Project Summary/Abstract It is well established that drug-induced alterations to gene expression contribute to the development of drug- seeking behaviors. For instance, both acute and chronic exposure to cocaine increases histone acetylation within and significantly alters transcriptional profiles within the nucleus accumbens (NAc). Our lab has demonstrated that HDAC3, a histone deacetylase enzyme, within the NAc negatively regulates cocaine-induced changes in histone acetylation, gene expression, and memory formation. However, it is unknown whether cocaine alters HDAC3-mediated transcriptional changes underlying reward-associated behavior in a sex-dependent manner. In a recent study, our lab identified Gilz (glucocorticoid-induced leucine zipper) as an HDAC3 target gene that may be critical for memory formation. Gilz is an X-chromosome linked gene which may provide novel insight into sex-differences observed in response to cocaine exposure. I have collected preliminary data suggesting Gilz positively regulates reinstatement of previously extinguished cocaine-seeking behavior, perhaps through transcription-dependent mechanisms of synaptic plasticity. However, the precise role of Gilz in reinstatement remains unknown, as does whether these observations are consistent across both sexes. The experiments proposed in this application will allow me to test the overall hypothesis that Gilz acts in the NAc to regulate transcription underlying cellular and behavioral responses to cocaine.