Based selleckchem EPZ-5676 on our findings, we propose a potential mechanism for priming genes through activity dependent hyperacetylation of H4K5 in the promoter upon learning. Results Fear memory induces H4K5ac in the hippocampus Inhibitors,Modulators,Libraries in a training dependent manner To examine the epigenetic and transcriptional profile of genes associated with memory formation in the hippocam pus, we trained adult mice on a CFC paradigm. We chose CFC because it is a robust, long lasting learning paradigm in which memory for a context can persist for more than one year after a single training session. Mice were exposed to a novel context in which they re ceived a foot shock, either once or twice on two consecutive days, then tested for fear memory 24 hours later.

After a single foot shock, the animals expressed a significant freezing response compared to control mice that was maintained when Inhibitors,Modulators,Libraries tested 24 hours later. However, with a second training session on day 2, the freez ing response was increased further by 20% when tested 24 hours later. In control mice, freezing on days 2 and 3 compared to day 1 was significant, but was not significant compared to day 1, which is the measure by which we make all compar isons. Inhibitors,Modulators,Libraries It is also worth noting that control mice plateau on day 2 while FC mice continue to have higher freezing. FC has been associated with transcriptional Inhibitors,Modulators,Libraries programs that are activated within 1 hour after conditioning, and that persist for up to 6 hours. Subsequent training, how ever, may increase gene expression, recruit additional Inhibitors,Modulators,Libraries genes to reinforce the memory, or prime existing transcriptional programs for rapid induction of genes for synaptic strengthening.

selleck Since memory formation has been associ ated with histone acetylation in the brain, we examined whether memory performance correlates with higher acetylation levels following additional training sessions. We determined the level of H4K5ac, a PTM recently implicated in gene bookmarking, and increased with FC and object recognition memory tasks, following one or two days of CFC. Western blots show that H4K5ac was increased ap proximately 3 fold in the hippocampus 1 hour after one CFC session. With two conditioning sessions, H4K5ac level was increased 4. 6 fold over controls following a memory test on day 3, suggesting that H4K5ac induction is proportionate to the amount of training. H4K5ac was ex amined 1 hour after memory test on day 3 because 1 gene expression is activated within 1 hour following fear condi tioning and memory retrieval, 2 memory is consol idated or reconsolidated within 6 hours, 3 histone acetylation decreases to baseline levels within 2 4 hours, 4 memory for the context is enhanced by an add itional training session, and 5 H4K5ac levels are higher at this time point.