Figure 9.

SIRT1 regulates gene expression in NAc via an H4K16ac- and a FOXO3a-dependent pathway. Cocaine regulation of SIRT1 induces gene expression in the NAc via two distinct actions. Mechanism 1, Despite the global increase in SIRT1 levels in NAc after cocaine, there is a significant depletion, through unknown mechanisms, of SIRTI binding to the promoter of certain genes, which leads to increased H4K16ac enrichment at those genes. Mechanism 2, SIRT1 deacetylates FOXO3a resulting in activation of FOXO3a's transcriptional activity and increased expression of its downstream targets. Such cocaine regulation of SIRT1, and SIRT1's regulation of gene expression through these distinct mechanisms, contributes to aspects of cocaine-induced neural and behavioral plasticity.