The identification of the LS-A2AR+ → LHb pathway as a downstream target for LS-A2AR control of depressive-like behavior is consistent with the role of the LHb in the development of depression, as heralded by the persistent and robust activity in the LHb of depressed animals48,49 (reviewed in50), by the experimental ability of increased LHb activity to trigger depressive-like behaviors51–53, by the ability of the fast-acting antidepressant drug ketamine to wane LHb neuronal activity54 and by the impact of deep-brain stimulation in the LHb to alleviate depressive-like symptoms55,56. This evidence concerns the gene LHB and major depressive disorder.