Moreover, our previous animal studies have demonstrated that oral administration of kososan counteracted the depression-like behaviors of chronic mild stress-exposed or IFN-α-treated mice by normalizing the dysfunction of the hypothalamic-pituitary-adrenal axis, a region strongly associated with the pathogenesis of depression [26, 27], regulating the orexin/neuropeptide Y signaling system [28, 29], and by modulating metabotropic glutamate receptor 2 and 2′,3′-cyclic nucleotide 3′-phosphodiesterase 1 in the hypothalamus using a proteomic analysis [30]. Here, HCRT is linked to major depressive disorder.