Two time periods of hippocampal mRNA synthesis are required for memory consolidation of fear-motivated learning.

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.