IGF-I is essential to normal brain growth and exerts actions on neural stem cells and each major neural cell lineage. Whereas many studies show that IGF-I regulates gene expression, mechanisms by which it modulates transcription have not been explored. Chromatin modifications, such as histone phosphorylation, acetylation, and methylation, are known to be important initial steps in gene regulation, and acetylation of histone H3 and H4 is associated with gene activation. In this study, we show that IGF-I modulates the acetylation of H3 and H4 histones in the brain of two transgenic mouse lines and that these effects are associated with activation of the phosphoinositide 3-kinase/Akt signaling pathway. This provides evidence that the chromatin architecture modification contributes to the action of IGF-I on gene expression in the mammalian central nerve system.