Moreover, based on modern experimental techniques—such as CRF over-expression and the site-specific knock-out of CRF1 and CRF2—it was recently proposed that the role of CRF1 and CRF2 in stress, anxiety, and depression is not a matter of simple dualism, but that it depends on the brain regions and neuronal populations being activated [54,55]. This evidence concerns the gene CRHR1 and major depressive disorder.