Molecular mechanisms of memory stabilization and amnesia

Memory is a dynamic process that can be defined as the neurobiological order of operations by which new, incoming information is encoded and then stored in the brain. A large body of evidence indicates that long-term memory formation in a variety of species, ranging from invertebrates to mammals, depends on activation of new gene expression and protein synthesis regulated by members of the cAMP response element binding protein (CREB) transcription factor family. The present work reports a molecular correlation between CREB-dependent gene expression and long-term memory formation and disruption in the mammalian hippocampus. Rats with amnesia of an inhibitory avoidance memory due to lesions of the fornix, a major axonal thoroughfare of information into the hippocampus, fail to show downstream hippocampal CREB activation, or phosphorylation, that is typically seen in normal animals. Previously described in the invertebrate Aplysia, a second cAMP-dependent event necessary for enduring, learning-related changes in the nervous system is the induction of another transcription factor, CCAAT enhancer-binding protein (C/EBP). In this study, two mammalian homologs of C/EBP, C/EBPbeta and C/EBPdelta, are seen induced at discrete times after inhibitory avoidance training. This learning event results in C/EBP induction the same hippocampal neuronal populations that several hours earlier exhibit CREB phosphorylation, and like CREB, their induction is blocked in amnesic animals with fornix lesions. These results suggest that C/EBP is an evolutionarily conserved component of the gene cascade initiated by CREB and activated during the consolidation of a new memory. When a previously consolidated memory is recalled, or reactivated, it re-enters a new phase of vulnerability and appears to require a reconsolidation process in order to be maintained. Using a DNA antisense disruption technique, results revealed that hippocampal C/EBPbeta is a genetic marker for the consolidation of new but not reactivated inhibitory avoidance memory. Protein synthesis inhibitor treatment following memory reactivation further demonstrate that, while new protein synthesis is required for reconsolidation of this memory somewhere in the brain, the hippocampus is not a region where this occurs. This is the first evidence suggesting divergent molecular and/or anatomical mechanisms of memory consolidation and reconsolidation.