Memory in Mice as Affected by Intracerebral Puromycin

Flexner, Josefa B.; Flexner, Louis B.; Stellar, Eliot

doi:10.1126/science.141.3575.57

Cited by 458 publications

(211 citation statements)

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“…Full restoration of protein synthesis within 6 h following a potentially lethal cell injury thus seems to be in dicative of an escape from neuronal necrosis. This is in agreement with studies using a variety of in hibitors including cycloheximide and puromycin, which reduce the rate of cerebral protein synthesis to <20% of control values for several hours (Mc Innes and Luttges, 1973;Kesner et a!., 198 J), in terrupt axonal transport (Nichols et a!., 1982), and prevent the formation of long-term memory (Flexner et a!. , 1963;Barondes, 1970;Eichenbaum et a!.…”

Section: Discussionsupporting

confidence: 88%

Cerebral Protein Synthesis during Long-Term Recovery from Severe Hypoglycemia

Kiessling

Auer

Kleihues

et al. 1986

J Cereb Blood Flow Metab

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Summary: Regional protein synthesis was investigated in the rat brain during long-term recovery from insulin induced hypoglycemia with 30 min of cerebral electrical silence, At various time intervals up to 14 days after glu cose replenishment, animals received a single dose of L [3,5-3 H]tyrosine and were killed 30 min later. Brains were processed for autoradiography using the stripping film technique, Although hypoglycemia sufficiently severe to cause cessation of EEG activity leads to almost complete inhibition of amino acid incorporation in all "vulnerable" forebrain structures (cerebral cortex, hippocampus, cau doputamen), autoradiographs revealed a very specialized sequence with differential posthypoglycemic restoration of biosynthetic activity in certain neuronal cell types. Three major subpopulations could be distinguished: Neu rons that fully regained their protein synthetic capacity within 6 h following hypoglycemia (cortical neurons of layer III-VI, large neurons in the caudoputamen, CA 3 and CA4 pyramidal neurons, the majority of granule cells Although hypoglycemia is a global insult, its ef fects on the brain are regionally different. This het erogeneity applies to changes in glucose consump tion, blood flow, energy homeostasis, protein syn thesis, and neuronal cell death. Application of the [ 1 4 C]deoxyglucose technique to hypoglycemic "coma" (defined by us as hypoglycemia of suffi cient severity to cause cessation of spontaneous EEG activity) showed a striking heterogeneity in glucose consumption, with low values in the neo cortex, hippocampus, and caudoputamen and high values in the brains tern and cerebellum (Abdul Rahman and Siesjo, 1980 42of the dentate gyrus) seemed to escape neuronal necrosis.Prolonged impairment of protein synthesis with only par tial restoration during the early posthypoglycemic re covery period (CAl neurons, most small-to medium sized neurons of the caudoputamen) carried an increased risk of permanent cell damage. The large majority of these neurons, however, showed full recovery of protein synthesis as late as 7 days after hypoglycemia. Neurons with complete lack of amino acid incorporation after 6 h of recovery (granule cells at the crest of the dentate gyrus, small neurons of the dorsolateral caudoputamen) never resumed protein synthesis, regressed, and died. These studies in conjunction with morphological analysis indicate that the sequential recovery of protein synthesis reflects the extent to which neuronal populations are at risk during severe hypoglycemia. Key Words: Autora diography-Cerebral protein synthesis-Hypogly cemia-Selective vulnerability.zation during severe hypoglycemia, these data dem onstrate interregional differences in glucose avail ability. In addition, the blood flow response to hy poglycemia is regionally different both during hypoglycemia and in the recovery phase (Abdul Rahman et aI. , 1980). While many regions lose vas cular autoregulation during hypoglycemia and be come hypoperfused at very moderate degrees of ar terial hypotension, others...

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Section: Discussionsupporting

confidence: 88%

Cerebral Protein Synthesis during Long-Term Recovery from Severe Hypoglycemia

Kiessling

Auer

Kleihues

et al. 1986

J Cereb Blood Flow Metab

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“…Our argument for such a slowly developing process rests heavily on earlier findings that memory is differentially susceptible to amnesic treatment during this period. For example, puromycin (17) (B, 21 trials) Saline-treated mice performed significantly better than cycloheximide-treated mice 1 day (P < 0.001, t = 4.1) and 2 days (P < 0.05, t = 2.4) after training. The group given cycloheximide and tested 7 days after training exhibited significant savings (P < 0.001, t = 4.7) and was significantly different from cycloheximide-treated mice tested 1 day (P < 0.001, t = 4.2) or 2 days (P < 0.01, t = 2.5) after training.…”

Section: Discussionmentioning

confidence: 99%

Variable Decay of Memory and Its Recovery in Cycloheximide-Treated Mice

Squire

Barondes

1972

Proc. Natl. Acad. Sci. U.S.A.

