Abstract
The mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate (cAMP) signal transduction pathways have critical roles in the consolidation of hippocampus-dependent memory. We found that extracellular regulated kinase 1/2 MAPK phosphorylation and cAMP underwent a circadian oscillation in the hippocampus that was paralleled by changes in Ras activity and the phosphorylation of MAPK kinase and cAMP response element-binding protein (CREB). The nadir of this activation cycle corresponded with severe deficits in hippocampus-dependent fear conditioning under both light-dark and free-running conditions. Circadian oscillations in cAMP and MAPK activity were absent in memory-deficient transgenic mice that lacked Ca2+ -stimulated adenylyl cyclases. Furthermore, physiological and pharmacological interference with oscillations in MAPK phosphorylation after the cellular memory consolidation period impaired the persistence of hippocampus-dependent memory. These data suggest that the persistence of long-term memories may depend on reactivation of the cAMP/MAPK/CREB transcriptional pathway in the hippocampus during the circadian cycle.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenylyl Cyclases / metabolism
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Analysis of Variance
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Animals
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Association Learning / drug effects
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Association Learning / physiology
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Butadienes / pharmacology
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CREB-Binding Protein / metabolism
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Calcium / administration & dosage
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Circadian Rhythm / physiology*
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Conditioning, Classical / drug effects
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Conditioning, Classical / physiology
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Cyclic AMP / deficiency
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Cyclic AMP / metabolism*
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Fear
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GTP-Binding Proteins / metabolism
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology*
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Hippocampus / anatomy & histology
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Hippocampus / drug effects
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Hippocampus / metabolism*
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Memory / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitogen-Activated Protein Kinase Kinases / deficiency
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Motor Activity / physiology
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Nitriles / pharmacology
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Signal Transduction / physiology
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Statistics, Nonparametric
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Time Factors
Substances
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Butadienes
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Enzyme Inhibitors
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Nitriles
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U 0126
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Cyclic AMP
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CREB-Binding Protein
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Mitogen-Activated Protein Kinase Kinases
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GTP-Binding Proteins
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Adenylyl Cyclases
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Calcium