Newborn neurons compete with neuronal ensembles to moderate behavioral responses to stress

Newborn neurons in the adult hippocampal dentate gyrus (DG) are hyperexcitable, competitive cells involved in behavioral responses to stress and antidepressants. The role and the mechanisms underlying the competitiveness of the newborn neurons in moderating behavioral responses to stress have not yet been comprehensively investigated. Using FosTRAP2 transgenic mice in the learned helplessness (LH) paradigm, we report that voluntary running, a guideline-supported intervention for depression, induces neurogenesis, and that the newly generated neurons compete with LH-TRAPed neurons, thereby reducing stress-induced helpless behavior. Mechanistically, we found that increasing neurogenesis is sufficient to reduce spine density in LH-TRAPed neurons via p21-activated kinase 4 (Pak4) and to attenuate Ca²⁺ activity in these neurons. Taken together, our findings suggest that highly excitable newborn neurons compete with LH-TRAPed neurons, attenuating helpless behaviors and providing therapeutic value for depressed individuals, who typically show enhanced memory for negative events.