Neural mechanism underlying depressive-like state associated with social status loss

Downward social mobility is a well-known mental risk factor for depression, but its neural mechanism re-mains 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 depres-sive-like behaviors can be reversed by regaining social status. In vivo fiber photometry and single-unit elec-trophysiological 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 mutu-ally 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.

Automated summary

This study demonstrates that downward social mobility and depressive behaviors are interconnected through neural mechanisms involving negative reward prediction error and the activation of the lateral habenula (LHb). Forced loss in a non-violent social contest generates negative reward prediction error, leading to the activation of LHb and inhibition of the medial prefrontal cortex (mPFC), resulting in retreats in contests. These findings provide insights into the relationship between social status loss and depression, and offer a potential target for intervention.