Orexinergic lateral hypothalamus-anterior cingulate cortex circuit alleviates chronic stress-induced anxiety-like...

Chronic stress is a major contributor to anxiety disorders, but the specific neural circuits and molecular mechanisms involved remain poorly understood. Recent evidence suggests that orexin (ORX) plays a role in stress-related behaviors, but its precise role in anxiety regulation remains undefined. Here, we identify and characterize an orexinergic circuit from the lateral hypothalamus (LH) projecting to the anterior cingulate cortex (ACC) that regulates chronic stress-induced anxiety-like behaviors via the orexin 2 receptor (OX2R). We found that LH^Orx neurons were significantly suppressed in stress-induced anxiety-like behaviors. Chemogenetic activation of LH^Orx neurons alleviated anxiety-like behaviors in chronic unpredictable mild stress (CUMS) mice. Furthermore, LH^Orx neurons projected to the ACC glutamatergic (Glu) neurons, which were also inhibited following CUMS. In addition, activation of the LHOrx-ACC pathway or exogenous application of ORX to the ACC significantly alleviated CUMS-induced anxiety-like behaviors, whereas pharmacologically blocking OX2R but not orexin 1 receptor (OX1R) in the ACC prevented the anxiolytic effects of LH^Orx-ACC activation. Taken together, our study reveals the critical role of the orexigenic LH-ACC circuit in chronic stress-induced anxiety-like behaviors, providing a potential therapeutic target for anxiety and stress-related disorders.