Extensive review would be out of place, but we note that clinical administration of 'challenge' ligands (DG in mouse) such as IL-1α, IL-2, IFN-α, IFN-β, and TNF-α produces malaise and sickness behavior [59–64], that has been suggested to be akin to anxiety/depression, whereas 'sufficiency' ligands (CA regions in mouse) such as androgens, IGF-1, and thyroid hormone have converse positive effects (e.g., [65–67]), all of which target HPC receptors, indicating that the axis is also functional in human. This evidence concerns the gene IL1A and major depressive disorder.