107

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Mice were trained in an automated visualdiscrimination task. When injected with cycloheximide before training, mice showed: (a) some impairment of memory within minutes after the beginning of training, (b) gradual development of total amnesia in less than 3 hr or in more than 6 hr after training, depending on the extent of training, and (c) spontaneous recovery of memory within 3 days after training. The results are consistent with the operation of three processes of memory storage: (i) a short-term process that is independent of protein synthesis, (ii) a long-term process that is dependent on protein synthesis, and (iii) a slow-developing memory storage that becomes apparent during the days after training.Previous studies on effects of cycloheximide and acetoxycycloheximide on learning and memory in mice given brief training have repeatedly demonstrated normal acquisition in the presence of these potent inhibitors of cerebral protein synthesis, normal retention for about 3 hr, and then marked and permanent amnesia by 6 hr after training (1, 2). These experiments suggested a simple view of learning and memory in mice. Since acquisition and retention for at least 3 hr were normal during marked inhibition of cerebral protein synthesis, it seemed reasonable to postulate a "short-term" memory storage process that is independent of protein synthesis, with a fixed lifetime of 3-6 hr. Since long-term retention was impaired only if the drug were given shortly before or very shortly after training, a "long-term" memory storage process that is dependent on protein synthesis was also postulated that is normally initiated during training or within minutes there-FIG. 1. The Deutsch Carousel for training a discrimination habit in mice. Mice are placed in the apparatus while facing position A. The mouse is then rotated to position B for trial one, and then to adjacent positions for subsequent trials. At each position, the mouse must touch the small object to escape shock. Once the mouse has been secured in the apparatus, the entire training procedure is controlled by a PDP/8L computer.after. With decline of the proposed "short-term" process after 3 hr, absence of the "long-term" process is detectable and amnesia is observed.Recent experiments in a multiple-trial, automated discrimination task and the work of others suggest that the situation is somewhat more complex. In the present report, we describe studies indicating that (a) cycloheximide impairs the gradual acquisition of a discrimination task when training is continued beyond 20-30 trials, although it does not affect acquisition up to this point, (b) memory is detectable for less than 3 hr after training when cycloheximide-treated mice are given brief training, but considerable memory is detectable for more than 6 hr after training when cycloheximide-treated mice are given more extended training, and (c) once amnesia has developed, it may persist for only several days, followed by complete, spontaneous recovery of memory. We will present an interpretation of thes...

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“…As with protein synthesis inhibitors (Flexner et al, 1963;Schafe and LeDoux, 2000;Hernández et al, 2002;Scharf et al, 2002;Naghdi et al, 2003;Agnihotri et al, 2004;Quevedo et al, 2004;Santini et al, 2004), transcription inhibitors block longterm memory (LTM), while not interfering with short-term memory (STM) (Squire and Barondes, 1970;Ohi, 1977;Nguyen et al, 1994;Bailey et al, 1996;Frey et al, 1996;Pedreira et al, 1996;Wustenberg et al, 1998;Igaz et al, 2002;Calixto et al, 2003). Specific transcription factors (Alberini et al, 1994;Kida et al, 2002;Malkani et al, 2004) have been implicated in LTM.…”

Section: Introductionmentioning

confidence: 99%

An Inhibitor of DNA Recombination Blocks Memory Consolidation, But Not Reconsolidation, in Context Fear Conditioning

Colón-Cesario¹,

Wang²,

Ramos³

et al. 2006

J. Neurosci.

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Genomic recombination requires cutting, processing, and rejoining of DNA by endonucleases, polymerases, and ligases, among other factors. We have proposed that DNA recombination mechanisms may contribute to long-term memory (LTM) formation in the brain. Our previous studies with the nucleoside analog 1-␤-D-arabinofuranosylcytosine triphosphate (ara-CTP), a known inhibitor of DNA ligases and polymerases, showed that this agent blocked consolidation of conditioned taste aversion without interfering with short-term memory (STM). However, because polymerases and ligases are also essential for DNA replication, it remained unclear whether the effects of this drug on consolidation were attributable to interference with DNA recombination or neurogenesis. Here we show, using C57BL/6 mice, that ara-CTP specifically blocks consolidation but not STM of context fear conditioning, a task previously shown not to require neurogenesis. The effects of a single systemic dose of cytosine arabinoside (ara-C) on LTM were evident as early as 6 h after training. In addition, although ara-C impaired LTM, it did not impair general locomotor activity nor induce brain neurotoxicity. Importantly, hippocampal, but not insular cortex, infusions of ara-C also blocked consolidation of context fear conditioning. Separate studies revealed that context fear conditioning training significantly induced nonhomologous DNA end joining activity indicative of DNA ligasedependent recombination in hippocampal, but not cortex, protein extracts. Finally, unlike inhibition of protein synthesis, systemic ara-C did not block reconsolidation of context fear conditioning. Our results support the idea that DNA recombination is a process specific to consolidation that is not involved in the postreactivation editing of memories.

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Memory in Mice as Affected by Intracerebral Puromycin

Cited by 458 publications

References 5 publications

Cerebral Protein Synthesis during Long-Term Recovery from Severe Hypoglycemia

Cerebral Protein Synthesis during Long-Term Recovery from Severe Hypoglycemia

Variable Decay of Memory and Its Recovery in Cycloheximide-Treated Mice

An Inhibitor of DNA Recombination Blocks Memory Consolidation, But Not Reconsolidation, in Context Fear Conditioning

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