protein synthesis inhibitors in these models.

Topics: Amnesia; Animals; Anisomycin; Avoidance Learning; Cycloheximide; Escape Reaction; Male; Memory; Mice; Naloxone; Pyrrolidines; Rats; Rats, Inbred Strains

Topics: Adrenal Cortex Hormones; Amnesia; Animals; Anisomycin; Brain; Catecholamines; Chlorides; Conditioning, Classical; Cycloheximide; Humans; Learning; Lithium; Lithium Chloride; Memory; Memory, Short-Term; Mice; Nerve Tissue Proteins; Puromycin; Retention, Psychology; Time Factors

The ergot alkaloid Hydergine was tested for its ability to reverse an amnesia for approach-avoidance training. Thirsty mice were trained to drink in a test chamber and then punished with brief electric shocks for drinking. Those mice injected with the protein-synthesis inhibitor anisomycin immediately after training were amnesic for the shock when tested 48 h later. Pre-test injection of 10.0 or 1.0 mg/kg of Hydergine effectively reversed the amnesia while 0.1 mg/kg was ineffective. Non-contingent shock control groups ruled out the possibility that the effect was due to non-specific effects of the drug or training stimuli.

Topics: Amnesia; Animals; Anisomycin; Avoidance Learning; Dihydroergotoxine; Humans; Male; Mice; Mice, Inbred Strains

Tests were made of the postulates stating that the degree of inhibition of protein synthesis either (a) at training or (b) following training is the critical variable that determines the degree of amnesia. As a first step it was found that the concentrations of numerous cerebral amino acids were substantially increased in 2 strains of mice 0.5 hr after treatment with amnesic doses of the inhibitors of protein synthesis, cycloheximide (CXM) and anisomycin. This observation led, in several different experiments, to a comparison of the apparent degree of inhibition of protein synthesis derived from the acid-soluble radioactivity with that derived from the specific radioactivity of tyrosine tagged with L(1-14C)-tyrosine. In all instances the apparent degree of inhibition was decreased when based upon tyrosine's specific radioactivity. The effect of several treatments with CXM on memory of a 1-trial passive avoidance task provided data for analysis of the relationship between the degrees of amnesia and those of the more accurate estimates of inhibition of protein synthesis based upon the specific radioactivity of tyrosine. The results failed to support the views that the level of inhibition of protein synthesis at or after training are entirely sufficient to account for the behavioral rr indirect change in the brain that antagonizes the amnesic effects of the antibiotic and that consequently contributes to the survival of memory in mice trained 2 hr after a large amnesic dose of CXM.

Topics: Amino Acids; Amnesia; Animals; Anisomycin; Brain; Cycloheximide; Humans; Male; Memory; Mice; Nerve Tissue Proteins; Pyrrolidines

Retrograde amnesia following inhibition of cerebral protein synthesis has generally been explained as either a failure of consolidation or impairment of a retrieval mechanism. Major evidence for the retrieval hypothesis is provided by studies which utilize a reminder (usually footshock) to attenuate the effect of the protein inhibitor. To examine this question, mice were injected subcutaneously with anisomycin (1 mg/animal, 7 mg/animal, or 1 mg/animal every 2 hr x 7) and given one training trial in a passive avoidance box. All animals received a single retention test on each of four consecutive days, starting either 1, 7, or 21 days after training. One-half of the mice in each group received a footshock reminder 1 hr after their initial test. The footshock reminder did not attenuate the inhibitor-induced amnesia, but multiple testing did produce partial recovery in animals demonstrating some memory of training (both Saline and Anisomycin animals). Animals injected with anisomycin whose testing began 1 day after training demonstrated partial recovery irrespective of drug dosage level. The extent of amnesia and recovery were dependent upon both drug dosage and training-test interval. Implications for the consolidation and retrieval hypotheses are discussed.

