Leucine deprivation results in antidepressant effects via GCN2 in AgRP neurons.

Essential amino acids (EAAs) are crucial nutrients, whose levels change in rodents and patients with depression. However, how the levels of a single EAA affects depressive behaviors remains elusive. Here, we demonstrate that although deprivation of the EAA leucine has no effect in unstressed mice, it remarkably reverses the depression-like behaviors induced by chronic restraint stress (CRS). This beneficial effect is independent of feeding and is applicable to the dietary deficiency of other EAAs. Furthermore, the effect of leucine deprivation is suppressed by central injection of leucine or mimicked by central injection of leucinol. Moreover, hypothalamic agouti-related peptide (AgRP) neural activity changes during CRS and leucine deprivation, and chemogenetically inhibiting AgRP neurons eliminates the antidepressant effects of leucine deprivation. Finally, the leucine deprivation-regulated behavioral effects are mediated by amino acid sensor general control non-derepressible 2 (GCN2) in AgRP neurons. Taken together, our results suggest a new drug target and/or dietary intervention for the reduction of depressive symptoms.