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Abstract Biological assay and imaging techniques have made visible a great deal of the machinery of mental illness. Over fifty years of investigation of mood disorders using these technologies has identified several biological regularities in these disorders. Here we present a narrative connecting genetic, cytokine, neurotransmitter, and neural-systems-level findings in major depressive disorder (MDD). Specifically, we connect recent genome-wide findings in MDD to metabolic and immunological disturbance in this disorder and then detail links between immunological abnormalities and dopaminergic signaling within cortico-striatal circuitry. Following this, we discuss implications of reduced dopaminergic tone for cortico-striatal signal conduction in MDD. Finally, we specify some of the flaws in the current model and propose ways forward for advancing multilevel formulations of MDD most efficiently.