Chronic social stress causes long-term structural alterations of neuronal projections to the medial prefrontal cortex in mice

Chronic social stress affects emotional and cognitive functions and risks psychiatric illnesses such as depression. Rodent studies have shown that chronic social stress induces dendritic atrophy of pyramidal neurons in the medial prefrontal cortex (mPFC), leading to depression-related behaviors. However, how chronic social stress remodels neuronal circuits connected with mPFC neurons is unknown. Here we examined the brain-wide effects of chronic social stress on neuronal projections to the mPFC in mice. Chronic social stress induced behavioral changes, such as social avoidance, decreased reward-directed behavior, and cognitive impairment, which lasted over a month. By unilaterally injecting the retrograde rabies viral vector expressing a fluorescent protein into the mPFC, we visualized the neurons sending axons to the mPFC in more than 150 brain regions. Fluorescently labelled cells in the hippocampus and piriform cortex decreased in stressed mice, while they increased in the orbitofrontal cortex. All these changes were pronounced over a month after the stress. These findings demonstrate that chronic social stress causes long-lasting structural alterations of neuronal projections to the mPFC, which might contribute to post-stress consolidation of depression-related behaviors.