Orexin has been implicated in comorbid diseases of depression, making it a promising target for anti-depression treatment. Although orexin neurons exhibit abnormal activity in depression, the neurocircuit mechanism of orexin remains unclear. As one of the important downstream factors of orexin neurons, the ventral tegmental area (VTA) is considered crucial to the mechanism of depression. However, the role of VTA orexinergic afferents in depression remains unclear. In this study, we applied a combination of opto/chemogenetic and neuropharmacology methods to investigate whether the VTA orexinergic afferents participate in the pathogenesis of depression in a chronic unpredictable mild stress (CUMS) mouse model. We found that c-Fos expression in these VTA-projecting orexin neurons specifically decreased in CUMS-treated mice. Optogenetic and chemogenetic activation of orexin terminals in the VTA significantly reversed depressive behavior. Microinjection of orexin-A, but not orexin-B, into the VTA significantly improved depressive-like behavior. Our study provided direct evidence that the VTA orexinergic afferents participate in the mechanism of depression, and the orexin-1 receptor plays a major role.
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