Subregion‐specific perineuronal net remodelling in the dorsal hippocampus drives vulnerability and resilience to chronic stress: The role of venlafaxine treatment

Background and Purpose Neuronal plasticity enables the brain to adapt to internal and external demands by dynamically regulating synaptic connectivity and emotional circuitry. Impaired neuroplasticity represents a core pathophysiological framework of major depressive disorder, one of the leading causes of disability worldwide. Chronic stress is a major determinant of vulnerability, with individuals displaying either maladaptive responses or resilient coping strategies. Emerging evidence links dysfunctional plasticity to alterations in extracellular matrix components, particularly perineuronal nets (PNNs), specialized structures that predominantly enwrap parvalbumin‐positive interneurons and regulate synaptic stability and cortical inhibition. Experimental Approach We employed the chronic mild stress (CMS) model for 6 weeks to distinguish vulnerable and resilient rats based on the hedonic behaviour, and we investigated whether differential susceptibility to chronic stress was associated with region‐specific alterations in PNN organization. Furthermore, we studied whether treatment with venlafaxine (VLX; 10 mg·kg −1 ) administered during CMS could restore stress‐induced impairments in plasticity. Key Results We found that vulnerable animals showed increased PNNs enwrapping PV+ interneurons specifically in the CA3 and an impairment in the BDNF–TRKB pathway, reflecting a less permissive plastic environment, whereas resilient rats appeared to induce PNNs remodelling via MMP9 to face with stress. Notably, chronic VLX administration seemed to restore resilience to CMS by normalizing PNNs composition, PNNs surrounding PV+ interneurons in CA3 and by regulating MMP9 expression, supporting a role for the antidepressant in promoting a more adaptive hippocampal landscape. Conclusions and implications Our findings identify PNN remodelling as a potential mechanism underlying stress susceptibility and suggest that VLX promotes resilience by selectively modulating PNN composition possibly via MMP9 regulation in the rat dorsal hippocampus.