Orexin improves chronic restraint stress induced depressive-like behavior via modulating the lateral septum in mice.

The orexin system participates in the regulation of depression; however, its effects show significant heterogeneity, indicating the involvement of complex downstream neural circuit mechanisms. The lateral septum (LS), located downstream of the orexin system, contributes to depression. However, the effects and mechanisms underlying the orexin-mediated modulation of the LS in patients with depression remain unclear. Herein, we applied fiber photometry, chemogenetics, neuropharmacology, and in vitro electrophysiology to show that LS orexinergic afferents are sensitive to acute restraint and that chronic restraint stress (CRS) inhibits LS-projecting orexin neurons. Chemogenetic activation of LS orexinergic afferents or injection of orexin-A into the LS improved CRS-induced depression-like behavior. In vitro perfusion of orexin-A increased the action potential of somatostatin neurons in the LS. Overall, this study provides evidence that orexin improves depressive-like behavior by modulating the LS, and that this effect is probably mediated by the upregulation of LS somatostatin neurons.