Targeting dopamine transporter for treating social transmission of depression-like behaviors in male mice

Mounting evidence has validated the social transmissibility of depression-like behaviors. This study identifies the essential roles of dopamine signaling and the olfactory system in mediating socially transmitted depression (STD) in male mice. Breath odors from defeated conspecifics induce approach behaviors through the main olfactory bulb-piriform cortex (MOB-PiC) pathway, whereas urine odors trigger avoidance via the accessory olfactory bulb-medial amygdala (AOB-MeA) pathway. Both chemosensory inputs ultimately converge in the medial prefrontal cortex (mPFC). Social interactions with defeated conspecifics markedly enhance dopamine release from the ventral tegmental area (VTA) to the mPFC. In STD-sensitive mice, upregulated dopamine transporter (DAT) expression in the mPFC reduces basal dopamine levels and facilitates depression-like phenotypes. The MOB-PiC-mPFC-VTA axis mediates social interaction-evoked dopamine elevation, and DAT modulates dopamine reduction. Elevated dopamine variability within the mPFC is sufficient to drive STD. Notably, DAT-targeted intervention confers superior therapeutic efficacy against STD compared with serotonin system modulation.