Efforts to advance health practice and research in the area of depression are hindered by the absence of a biomarker that can be objectively measured to establish diagnosis or monitor and predict treatment response. It has been suggested that multiple cellular and molecular pathways are likely to be involved with major depression. Therefore, it is critical to apply a systems biology approach to identify biomarkers that can aid in diagnosis and treatment selection. Our laboratory has collected behavioral data for over 30 mouse inbred strains for the tail suspension test, in both nave mice and mice chronically-treated with the antidepressant fluoxetine. We have also analyzed whole-genome gene expression in the same inbred strains in multiple brain regions believed to play a role in the regulation of mood. In this application, we propose to quantify 40 biochemical biomarkers in the same three brain regions among all 30 inbred strains in both nave mice and mice that have been chronically-treated with the antidepressant fluoxetine. The biochemical markers, which were chosen based on literature searches and in consultation with experts in the field of psychiatry and psychiatric genetics, assess multiple mechanisms that have been implicated in human depression, including neuronal modulation, neurogenesis, gliogenesis, and hypothalamic-pituitary-mediated immunomodulation. By comparing biochemical and behavioral profiles in both nave and drug-treated mice, we will identify biomarkers that can predict predisposition to depressive-like behavior and treatment response. Furthermore, comparison of these data with inter-strain gene expression differences will provide information regarding the role of gene regulation on depression. Genetic and biochemical markers that are significantly correlated with differences in behavior in the treatment nave group can predict predisposition to depressive-like behavior in mice that may influence response to treatment, while genetic and biochemical markers that are significantly different between response groups can provide a biological explanation for differences in treatment response. By using a multi-faceted approach that investigates connections on genetic, neurobiochemical, and behavioral levels, we were able to identify genetic and neurobiochemical markers that can potentially assess risk for despair and poor treatment outcome. Importantly, our research study provides an innovative and powerful platform for pre-clinical assessment of antidepressant drugs in depressive-like susceptible strains and non-responsive lines
