Stress-Induced Dysregulation of the Guidance Cue Receptor DCC Alters Corticolimbic Circuit Architecture

Elevated expression of the guidance cue receptor gene DCC in the adult prefrontal cortex (PFC) is a hallmark of major depressive disorder. DCC receptors regulate neuronal connectivity and plasticity in adulthood. In male mice, Dcc knockout in the PFC promotes resilience to behavioral dysregulation following chronic social defeat stress (CSDS), whereas Dcc upregulation increases susceptibility. However, the underlying mechanisms remain to be elucidated.

We combined CSDS, behavioral tests (i.e., social interaction, nestlet shredding, and dark-light tests), retrograde neuronal tracing, and quantitative neuroanatomical analysis in adult male mice (N = 90) to investigate whether DCC receptors contribute to stress susceptibility/resilience by remodeling dendritic spine architecture of selective PFC neuronal networks.

CSDS reduced both mature and newly formed spines on the apical, but not basal, dendrites of PFC pyramidal neurons. This effect was prevented by downregulating DCC receptors in these neurons, a manipulation that also prevented depression-like behaviors, suggesting a mechanistic link. DCC-expressing neurons in the PFC predominantly projected to the nucleus accumbens, and social defeat stress induced dendritic spine loss specifically in projections from the infralimbic PFC. Notably, knockout of DCC receptors in infralimbic PFC neurons projecting to the nucleus accumbens shell protected against stress-induced social avoidance.

DCC receptors may influence susceptibility or resilience to social stress-induced depression-like behaviors by altering the apical dendritic architecture of PFC pyramidal neurons, particularly those projecting to the nucleus accumbens shell. This mechanism may be at play in the neurobiology of depression, pointing to DCC receptors as promising therapeutic targets.