We report that, in the rat, administering insulin-like growth factor II (IGF-II) significantly enhances memory retention and prevents forgetting. Inhibitory avoidance learning leads to an increase in hippocampal expression of IGF-II, which requires the transcription factor CCAAT enhancer binding protein β and is essential for memory consolidation. Furthermore, injections of recombinant IGF-II into the hippocampus after either training or memory retrieval significantly enhance memory retention and prevent forgetting. To be effective, IGF-II needs to be administered within a sensitive period of memory consolidation. IGF-II-dependent memory enhancement requires IGF-II receptors, new protein synthesis, the function of activity-regulated cytoskeletal-associated protein and glycogensynthase kinase 3 (GSK3). Moreover, it correlates with a significant activation of synaptic GSK3β and expression of GluR1 a-amino-3-hydroxy-5-methyl-4-isoxasoleproprionic acid receptor subunits. In hippocampal slices, IGF-II promotes IGF-II receptor-dependent, persistent long-term potentiation after weak synaptic stimulation. Thus, IGF-II may represent a novel target for cognitive enhancement therapies.

Little is known about the temporal progression and regulation of the mechanisms underlying memory consolidation. Brain-derivedneurotrophic-factor (BDNF) has been shown to mediate the maintenance of memory consolidation, but the mechanisms of this regulation remain unclear. Using inhibitory avoidance (IA) in rats, here we show that a hippocampal BDNF-positive autoregulatory feedback loop via CCAAT-enhancer binding protein ␤ (C/EBP␤) is necessary to mediate memory consolidation. At training, a very rapid, learninginduced requirement of BDNF accompanied by rapid de novo translation controls the induction of a persistent activation of cAMPresponse element binding-protein (CREB) and C/EBP␤ expression. The latter, in turn, controls an increase in expression of bdnf exon IV transcripts and BDNF protein, both of which are necessary and, together with the initial BDNF requirement, mediate memory consolidation. The autoregulatory loop terminates by 48 h after training with decreased C/EBP␤ and pCREB and increased methyl-CpG binding protein-2, histone-deacetylase-2, and switch-independent-3a binding at the bdnf exon IV promoter.

Emotionally important events are well remembered. Although memories of emotional experiences are known to be mediated and modulated by the stress hormones glucocorticoids, little is known about the underlying molecular mechanisms. Here we show that the hippocampal glucocorticoid receptors critically engaged during the formation of long–term inhibitory avoidance memory in rats are coupled to the activation of CaMKIIα, TrkB, ERK, Akt, PLCγ and CREB, as well as a significant induction of Arc and synaptic GluA1. Most of these changes, which are initiated by a non–genomic effect of glucocorticoid receptors, are also downstream of the activation of brain–derived neurotrophic factor (BDNF). Hippocampal administration of BDNF, but not other neurotrophins, selectively rescues both the amnesia and the molecular impairments produced by glucocorticoid receptor inhibition. Hence, glucocorticoid receptors mediate long–term memory formation by recruiting the CaMKIIα–BDNF–CREB–dependent neural plasticity pathways.