Molecular mechanisms of hippocampal dependent long-term memory consolidation

Memory is a key cognitive function for the survival of all behaving organisms. Newly learned information undergoes a process known as consolidation to become stabilized and long lasting. Consolidation requires a temporally-limited phase of de novo gene expression and protein synthesis. Significant advances in the molecular understanding of memory consolidation over the last twenty years have identified the cAMP-response element binding protein (CREB) -- CCAAT-enhancer binding protein (C/EBP) cascade as an evolutionarily conserved requirement for long-term memory consolidation.;In this thesis, I use rat inhibitory avoidance to investigate the upstream and downstream molecular pathways that are linked to the activation of CREB-C/EBP in the hippocampus during memory consolidation. My studies provide a molecular mechanism by which stress modulates memory consolidation. I find that learning of a stressful event such as inhibitory avoidance, via stress hormone glucocorticoids and its receptor glucocorticoid receptors (GRs), recruits brain-derived neurotrophic factor (BDNF) and its receptors tropomyosin receptor kinase B (TrkB) to activate CREBC/ EBP. Blockade of hippocampal glucocorticoid receptors or BDNF impairs long term memory retention as well as TrkB-dependent signaling including CREB activation. Importantly, BDNF rescues the amnesia and molecular impairments triggered by GR inhibition, further suggesting that GR recruits the BDNF pathway to mediate memory consolidation.;I also find that insulin-like growth factor II (IGF-II), a target gene of C/EBPbeta during memory consolidation, significantly enhances long-term memory retention if given immediately after training or after memory retrieval -- during the active phases of memory consolidation. The IGF-II dependent memory enhancement requires de novo protein synthesis but does not recruit additional CREB-C/EBP. Rather, IGF-II appears to engage synaptic mechanisms to mediate its memory enhancement.;Lastly, I characterize the temporal evolution of the hippocampal protein synthesis and BDNF requirements in memory consolidation. I find that training induces an immediate and rapid wave of BDNF-dependent protein synthesis to establish memory consolidation. In addition, BDNF is also required for the maintenance of memory consolidation as disruption of BDNF after learning leads to memory decay.;Together, my findings propose an essential molecular sequence of events for memory consolidation that is initiated by inhibitory avoidance learning.