UC Irvine

Exposure to drugs of abuse, such as cocaine, engages transcriptional machinery to alter gene expression profiles, ultimately giving rise to long-term changes in cellular function, synaptic plasticity, and drug-related behavior. Previous work from our lab has identified glucocorticoid-induced leucine zipper (Gilz) as an epigenetically regulated gene that may be responsible for orchestrating long-term transcriptional adaptations underlying such behaviors. However, it remains unknown whether the distinct mRNA splice variants encoded by the Gilz gene play unique roles in this context. It is also unclear whether Gilz splice variants in the brain differentially respond to stress-related events, despite the body of literature demonstrating Gilz as a downstream transcriptional regulator of glucocorticoid-signaling. In the present dissertation, we investigated whether Gilz splice variants exhibit differential responses to cocaine- or stress-exposure, and we investigated whether Gilz is necessary for (1) long-term potentiation (LTP) in the nucleus accumbens (NAc), (2) cocaine-conditioned place preference, and (3) cocaine self-administration behaviors. We demonstrate that Gilz acts in the NAc to regulate LTP, in the VTA to regulate CPP, and that Gilz is necessary for reinstatement of cocaine-seeking behavior in male mice. We also demonstrate that Gilz splice variants differentially respond to a variety of stress-related stimuli. Overall, this work illustrates how cocaine or stress may engage Gilz in distinct brain regions to regulate cellular and behavioral responses to maladaptive experiences.