Topics: Amnesia; Animals; Anisomycin; Brain; Conditioning, Operant; Electroshock; Humans; Male; Mice; Nerve Tissue Proteins; Time Factors

Topics: Amnesia; Animals; Anisomycin; Arousal; Avoidance Learning; Central Nervous System Stimulants; Chloral Hydrate; Conditioning, Operant; Dextroamphetamine; Drug Antagonism; Drug Synergism; Humans; Hypnotics and Sedatives; Male; Memory; Mice; Nerve Tissue Proteins; Phenobarbital; Picrotoxin; Retention, Psychology; Strychnine; Time Factors

Two antibiotic inhibitors of protein synthesis, emetine and pactamycin, have been tested for their effects on cerebral and peripheral protein synthesis and amnesia. Peripherally administered emetine but not pactamycin inhibited cerebral protein synthesis, although this inhibition was lower than that observed with cycloheximide or anisomycin. Pactamycin had a lesser effect on adrenal protein synthesis than emetine. This was reflected in the ability of emetine but not pactamycin to block ACTH-induced corticosteroidogenesis. Anisomycin and cycloheximide caused amnesia in a passive avoidance task, whereas pactamycin and emetine did not. These results are inconsistent with the amnesia being due to inhibition of protein synthesis in a peripheral organ. They are also inconsistent with the amnesia being due to the suppression of an adrenocortical response as previously suggested. No obvious correlation between amnesia and the mechanism of protein synthesis was observed. The most parsimonious explanation is that inhibition of cerebral protein synthesis is necessary for amnesia.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Amnesia; Animals; Anisomycin; Antibiotics, Antineoplastic; Avoidance Learning; Brain; Corticosterone; Cycloheximide; Depression, Chemical; Emetine; Humans; Liver; Male; Mice; Mice, Inbred ICR; Nerve Tissue Proteins; Pactamycin; Protein Biosynthesis; Time Factors

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Aminoglutethimide; Amnesia; Animals; Anisomycin; Avoidance Learning; Corticosterone; Cycloheximide; Desoxycorticosterone; Dexamethasone; Humans; Male; Mice; Nerve Tissue Proteins; Retention, Psychology; Time Factors

Topics: Amnesia; Amnesia, Retrograde; Animals; Anisomycin; Avoidance Learning; Brain; Electroshock; Humans; Memory; Memory, Short-Term; Mice; Nerve Tissue Proteins; Sleep, REM; Time Factors

The effects of peptides derived from ACTH on the formation of long-term memory have been investigated in male mice. Post-training administration of ACTH 4-10-L-Phe-7 (ACTH-L) improved retention for both passive and active avoidance tasks. Administration of ACTH 4-10-D-Phe-7 (ACTH-D) impaired retention for both tasks. The optimum dose for ACTH-L was about 0.3 mg/kg; the optimum dose for ACTH-D was in the range of 1.0-3.0 mg/kg. Using the passive avoidance task, it was shown that either drug had to be administered within 60 min of training to be highly effective. Amnesia produced by anisomycin (Ani), an inhibitor of protein synthesis, was lessened by ACTH-L and increased by ACTH-D, ACTH-D opposed the memory facilitating effects of ACTH-L. Using intact mice, ACTH-L or ACTH-D did not significantly change the incorporation of valine into protein, nor did these peptides influence the inhibition of protein synthesis caused by anisomycin. The results show that ACTH may play a major role in memory processing, perhaps by facilitating essential protein synthesis at sites specific for the memory being established.

Topics: Adrenocorticotropic Hormone; Amnesia; Animals; Anisomycin; Avoidance Learning; Brain; Dose-Response Relationship, Drug; Drug Interactions; Humans; Male; Memory; Mice; Nerve Tissue Proteins; Peptide Fragments; Stereoisomerism; Time Factors; Valine

Topics: Amnesia; Animals; Anisomycin; Avoidance Learning; Brain; Conditioning, Psychological; Cycloheximide; Discrimination Learning; Dogs; Female; Humans; Lithium; Male; Memory; Mice; Protein Biosynthesis; Proteins; Pyrrolidines

Anisomycin, an inhibitor of brain protein synthesis, was used to control the time and duration of protein synthesis occurring in mice after they were trained on a one-trial passive avoidance task. It was found that if synthesis was strongly inhibited for 6 to 8 hr, a high percentage of the animals was amnesic. However, if small amounts of protein synthesis were allowed to occur by permitting intervals of partial recovery of protein synthesis during the period of inhibition, then fewer mice were amnesic. The longer the duration of this interval of controlled synthesis and the closer it occurred to training, the greater the percentage of subjects remembering the training.

Topics: Amnesia; Animals; Anisomycin; Avoidance Learning; Brain; Brain Chemistry; Depression, Chemical; Female; Humans; Injections; Memory; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Reaction Time; Time Factors