Smart-seq2 analysis of tdTomato-positive neurons from LH+ NR and LH+ Run mice

The role and the mechanisms underlying the competitiveness of the newborn neurons in moderating behavioral responses to stress have not yet been comprehensively inves-tigated. 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.