Orexin induces antidepressant-like effects via promoting resilience to acute stress

摘要: Stress resilience protects against depression and holds a key position in the maintenance of psychological well-being. Intriguingly, hypothalamic neuropeptide orexin is critically involved in coping with acute stress, and reduced orexin levels in the cerebrospinal fluid have been reported in patients with depression. However, role of orexin in stress resilience and depression, as well as the underlying neural substrates and mechanisms, is still largely unknown. Here, we reveal a direct projection from hypothalamic orexinergic neurons to the ventral pallidum (VP), which receives an increasing attention for its critical position in rewarding processing and stress responses. By electrophysiology, western blotting, immunohistochemistry, combined with behavioral tests, we find that orexin directly excites VP neurons and induces antidepressant-like behavioral effects in forced swimming test and sucrose preference test. Two orexin receptors, OXR1 and OXR2, and their downstream Na~+-Ca~(2+) exchangers and L-type Ca~(2+) channels co-mediate the effect of orexin. Interestingly, pharmacologically blockade or genetically knockdown of orexin receptors to block orexinergic inputs in VP increases depressive-like behaviors in paradigms with acute stressors, such as forced swimming test and sucrose preference test, while has no impact on novel social proximity in social interaction test without acute stressors. Nevertheless, knockdown of orexin receptors in VP strengthens social avoidance in social interaction test following an acute defeat stress. These results suggest that endogenous orexinergic modulation on VP is essential for generation of …