An enduring question in neuroscience is how memories persist over long periods (see Roth and Sweatt). Eckel-Mahan et al. report that a mitogen-activated protein kinase (MAPK) signaling pathway--composed of Ras, extracellular signal-regulated kinases 1 and 2 (ERK1/2), MEK1 and 2 (kinases upstream of ERK), and the downstream transcriptional regulator CREB--that is activated by cAMP undergoes circadian changes in activity, with the peak of activity during the day and the minimum during the night. This circadian oscillation persisted after entraining even when the animals were placed under constant dark conditions and was only detected in the CA1 and CA3 regions of the hippocampus and not in the cerebellum, suggesting that this oscillating biochemical pathway may contribute to learning and memory. Mice that were trained during the day, which corresponded to the peak of activity of this ERK, cAMP, and CREB pathway, exhibited enhanced memory consolidation compared with those trained during the dark. Enhanced memory consolidation was also observed if the circadian-entrained mice were then placed in constant dark and then trained during the circadian peak in ERK signaling. Short-term contextual memory did not differ with the time of training, suggesting that the circadian oscillations were important for memory consolidation and long-term storage and retrieval rather than short-term memory formation. Mice in which the two calcium-sensitive adenylyl cyclase isoforms were knocked out lacked any circadian oscillations in cAMP or ERK and showed impaired memory 24 hours after training in either the day or the night. Exposure of mice to constant light conditions, which disrupted the circadian rhythm and the circadian oscillations in phosphorylated ERK, or disruption of the daytime peak of phosphorylation of ERK pharmacologically, resulted in impaired memory persistence. Thus, it appears a circadian oscillating MAPK pathway contributes to memory persistence.
K. L. Eckel-Mahan, T. Phan, S. Han, H. Wang, G. C.-K. Chan, Z. S. Scheiner, D. R. Storm, Circadian oscillation of hippocampal MAPK activity and cAMP: Implications for memory persistence. Nat. Neurosci. 11, 1074-1082 (2008). [PubMed]
T. L. Roth, J. D. Sweatt, Rhythms of memory. Nat. Neurosci. 11, 993-994 (2008). [PubMed]