CRH and major depressive disorder: Our circuit-level analysis identified the LS-A2AR+ → DMH and LS-A2AR+ → LHb pathways as the main downstream target for top-down control of depressive-like behavior by LS-A2AR. The DMH is a main output of the LS, establishing a feedback loop to control LS circuits through peptidergic signals such as CRF and vasopressin, which is proposed to be involved in depression, fear and anxiety (reviewed in22,24).