Addiction to psychostimulants such as cocaine represents a major public health issue exacting tremendous financial and social costs. Despite this, psychostimulant use disorder remains a recalcitrant condition with no currently FDA-approved medications for its treatment. In many fields of psychiatric research, the link between the brain and the immune system has been heavily studied as a way to determine pathophysiology and to find new methods of treatment. While it is known that cocaine can alter the function of both the innate and adaptive immune systems, the link between these immune changes and maladaptive drug taking and seeking behaviors remains minimally explored. In a series of initial experiments, we examined how experimenter or self- administered cocaine altered the serum profile of 32 cytokines. Of these, we found that granulocyte-colony stimulating factor (G-CSF) was increased by cocaine, and the serum levels showed linear correlation with behavioral response to cocaine. Behaviorally, injections of G-CSF alter the dose-response curve for cocaine place preference, and facilitate extinction and reduce reinstatement of cocaine seeking. Taken together, these preliminary studies demonstrate that G-CSF is a potent modulator of cocaine-induced behavioral plasticity, and may be a potential therapeutic target for prolonging abstinence in cocaine use disorder. Under the mentorship of Drs. Eric Nestler and Yasmin Hurd I will seek to further clarify the role of G-CSF in addiction while gaining additional training to allow me to transition to independence. In Aim 1 of this proposal I will interrogate the effects of G-CSF in the nucleus accumbens (NAc) in a cell-type specific manner by using viral vectors to knock down the G-CSF receptor in populations of D1 and D2 positive medium spiny neurons prior to cocaine self- administration, extinction and reinstatement. These experiments will provide insight into the microcircuitry underlying the behavioral effect of G-CSF, and will provide me crucial training in self-administration and targeted manipulation of gene expression. In Aim 2, I will seek to identify G-CSF responsive genes in NAc that account for its behavioral effect. I will perform mRNA sequencing of the NAc from animals self-administering cocaine, followed by differential expression and pathway analysis. The behavioral effect of highly regulated genes and pathways will be interrogated by viral gene manipulation prior to cocaine self-administration, extinction and reinstatement. These experiments will provide me with crucial mentoring in creation, analysis and utilization of large sequencing datasets, while also providing detailed information as to how G-CSF affects cocaine-related behavioral plasticity. In summary, the research proposed in this award will elucidate the neural and molecular mechanisms of a translationally-relevant treatment target, while providing me with sufficient mentorship to tr...