Investigating the Role of Perineuronal Nets in the Orbitofrontal Cortex on Functional Connectivity

Functional connectivity reflects coordinated activity between distributed brain regions and is essential for maintaining stable neural network function. The orbitofrontal cortex (OFC) plays a central role in cognitive and behavioral regulation, and disruptions in OFC connectivity are associated with impaired function, yet cellular mechanisms supporting OFC network stability remain unclear. Perineuronal nets (PNNs), specialized extracellular matrix structures that preferentially enwrap parvalbumin-expressing interneurons, regulate neuronal synchrony and stabilize cortical circuits, suggesting they may be critical for maintaining functional connectivity. To test this hypothesis, adult male and female Sprague Dawley rats (N=16; n=9 ChABC, n=7 vehicle) received bilateral OFC infusions of vehicle control or chondroitinase ABC (ChABC) to enzymatically degrade PNNs. Resting-state functional magnetic resonance imaging (fMRI) was conducted four days post-infusion to assess functional connectivity, followed by immunohistochemical verification of PNNs. Quantitative analysis (N=12; n=7 ChABC, n=5 vehicle) confirmed significant reductions in PNN number and density in ChABC-treated animals compared to controls, while PNN size remained unchanged. ChABC-treated animals exhibited reduced functional connectivity between the OFC and cerebellum and the OFC and hippocampus. These findings demonstrate that PNN integrity contributes to OFC network connectivity and suggest PNN disruption alters large-scale brain network organization, providing insights into cellular mechanisms regulating functional connectivity.