Downward social mobility is a well-known mental risk factor for depression, but its neural mechanism remains elusive. Here, by forcing mice to lose against their subordinates in a non-violent social contest, we lower their social ranks stably and induce depressive-like behaviors. These rank-decline-associated depressive-like behaviors can be reversed by regaining social status. In vivo fiber photometry and single-unit electrophysiological recording show that forced loss, but not natural loss, generates negative reward prediction error (RPE). Through the lateral hypothalamus, the RPE strongly activates the brain’s anti-reward center, the lateral habenula (LHb). LHb activation inhibits the medial prefrontal cortex (mPFC) that controls social competitiveness and reinforces retreats in contests. These results reveal the core neural mechanisms mutually promoting social status loss and depressive behaviors. The intertwined neuronal signaling controlling mPFC and LHb activities provides a mechanistic foundation for the crosstalk between social mobility and psychological disorder, unveiling a promising target for intervention.

社会向下流动是众所周知的抑郁症心理危险因素，但其神经机制仍然难以捉摸。在这里，通过强迫老鼠在非暴力的社会竞争中输给它们的下属，我们稳定地降低了它们的社会等级并诱发抑郁样行为。这些与等级下降相关的抑郁样行为可以通过重新获得社会地位来逆转。体内光纤光度测定和单单元电生理记录表明，强制损失而不是自然损失会产生负奖励预测误差（RPE）。通过外侧下丘脑，RPE 强烈激活大脑的反奖赏中心，外侧缰核 (LHb)。LHb 激活会抑制内侧前额叶皮层 (mPFC)，而 mPFC 控制着社会竞争力并强化了竞赛中的退却。这些结果揭示了相互促进社会地位丧失和抑郁行为的核心神经机制。控制 mPFC 和 LHb 活动的相互交织的神经元信号为社会流动性和心理障碍之间的串扰提供了机制基础，揭示了一个有希望的干预目标。