Our recent findings disclosed a mechanism of PARP-1 activation in the absence of DNA damage, involving the ERK signaling pathway (Cohen-Armon et al., 2007 Mol. Cell 25: 297). Results showed that PARP-1 activated by phosphorylated ERK2 acts as a scaffold protein, dramatically enhancing ERK-induced phosphorylation of transcription factor Elk1, thereby promoting core histone acetylation and the expression of Elk1 target gene c-fos, which are essential for long-term memory. These findings were in line with evidence associating polyADP-ribosylation with memory formation during learning in Aplysia (Cohen-Armon M., et al., 2004, Science 304:1820). In this project we plan (1) to identify the role of PARP activation in the molecular mechanisms underlying memory formation during learning in mammals, (2) to find out whether aging affects these mechanisms, (3) to mimic by electrical stimulation of cortical neurons in tissue culture the effect of learning on immediate early gene expression, and (4) to allocate in the chromatin genes expressed by electrical stimulation by using the ChIP on chip technique. The ChIP (chromatin immunoprecipitation) assay and Q-PCR will be used to identify molecular mechanisms in the chromatin inducing early gene expression in trained mice and in electrically stimulated brain cortical and hippocampal neurons. DNA hypridization on cDNA chips will be used to allocate the expressed genes in the DNA. We expect this project to elucidate the eomplex mechanisms of memory formation and to offer new therapeutic approaches for memory disorders.