Modulation Of Central Orexinergic System On Ventral Pallidum Prevents Depressive-like Behavior By Promoting Stress Resilience

Orexin is a neuropeptide synthesized only in hypothalamus,but widely regulates brain activity.In recent years,orexin has been considered to be related to the pathophysiology of mental disorders,and more and more clinical evidences indicate that orexin is potentially associated with depression.However,the exact role of orexin in depression,especially the underlying neurological basis and circuits mechanism,remains unclear.In this study,we revealed the direct projection of hypothalamic orexinergic neurons to ventral pallidum(VP).The role of VP in reward process,stress response and depression has attracted more and more attention.We found that orexin directly excited GABAergic neurons in VP could alleviate depression-like behavior in rats.Two receptors of orexin,OX1R and OX2R,and their downstream coupled Na+-Ca2+ exchangers and L-type Ca2+ channels jointly mediate the antidepressant effect of orexin.In addition,pharmacological blockade or gene knockout of orexin receptor in VP increased depressive-like behavior in rats during forced swimming test and surcose preference tests.Interestingly,blocking the orexinergic inputs in VP had no effect on the social proximity between novel rats,but significantly enhanced the social avoidance behavior of rats under severe social psychological pressure triggered by social rank.It is noteworthy that when animals undergo tests containing acute stress,such as forced swimming,food/water deprivation and social rank stress,orexin levels in VP and corticosterone levels in serum increased significantly.These results suggest that the regulation of VP by endogenous orexin is essential to prevent depressive response to stress events.These findings demonstrate that the central orexinergic system plays an indispensable role in preventing depression by promoting stress resilience.