Distinct perineuronal net adaptations underlie vulnerability and resilience to chronic stress: role of dorsal hippocampus subregions

Background Stress is a major risk factor for depression, but not all individuals exposed to adversity develop the pathology, highlighting the need to understand individual differences in stress susceptibility. Perineuronal nets (PNNs), specialized extracellular matrix structures regulating neuronal plasticity, have gained attention in this field. Here we examined the role of PNNs in defining the vulnerability or resilience to chronic stress. Methods Adult male Wistar rats underwent six weeks of chronic mild stress (CMS) and classified as vulnerable or resilient based on hedonic behavior. PV+ interneurons and PNNs were evaluated in CA1, CA3, and DG subregions of the dorsal hippocampus via immunohistochemistry, while matrix metalloproteinase-9 (MMP-9), involved in PNNs degradation, was assessed by Western blot. Data were analyzed with one/two-way ANOVA followed by Tukey’s post hoc test (n=6/group). Results CMS reduced sucrose intake in vulnerable vs No stress rats (p<0.001). Vulnerable rats displayed increased percentages of PV+ cells enwrapped by PNNs compared to No stress (CA1: p<0.05; CA3: p<0.001) and resilient animals (CA3: p<0.01). Differently, PV+ interneuron intensity was decreased in resilient rats in comparison to both no stress (CA1: p<0.001; CA3: p<0.001) and vulnerable rats (CA1: p<0.01, CA3: p<0.001) while in the DG stress decreased PV+ cells intensity and increased PV+ neurons enwrapped by PNNs regardless of phenotype. Finally, MMP-9 levels were higher resilient rats (p <0.05 vs No stress; p<0.05 vs CMS/vul). Conclusions These findings reveal distinct neuroplastic mechanisms underlying vulnerability and resilience and suggest PNNs-related pathways as promising therapeutic targets to foster stress resilience and prevent MDD.